Early-stage endometrial carcinomas should be treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. In a small subset of patients, who wish to have children, conservative treatment (hormonal therapy) could be considered. The most effective agents for palliation of advanced disease are doxorubicin plus cisplatin.

Antineoplastic Agents↗

PubMed2003

Cisplatin, doxorubicin and ifosfamide in carcinosarcoma of the female genital tract. A phase II study of the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group (EORTC 55923).

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Adult↗

PubMed2002

Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer.

Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8(+) cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8(+) T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccessful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8(+) T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8(+) T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-gamma expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8(+) T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8(+) CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy.

Carcinoma, Papillary↗

PubMed2002

Novel immunotherapeutic strategies in gynecologic oncology. Dendritic cell-based immunotherapy for ovarian cancer.

The recognition of tumor antigen loaded dendritic cells as one of the most promising approaches to induce a tumor specific immune response in vivo has recently generated widespread interest in the use of these natural adjuvants for the therapy of human malignancies refractory to standard treatment modalities. However, many cancer patients may not benefit from current strategies of cancer vaccination because an effective tumor antigen associated with their cancer has not yet been identified or because sufficient amounts of tumor tissue cannot be obtained for antigen preparation. The recent identification and cloning of a group of preferentially expressed serine proteases as novel ovarian tumor-associated antigens may offer the opportunity to test in a large group of patients the potential of DC-based immunotherapy. In this review, we describe these ovarian tumor antigens and assess the potential for therapeutic DC vaccination for the treatment of chemotherapy-resistant ovarian cancer.

Adult↗

PubMed2001

Bleomycin, methotrexate, and CCNU in locally advanced or recurrent, inoperable, squamous-cell carcinoma of the vulva: an EORTC Gynaecological Cancer Cooperative Group Study. European Organization for Research and Treatment of Cancer.

OBJECTIVE: To investigate tumor response rate and treatment toxicity of a modified combination chemotherapy consisting of bleomycin (B), methotrexate (M), and CCNU (C) for patients with locally advanced, squamous-cell carcinoma of the vulva (not amenable to resection by standard radical vulvectomy) or recurrent disease (after incomplete resection). Tumor resectability was reassessed in patients who had responded to chemotherapy. METHODS: The regimen consisted of bleomycin 5 mg intramuscular (im) days 1-5, CCNU 40 mg per os (po) days 5-7, and methotrexate 15 mg po days 1 and 4 during the first week. During weeks 2-6 the patient was administered bleomycin 5 mg im days 1 and 4, and methotrexate 15 mg po on day 1 of the week. This 6-week cycle was repeated at 49-day intervals. RESULTS: Twenty-five eligible patients with a median age of 66 years (range, 39-82 years) were entered in this phase II trial. Twelve patients had primary locally advanced disease, 13 patients had a locoregional recurrence, and all received up to three BMC cycles. Two complete and twelve partial responses were observed (response rate, 56%; 95% confidence limits, 35-76%). The BMC regimen was associated with major hematological side effects and mild signs of bleomycin-related pulmonary toxicity. At a median follow-up of 8 months, 3 patients were alive, 18 had died due to malignant disease, 2 had died due to toxicity, and 2 had died due to intercurrent disease and unknown cause. The median progression-free survival was 4.8 months and the median survival was 7.8 months. The 1-year survival was 32% (95% confidence limits, 13-51%). CONCLUSION: The present data confirm the therapeutic activity of the BMC regimen in locoregionally advanced or recurrent squamous-cell carcinoma of the vulva. Following neoadjuvant chemotherapy, the overall response rate was 56%. BMC is an outpatient treatment that may play a role in the palliative therapy of advanced or recurrent vulva cancer.

Adult↗

PubMed2001

Tumor-infiltrating lymphocytes contain higher numbers of type 1 cytokine expressors and DR+ T cells compared with lymphocytes from tumor draining lymph nodes and peripheral blood in patients with cancer of the uterine cervix.

OBJECTIVE: The aim of this study was to compare the phenotype and function of lymphocytes collected from the peripheral blood (PBL), tumor draining regional lymph nodes (LND), and infiltrating tumor tissues (TIL) of patients with stage IB-IIA cervical cancer. METHODS: Leukocytes from peripheral blood (n = 35), tumor draining lymph nodes (n = 33), and tumor tissues (n = 15) of cervical cancer patients were evaluated for the relative proportions of lymphocyte subsets including CD3+, CD4+, CD8+, CD19+, CD56, and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells, as well as the ability to synthesize type 1 cytokines (IFN-gamma and IL-2) and a type 2 cytokine (IL-4) by flow cytometry. RESULTS: In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in PBL and LND, while CD8+ T cells predominated in TIL (CD4:CD8 ratios, 2.4 vs 4.0 vs 0.7, respectively). CD19+ lymphocytes (B cells) were significantly higher in LND compared to PBL and TIL (P > 0.01) while CD56+ lymphocytes were higher in PBL compared to LND (P > 0.01) and TIL (P > 0.05). The early activation marker CD25 was significantly up-regulated in LND, while TIL had a higher proportion of T cells expressing the late activation marker HLA-DR. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-gamma+ CD4+ and CD8+ T cells (i.e., Th1 and Tc1) and IL-2+ CD8+ T cells (Tc1) seen in TIL, as compared with LND and PBL (P > 0.01). Low percentages of IL-4+ T cells (i.e., Th2 and Tc2) were detected only in PBL. CONCLUSIONS: This study demonstrates significant differences in the phenotype and activation state of lymphocyte subsets from different anatomical sites, as well as differences in their ability to synthesize immunostimulatory cytokines. The recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in the cervical tumor tissue may represent an important local barrier to neoplastic dissemination.

Adenocarcinoma↗

PubMed2001

Staging of gynecologic malignancies.

The staging of gynecologic cancer is one of the fundamental aspects of the activity of the Committee on Gynecologic Oncology of the International Federation of Gynecology and Obstetrics. The rules for proper staging according to scientific evidence are presented in this article. Some of the most debatable issues are also discussed.

Female↗

PubMed2001

Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study.

The aim of this study was to investigate the tumour response rate and toxicity of a combination chemotherapy consisting of mitomycin-C and cisplatin in patients with disseminated squamous-cell carcinoma of the uterine cervix. Chemotherapy consisted of mitomycin, 6 mg/m(2) intravenously (i.v.), and cisplatin, 50 mg/m(2) given i.v., both administered on day 1 of each cycle. The regimen was repeated at 4-weekly intervals. Mitomycin-C/cisplatin were used to treat 33 evaluable patients aged 29-67 years (median: 50 years). All patients except 1 had previously been treated with either surgery, radiation or both. At the initiation of chemotherapy, 8 patients had loco-regional and disseminated disease and 25 women had only distant metastases. The overall response rate was 42% (95% confidence interval (CI): 26-61%). Five complete and nine partial responses were observed with a median duration of response of 7.9 months (95% CI: 3.7-23.5 months). 9 patients had stable disease and 10 developed progressive disease during mitomycin-C/cisplatin-treatment. World Health Organization (WHO) grade III/IV side-effects were documented in 15 women, of whom 10 had gastro-intestinal toxicity, 3 had haematological toxicity, 1 had alopecia and 1 developed an allergic reaction to cisplatin. There were neither drug-related deaths nor severe or irreversible renal or hepatic dysfunction or peripheral neuropathy. The median progression-free survival was 5.0 months (95% CI: 3.6-6.2 months) for all patients and 10.5 months (95% CI: 6.2-15.2 months) for the responders. The median overall survival was 11.2 months (95% CI: 6.5-18.4 months).The mitomycin-C/cisplatin combination showed antitumour activity in the treatment of advanced or recurrent squamous-cell carcinoma of the uterine cervix. The regimen was well tolerated and could be administered on an outpatient basis.

Adult↗

PubMed2001

Early stage ovarian cancer: the Italian contribution to clinical research. An update.

Early ovarian cancer (stages IA-IIA) accounts for 30% of all epithelial ovarian cancer. Even if relatively uncommon, when "high risk" patients are considered, it is lethal in 25-30% of the cases. Mainstay of treatment is surgery followed by either adjuvant chemotherapy or radiotherapy when indicated on the basis of still debatable prognostic factors. Literature data show a great variability in survival rate due to the great heterogeneity of patients considered in different reports and few randomized trials affected by a consequent low power. Italian groups have contributed both in investigating the role of surgery and of chemo or radiotherapy in the treatment of this disease. An important contribution in surgery has been made by Italian institutions in reducing the extent of surgery in young patients wishing to retain their reproductive capability showing that a "conservative surgery" (unilateral oophorectomy) can be safely performed in initial stages without affecting the probability of cure. Another important surgical topic investigated by Italian institutions concerns the role of lymphadenectomy. In early ovarian cancer the node involvement ranges between 14-24% in stage I and 37-50% in stage II. Although the node positivity rate detectable by sampling (SA) is lower than the one shown by a systematic procedure (LY), no data at the moment show that patients undergoing a sampling evaluation have a poorer prognosis. From 1992 through 1994, 202 patients (SA: 99; LY: 103) were enrolled by six Italian institutions in a randomized trial aimed to assess the diagnostic and therapeutic role of SA vs. LY in early stage ovarian cancer. Positive nodes were detected in 9.9% vs. 19.3% respectively as well as a different proportion of intra/perioperative complications occurred. No difference in time to relapse nor in overall survival were detected in the two groups showing no evidence of efficacy in favor of extensive staging of the retroperitoneum. From 1983 to 1990, 271 stage I ovarian cancer patients entered two prospective multicentric randomized trials conducted by Italian institutions. Trial I compared cisplatin (50 mg/m2, six cycles repeated every 28 days) vs. no further treatment in stage IA-B grade 2-3 patients; Trial II compared the same dose and schedule of cisplatin vs. intraperitoneal P32 in stage IC patients. Cisplatin significantly reduced the relapse rate by 65% in Trial I and by 61% in Trial II, but survival was not affected (Trial I: HR = 1.15, 95% CI = 0.44-2.98; Trial II: HR = 0.72, 95% CI = 0.37-1.43). The final conclusion drawn by these two important Italian studies was that adjuvant cisplatin treatment in early ovarian cancer prevents relapse although the impact of chemotherapy remains unclear. For this reason two international trials have been performed (ICON1 and ACTION) aimed at assessing the role of platinum-based chemotherapy on survival. Italian collaboration in both trials has been important, including about half of the total number of the 900 randomized patients. Results will probably be available during this year and are expected with a great interest by the whole scientific international community.

Adult↗

PubMed2001

Increased levels of interleukin-10 and transforming growth factor-beta in the plasma and ascitic fluid of patients with advanced ovarian cancer.

OBJECTIVES: To assess expression of the immunosuppressive cytokines IL-10 and TGF-beta in the ascitic fluid and plasma of advanced ovarian cancer patients. DESIGN: A prospective study. SETTING: The Department of Obstetrics and Gynaecology at the University of Arkansas for Medical Sciences. POPULATION: Twenty-eight women diagnosed with advanced ovarian cancer and ten normal female controls. METHODS: Plasma and ascitic samples were collected at the time of surgery and analysed for the presence of IL-10 and TGF-beta using a sensitive enzyme-linked immunosorbent assay. RESULTS: Elevated levels of IL-10 were detected in the plasma [mean (SD) = 12 (5) pg/mL; range 8 to 23 pg/mL] and in the peritoneal fluid [mean (SD) = 165 (137) pg/mL; range 50 to 556 pg/mL] of ovarian cancer patients, while no detectable IL-10 was found in any of the normal control plasma samples tested. Similarly, plasma levels of TGF-beta in ovarian cancer patients were significantly higher [mean (SD) = 1,506 (246) pg/mL; range 1,020 to 2,070 pg/mL] compared with controls [mean (SD) = 937 (187) pg/mL; range 770 to 1,140 pg/mL](P < 0.001). Surprisingly, however, although elevated TGF-beta levels were also detected in the peritoneal fluid of all ovarian cancer patients [mean (SD) = 407 (158) pg/mL; range 140 to 770 pg/mL], these levels were significantly lower than those seen in matched plasma samples (P < 0.001). CONCLUSIONS: Local and systemic secretion of immunosuppressive cytokines may play an important role in the impaired anti-tumour immune function commonly observed in advanced ovarian cancer. However, the observation that plasma levels of TGF-beta are significantly higher than those detected in the ascitic fluid raises the possibility that cells other than tumour cells are responsible for TGF-beta release in the bloodstream of these patients.

Adult↗

PubMed2001

Phenotypic and functional analysis of tumor-infiltrating lymphocytes compared with tumor-associated lymphocytes from ascitic fluid and peripheral blood lymphocytes in patients with advanced ovarian cancer.

To investigate and compare the phenotype and function of lymphocytes collected from patients harboring advanced ovarian cancer, leukocytes from peripheral blood (n = 18), ascitic fluid (n = 13) and tumor tissues (n = 13) were evaluated for the relative proportions of lymphocyte subsets, including CD3+, CD4+, CD8+, CD19+, CD56 and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells. The ability to synthesize type 1 cytokines (IFN-gamma and IL-2) and a type 2 cytokine (IL-4) was assessed by flow cytometry. In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in peripheral blood lymphocytes (PBL) and tumor-associated lymphocytes (TAL) but not in tumor-infiltrating lymphocytes (TIL) (CD4:CD8 ratios: 3.0 vs. 2.0 vs. 1.0, respectively). CD19+ lymphocytes (B cells) and CD56+ lymphocytes (NK cells) were significantly higher in PBL compared to TAL and TIL (p < 0.05). TAL and TIL had a higher proportion of T cells expressing the late activation marker HLA-DR compared to PBL. In contrast, no significant differences were detected in PBL, TAL and TIL in the expression of the early activation marker CD25. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-gamma+ T cells in TAL and TIL compared to PBL (p < 0.01), and a higher proportion of IL-2+ T cells in PBL compared with TAL and TIL (p < 0.05). Low percentages of IL-4+ T cells (i.e. Th2) were detected in each tissue. Taken together, these data demonstrate the recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in TAL and TIL compared to PBL. However, low surface expression of IL-2 receptor (i.e. CD25), as well as depressed intracellular IL-2 production in chronically stimulated TAL and TIL suggests that the impaired antitumor function commonly detected in these lymphocyte populations may be secondary to an acquired dysregulation of the IL-2 pathway.

Adult↗

PubMed2001

Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.

Human papillomavirus (HPV) infection represents the most important risk factor for developing cervical cancer. In this study, we examine the potential of full-length E7-pulsed autologous dendritic cells (DCs) to induce antigen-specific CTL responses from the peripheral blood of healthy individuals against HLA-A2-matched HPV-16 and HPV-18-positive tumor target cells in vitro. We show that DCs pulsed with E7 oncoprotein can consistently stimulate antigen-specific CTL responses that recognize and lyse HPV-16 or HPV-18-positive naturally infected cervical cancer cell lines. HPV-negative, EBV-transformed lymphoblastoid cell lines (LCLs) sharing the HLA haplotype of the target tumor cells, as well as autologous donor LCLs, were not significantly killed by E7-specific CTLs. Cytotoxicity against HLA-A2-matched HPV-16 and HPV-18 tumor target cells could be significantly inhibited by anti-HLA class I and by anti-HLA-A2 monoclonal antibodies. CD8+ CTLs expressed variable levels of CD56 and showed a strongly polarized Type 1 cytokine profile. Sorting of the CD8+ T cells on the basis of CD56 expression demonstrated that the most highly cytotoxic CTLs were CD56+ and expressed higher levels of perforin and IFN-gamma, compared with the CD8+/CD56- population. Taken together, these data demonstrate that full-length, E7-pulsed DCs can consistently induce E7-specific CD8+ CTL responses in healthy individuals that are able to kill naturally HPV-16 and HPV-18-infected cancer cells, and that CD56 expression defines a subset of CD8+ CTLs with high cytolytic activity against tumor cells.

CD56 Antigen↗