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S Pecorelli

Publications and source records attributed to S Pecorelli.

At least 91 records · Page 5Linked to original sources
PubMed1998

Radiation-enhanced expression of E6/E7 transforming oncogenes of human papillomavirus-16 in human cervical carcinoma.

BACKGROUND: Human papillomavirus (HPV) infection represents the most important risk factor for cervical carcinoma. Levels of expression of E6 and E7 transforming oncoproteins of high risk HPV genotypes (i.e., HPV-16 and HPV-18) have been linked specifically to the mitotic activity of cervical carcinoma and appear to be necessary for maintaining the malignant phenotype. However, E6/E7 viral proteins recently have been reported to be effective tumor rejection antigens in animal models and humans. Radiation treatment represents a standardized and effective modality for contemporary cervical carcinoma therapy. However, although the physiologic and cellular changes associated with high doses of irradiation have been well documented it has been shown only recently that an increased synthesis of specific cellular proteins is observed after irradiation. In this study, the authors analyzed the effects of high doses of gamma irradiation on the expression of E6/E7 oncoproteins in HPV-16-infected cervical carcinoma cell lines. In addition, the effects of radiation on major histocompatibility complex (MHC) restriction elements also were studied. METHODS: The effect of high doses of gamma irradiation (i.e., 1250, 2500, 5000, and 10,000 centigray [cGy]) on the kinetics of E6/E7 oncoprotein expression in two HPV-16 positive cervical carcinoma cell lines (i.e., CaSki and SiHa) was evaluated by Northern blot analysis. In addition, the effect of radiation on the expression of MHC molecules also was studied by Northern blot and fluorescence activator cell sorter (FACS) analysis. RESULTS: Dose ranging from 1250 (sublethal) to 10,000 (lethal) cGy significantly increased the expression of E6/E7 oncoproteins as well as MHC Class I molecules in CaSki and SiHa cell lines when compared with untreated tumor cells. Both cell lines showed increased mRNA expression for MHC Class I molecules in a dose-dependent manner. E6/E7 oncoproteins also were up-regulated in a dose-dependent manner in the CaSki cell line, whereas in the SiHa cell line their expression plateau at 5000 cGy. When the kinetics of radiation-induced up-regulation of E6/E7 were studied, persistent up-regulation of the viral oncoproteins was noted for all doses of irradiation, with the lower and sublethal doses (i.e., 1250-2500 cGy) inducing the most significant enhancement. CONCLUSIONS: High doses of irradiation can induce a significant and long-lasting up-regulation of E6/E7 oncogenes and MHC Class I restriction elements on HPV positive cervical carcinoma cell lines. These effects by themselves suggest that irradiation could enhance local tumor immunogenicity in patients receiving radiation therapy. However, in contrast to this possible beneficial effect, sublethal tumor irradiation (up-regulating E6/E7 transforming oncoproteins) also could confer a significant growth advantage to radiation-resistant tumor cells. These findings, combined with the previously reported acquisition of a radiation-induced drug resistance, could provide a biologic basis for the poor prognosis of patients with cervical carcinoma recurrence after radiation therapy.

Cell Transformation, Viral↗
PubMed1998

Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy.

BACKGROUND: Women diagnosed with invasive cervical carcinoma during pregnancy are faced with difficult decisions regarding therapy and the fate of their unborn child. A modest treatment delay for International Federation of Gynecology and Obstetrics Stage I cervical lesions is considered acceptable in patients who wish to continue their pregnancy. METHODS: Two patients with locally advanced cervical carcinoma diagnosed early in the second trimester strongly desired continuation of their pregnancies. They were treated with neoadjuvant chemotherapy until the third trimester, and then underwent delivery and definitive surgical treatment. The patients were evaluated during pregnancy for evidence of a clinical response to chemotherapy. Intraoperative findings and pathologic analysis of the surgical material provided further objective data regarding disease status. RESULTS: Both patients experienced a dramatic reduction in tumor volume, rendering radical hysterectomy feasible at the time of cesarean section. In addition, both patients tolerated chemotherapy well and there were no adverse fetal effects. Favorable neonatal outcomes were achieved. One patient experienced recurrence within 5 months of surgery, whereas the other patient remained without evidence of disease for 2 years. CONCLUSIONS: To the authors' knowledge, these reports constitute the first description of the use of neoadjuvant chemotherapy for invasive squamous cell carcinoma of the cervix in pregnancy (MEDLINE 1966-1997). This therapeutic option should be considered in selected women with locally advanced cervical carcinoma who do not want termination of their pregnancy.

Adult↗
PubMed1998

Effects of retinoic acid combined with interferon-gamma on the expression of major-histocompatibility-complex molecules and intercellular adhesion molecule-1 in human cervical cancer.

Retinoids and interferons are important regulators of human epithelial cell differentiation and have been successfully used in the clinical treatment of HPV-involved cervical cancer. In this study, 2 HPV-positive human cervical-carcinoma cell lines were analyzed for their surface expression of MHC-Class-I, MHC-Class-II and ICAM-1 surface antigens before and after exposure to all-trans retinoic acid, interferon-gamma and the combination of the 2 compounds. In addition, the effects on HLA-Class-I-mRNA expression were evaluated after such treatments. Both cell lines expressed MHC-Class-I molecules, and their levels were markedly up-regulated after exposure to IFN-gamma. Similarly, MHC-Class-II and ICAM-1 antigens were either induced or significantly up-regulated by IFN-gamma. Exposure to all-trans retinoic acid was also able to significantly increase the expression of MHC-Class-I and ICAM-I antigens as compared with untreated tumor cells. However, unlike IFN-gamma, retinoids were not able to induce the expression of HLA-Class-II surface antigens. Exposure to the combination of IFN-gamma plus retinoic acid significantly up-regulated (in an additive manner) HLA-Class-I and ICAM-1 molecules as compared with the levels obtainable after exposure to IFN-gamma alone. Finally, Northern-blot analysis of HLA-Class-I-mRNA expression confirmed that the activity of both of these biologic response modifiers was at transcriptional level. These data indicate that the combination of these modalities could induce an additive effect on the expression of immunologically important surface antigens on human cervical-cancer cells. These findings, together with the known anti-proliferative effects mediated by retinoids and IFN-gamma on tumor cells, further support the combination of these agents in the treatment of pre-invasive and invasive human cervical cancer.

Blotting, Northern↗
PubMed1998

Effects of retinoic acid combined with irradiation on the expression of major histocompatibility complex molecules and adhesion/costimulation molecules ICAM-1 in human cervical cancer.

OBJECTIVES: Radiation treatment is one of the most standardized and effective modalities for contemporary cervical cancer therapy. In addition, the radiation-potentiating effects of retinoic acid have been recently described. In order to investigate whether enhanced immunogenicity might be responsible for such potentiation, we have evaluated the effects of retinoic acid combined with high doses of gamma-irradiation on the expression of major histocompatibility complex (MHC) Class I and II and intercellular adhesion molecule-1 (ICAM-1) in human cervical carcinoma cell lines. METHODS: The expression of surface antigens (MHC Class I and II and ICAM-1) was evaluated by FACS analysis in untreated control cells and in cells following their exposure to retinoic acid, high doses of gamma-irradiation (i.e., 5000 and 10,000 cGy), or the combination of the two procedures. RESULTS: HT-3 and SiHa cervical cancer cells expressed variable levels of MHC Class I and ICAM-1 antigens while Class II surface antigens were not detectable. Exposure to either 5000 or 10,000 cGy completely inhibited cell replication in both cell lines and significantly and consistently increased the expression of all surface antigens present on the cells prior to irradiation. Irradiation was unable to induce neoexpression of antigens previously not expressed by these cells (i.e., MHC Class II). In a similar fashion, retinoic acid was also able to significantly increase the expression of MHC Class I and ICAM-1 antigens when compared to untreated tumor cells but was not able to induce the expression of HLA Class II surface antigens. Exposure to the combination of radiation plus retinoic acid significantly upregulated HLA Class I and ICAM-1 molecules in an additive manner when compared to the levels obtainable with the exposure to radiation or retinoic acid alone. CONCLUSIONS: These data indicate that the combination of these two treatments could induce an additive effect on the expression of immunologically important surface antigens in human cervical cancer cells. These findings, together with the powerful antiproliferative effect of retinoids and irradiation on tumor cells, suggest that the combined regimen may be a promising and more effective combination for the treatment of cervical cancer.

Antineoplastic Agents↗
PubMed1998

Retinoic acid up-regulates the expression of major histocompatibility complex molecules and adhesion/costimulation molecules (specifically, intercellular adhesion molecule ICAM-1) in human cervical cancer.

OBJECTIVE: Retinoids are a class of compounds that are structurally related to vitamin A and have been found to be effective in the prevention and treatment of cervical cancer. To investigate whether enhanced immunogenicity might be responsible for such efficacy, we evaluated the effects of retinoic acid on the expression of major histocompatibility complex class I and class II and intercellular adhesion molecule ICAM-1 in human cervical carcinoma cell lines. STUDY DESIGN: The expression of surface antigens (major histocompatibility complex class I and class II and ICAM-1) was evaluated by fluorescence-activated cell sorter analysis in 3 human cervical carcinoma cell lines after exposure to therapeutic doses of retinoic acid. In addition, the effects on human leukocyte antigen class I messenger ribonucleic acid expression were also evaluated by Northern blot analysis after such treatment. RESULTS: CaSki, SiHa, and HT-3 cervical cancer cells expressed variable levels of major histocompatibility complex class I and ICAM-1 antigens, whereas class II surface antigens were not detectable. Exposure to therapeutic doses of retinoic acid were able to significantly increase the expression of major histocompatibility complex class I and ICAM-1 antigens in all the cell lines when compared with untreated tumor cells but were not able to induce the expression of class II surface human leukocyte antigens. Northern blot analysis showed that for major histocompatibility complex class I molecules such up-regulation was the result of an increased expression at the transcriptional level of major histocompatibility complex class I messenger ribonucleic acid. CONCLUSIONS: These data indicate that retinoic acid increases the expression of immunologically important surface antigens, suggesting that the efficacy of retinoic acid in the treatment of cervical cancer may be, at least in part, the result of immunologic modulation. Such findings support additional clinical research investigating the use of retinoids for the treatment of cervical cancer.

Blotting, Northern↗
PubMed1998

PVB chemotherapy in patients with recurrent or advanced dysgerminoma: a Phase II study of the EORTC Gynaecological Cancer Cooperative Group.

Dysgerminoma accounts for 1% of all ovarian cancers and for 50% of all ovarian germ cell malignancies. Low stage patients (50%) can be cured with local treatment. The aim of this trial was to study the objective tumour response rate and toxicity of PVB (cisplatin, vinblastine, bleomycin) chemotherapy in patients with pure advanced or recurrent dysgerminoma. Eighteen eligible patients with advanced dysgerminoma were entered into this study. Three patients had local bulky recurrence only; all the others also had metastatic disease. The median age at entry was 27 years (range 1348). Seventeen patients had had prior surgery and one had undergone prior radiotherapy. The WHO performance status was 0 in 12 patients, 1 in three patients, and 2 in three patients. The treatment consisted of: intravenous or intramuscular bleomycin 30 mg on days 2, 9 and 16, intravenous vinblastine 0.15 mg/kg on days 1 and 2, and intravenous cisplatin 20 mg/m2 on days 1-5. This regimen was given at 3-week intervals for a total of four cycles. Twelve patients obtained a complete response (66%), five a partial response (28%), and one could not be evaluated because radiotherapy was administered immediately after chemotherapy. After a median follow-up of 76 months (range 4-132), 14 (78%) patients were alive and well. Two died of disease progression, one of neutropenic septicaemia and one of lung fibrosis. No unusual toxicity was reported. Alopecia, as well as nausea and vomiting, were common. Leucopenia (78%), thrombocytopenia (17%) and infection (11%) were the other severe (grade 3-4) side effects. The PVB chemotherapy regimen is highly effective in patients with advanced ovarian dysgerminoma. However, the BEP (bleomycin, etoposide, cisplatin) regimen, which is equally as potent and less toxic, is preferred.

Adolescent↗
PubMed1998

The effects of irradiation on the expression of a tumour rejection antigen (heat shock protein gp96) in human cervical cancer.

PURPOSE: Studies were designed to analyse the effects of high doses of gamma-irradiation on the expression of a tumour rejection antigen (heat shock protein gp96) in human cervical carcinoma cell lines. MATERIALS AND METHODS: The expression of heat shock protein gp96 was evaluated at the transcriptional (Northern blot) and post-transcriptional levels (Western blot) in two human cervical carcinoma cell lines following exposure to high doses of gamma-irradiation. RESULTS: Doses of gamma-irradiation ranging from 25 to 100 Gy significantly and consistently increased the expression of heat shock protein gp96 on CaSki and HT-3 cervical cancer cells. The increase in the amount of protein was due to transcriptional up-regulation of this gene. Radiation doses unable to inhibit completely cell replication in the totality of tumour cells (i.e. 25 Gy), as well as higher (fully lethal) doses of irradiation (i.e. 50 to 100 Gy), were shown to up-regulate significantly the expression of heat shock protein gp96 mRNA in a dose-dependent manner. CONCLUSIONS: Recently, gp96 molecules have been implicated in the presentation of endogenous and viral antigens. A number of key elements in this pathway, including major histocompatibility complex (MHC) class I molecules as well as adhesion/co-stimulation molecules such as ICAM-1, are known to be sensitive to irradiation effects. The results show that radiation can also increase the expression of other immunologically important cell molecules such as a tumour rejection antigen (heat shock protein gp96) in human cervical cancer. Such findings may partially explain the increased immunogenicity of tumour cells following irradiation and further support a role for local radiation therapy as a powerful biologic response modifier.

Antigens, Neoplasm↗
PubMed1998

Management of early ovarian cancer.

About one third of the women diagnosed with ovarian cancer present with localized disease. Accurate surgical staging is required to properly evaluate these patients, define appropriate treatment, and establish prognosis. A series of recent studies have clarified which patients can be managed with comprehensive surgical staging and disease removal alone, and which may benefit from adjuvant therapy. A series of national and international prospective randomized trials are evaluating a variety of adjuvant treatments that may enhance long-term survival in those patients with early ovarian cancer who do require additional therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Effects of retinoic acid on the expression of a tumor rejection antigen (heat shock protein gp96) in human cervical cancer.

Retinoids are a class of compounds structurally related to vitamin A which have been found to be active agents experimentally as well as clinically in the prevention and treatment of cervical cancer. Recent data have suggested that in addition to their key regulatory role during epithelial cell differentiation, they could also contribute to enhanced cellular and humoral immunity against tumor cells. Hsp gp96 molecules have recently been implicated in the presentation of tumor and viral antigens. A number of key elements in this pathway, including major histocompatibility complex (MHC) class I molecules as well as adhesion/co-stimulation molecules such as ICAM-1 have reported to be sensitive to retinoic acid up-regulation. In this study we analyzed at the transcriptional (Northern blot) and post-transcriptional levels (Western blot) the effects of retinoic acid on the expression of the tumor rejection antigen (heat shock protein gp96) in three human cervical carcinoma cell lines. Exposure of therapeutic doses of retinoic acid (i.e. 1 microM) significantly and consistently increased the expression of heat shock protein gp96 (Western blot analysis) on CaSki, SiHa and HT-3 cervical cancer cell lines. Northern blot analysis demonstrated that the increase in the amount of protein was due to the transcriptional upregulation of this gene. Taken together, our results show that retinoic acid can significantly increase the expression of yet another immunologically important cell molecule, the tumor rejection antigen heat shock protein gp96 in human cervical cancer. Such findings provide new information on the effects of retinoic acid on tumor cells and further support the role of retinoic acid as a powerful biologic response modifier.

Antigens, Neoplasm↗
PubMed1997

Effects of irradiation on the expression of major histocompatibility complex class I antigen and adhesion costimulation molecules ICAM-1 in human cervical cancer.

PURPOSE: We initiated studies to analyze the effects of high doses of gamma irradiation on the surface antigen expression of MHC Class I, Class II, and ICAM-1 on human cervical carcinoma cell lines. METHODS AND MATERIALS: The expression of surface antigens (MHC Class I, Class II, and ICAM-1) was evaluated by FACS analysis on two cervical cell lines at different time points, following their exposure to high doses of gamma irradiation (i.e., 25.00, 50.00, and 100.00 Gy). RESULTS: The CaSki and SiHa cervical cancer cells we analyzed in this study expressed variable levels of MHC Class I and ICAM-1 antigens, while Class II surface antigens were not detectable. Whereas irradiation doses of 25.00 Gy were not sufficient to totally block cell replication in both cell lines, exposure to 50.00 or 100.00 Gy was able to completely inhibit cell replication. Range doses from 25.00 to 100.00 Gy significantly and consistently increased the expression of all surface antigens present on the cells prior to irradiation but were unable to induce neoexpression of antigens previously not expressed by these cells (i.e., MHC Class II). Importantly, such upregulation was shown to be dose dependent, with higher radiation doses associated with increased antigen expression. Moreover, when the kinetic of this upregulation was studied after 2 and 6 days after irradiation, it was shown to be persistent and lasted until all the cells died. CONCLUSIONS: These findings may partially explain the increased immunogenicity of tumor cells following irradiation and may suggest enhanced immune recognition in tumor tissue in patients receiving radiation therapy.

Antigens, Neoplasm↗
PubMed1997

Differential transforming growth factor-beta secretion in adenocarcinoma and squamous cell carcinoma of the uterine cervix.

Tumor cells from eight freshly isolated cervical cancers (i.e., four adenocarcinomas and four squamous carcinomas) were analyzed for their production of the immune-inhibitory cytokine transforming growth factor-beta (TGF-beta) in vitro. All fresh adenocarcinomas secreted significant levels of TGF-beta (mean 397, range between 207 and 782 pg/ml/10(5) cells/48 hr). In contrast, no detectable TGF-beta was present in the supernatants from the four fresh squamous carcinoma cultures (P < 0.001). These data suggest that major differences in the secretion of the immunoinhibitory cytokine TGF-beta exist between squamous cell carcinomas and adenocarcinomas of the uterine cervix. Furthermore, these findings suggest that at least some of the differences in the natural biologic behavior, as well as in the response to radiation treatment, between these two histologic types of cervical cancer could be related to differences in secretion of this immune-inhibitory cytokine.

Adenocarcinoma↗
PubMed1996

In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDXI).

BACKGROUND: X-linked severe combined immunodeficiency (SCIDXI) is an inherited immune defect which leads to death in infancy from severe infections. The defect is caused by mutations of the IL-2RG gene that encodes for the common gamma chain shared by several cytokine receptors. The disease is characterised by lack of T and NK cells with normal numbers of B cells. SCIDXI can be cured by bone marrow transplantation (BMT) or prevented by abortion after prenatal diagnosis. METHODS: A male fetus was diagnosed as having SCIDXI by molecular, immunophenotypic, and functional analyses. The fetus was injected intraperitoneally under ultrasound guidance with CD34 haematopoietic progenitor cells purified from paternal bone marrow and T-cell depleted by E rosetting. Chimerism analysis was by HLA-DQ alpha typing and gamma-chain staining on cord blood. FINDINGS: A healthy 3.6 kg boy was delivered by caesarean section at 38 weeks of gestation with no clinical or laboratory signs of graft-versus-host disease. Engraftment of donor-derived CD2 cells was found at birth. At 3.5 months of age the infant is well and his T-cell counts and function are normal. INTERPRETATION: In-utero transplantation of haematopoietic progenitor cells allowed immune reconstitution of a fetus with SCIDXI and may be an alternative to elective abortion. Our report should encourage applications of this method to other inherited disorders curable by BMT.

Antigens, CD34↗
PubMed1996

Effects of cytokines combined with high-dose gamma irradiation on the expression of major histocompatibility complex molecules and intercellular adhesion molecule-1 in human ovarian cancers.

Tumor cells from 7 freshly isolated human ovarian tumors and 2 continuous human ovarian cancer cell lines were analyzed for their surface expression of MHC class-1, class 11 and ICAM-1 surface antigens before and after exposure to gamma-irradiation and/or the cytokines TNF-alpha plus IFN-gamma. All 7 fresh tumors expressed high levels of MHC class 1 and 1CAM-1 antigens, and levels were markedly up-regulated after exposure to TNF-alpha plus IFN-gamma Similarly, class-11 antigens were either induced (3 out of 7 tumors) or significantly up-regulated by TNF-alpha plus IFN-gamma. Exposure to high doses of gamma-irradiation also increased the expression of MHC class-1 and ICAM-1 antigens, albeit to a modest degree. MHC class 1 and ICAM-1 antigens expression was much lower on continuous human ovarian cell lines than on the fresh tumors. Exposure of these cells to TNF-alpha plus IFN-gamma markedly up-regulated antigen expression to levels comparable to those expressed on the freshly isolated tumors. With the established ovarian cell lines, removal of cytokines caused a rapid down-regulation of antigen expression to basal levels within 6 days, while in the fresh tumors a low level of up-regulation was still present at this time. In contrast, exposure to cytokines followed by high-dose gamma-irradiation resulted in a highly significant and long-lasting expression of each surface antigen which was either up-regulated or induced by the cytokines. These data indicated that the combination of these modalities may be beneficial in generating optimal antigen expression for use of tumor cells in vaccine studies.

Adenocarcinoma↗
PubMed1996

Effects of irradiation on the expression of surface antigens in human ovarian cancer.

Tumor cells from four established human ovarian carcinoma cell lines were analyzed for their expression of surface antigens including MHC Class I, Class II, ICAM-1, and the tumor-associated antigens CA 125 and Her2-neu before and after exposure to high doses of gamma irradiation. All four ovarian cell IInes expressed variable levels of MHC Class I and Her2-neu. ICAM-1 antigens were expressed in only two cell lines and Class II and CA 125 surface antigens were absent in all the cell lines evaluated. Exposure to high doses of gamma irradiation (i.e., 5000 to 10,000 cGy) significantly and consistently increased the expression of all surface antigens present on the cells prior to irradiation. Importantly, the irradiation-induced upregulation was persistent and lasted until all the cells died. Irradiation was unable to induce neoexpression of antigens previously not expressed by the cells (i.e., MHC Class II or ICAM-1). These findings may partially explain the increased immunogenicity of tumor cells following irradiation and may suggest enhanced immune recognition in tumor tissue in patients receiving radiation therapy.

Antigens, Neoplasm↗
PubMed1996

Development and characterization of an interleukin-2-transduced human ovarian carcinoma tumor vaccine not expressing major histocompatibility complex molecules.

OBJECTIVE: We initiated studies to develop cytokine-secreting human ovarian carcinoma cells for the purpose of using these cells as vaccines for the treatment of advanced epithelial ovarian cancer. STUDY DESIGN: A human ovarian carcinoma cell line (UCI-107) was genetically engineered to secrete the cytokine interleukin-2 by retroviral-mediated gene transduction. RESULTS: One clone, termed UCI-107A IL-2 AS, constitutively secreted high levels of interleukin-2 (i.e., 2000 to 2300 pg/ml/10(5) cells per 48 hours) for > 55 passages and 8 months of study. Unlike parental- and vector-transduced cells, UCI-107A IL-2 AS cells were aneuploid and failed to express major histocompatibility complex class I and HER2/neu surface antigens. UCI-107A IL-2 AS cells were highly resistant to killing by gamma irradiation and continued to produce high levels of interleukin-2 even after irradiation with 10,000 cGy. Balb/C nude mice injected intraperitoneally with UCI 107-A IL-2 AS cells survived significantly longer than control animals, with 25% of the animals totally rejecting their tumors. UCI-107A IL-2 AS was totally resistant to killing by fresh allogeneic peripheral blood lymphocytes in four hour chromium 51 release assays but induced high levels of killing in 72-hour long-term cytotoxic assays. CONCLUSION: The potential use of these interleukin-2-secreting ovarian carcinoma cells as vaccines for women with advance ovarian cancer will be discussed.

Adenocarcinoma, Papillary↗
PubMed1996

Clinical trials in patients with epithelial ovarian cancer: past, present and future.

Combinations of surgery and chemotherapy are crucial in the treatment of ovarian cancer. This article reviews the conclusions of all recently performed trials and gives information on the now open randomized studies. The importance of radical surgery in combination with chemotherapy in early disease is clear, but uncertainties still exist in relation to timing and choice of chemotherapy. Many data from trials are helpful in outlining the indications for cytoreductive surgery, the timing of this procedure, second-look laparotomy in clinically complete remission, and secondary cytoreduction, but many details are yet to be addressed in future randomized studies. The place of new chemotherapeutic agents (in advanced disease and in adjuvant setting) is currently being investigated in many clinical trials.

Antineoplastic Agents↗