Biomedical subjects
S Pecorelli
Publications and source records attributed to S Pecorelli.
Gestational trophoblastic diseases.
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Carcinoma of the corpus uteri.
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Carcinoma of the cervix uteri.
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Carcinoma of the Fallopian tube.
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Phase II study of a combination of cyclophosphamide, adriamycin and cisplatin in advanced fallopian tube carcinoma. An EORTC gynecological cancer group study. European Organization for Research and Treatment of Cancer.
OBJECTIVE: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease. METHODS: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days. RESULTS: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively. CONCLUSION: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.
Effects of concurrent cisplatinum administration during radiotherapy vs. radiotherapy alone on the immune function of patients with cancer of the uterine cervix.
PURPOSE: To compare the effects of concurrent administration of cisplatinum (40 mg/m(2)/weekly) with radiation therapy (C-RT) to those induced by radiation therapy alone (RT) on the immune function of patients with locally advanced cervical cancer. METHODS AND MATERIALS: In 8 prospectively randomized patients (i.e., 4 receiving RT vs. 4 receiving C-RT), lymphocyte populations including CD3+, CD4+ and CD8+ T-cell subsets, B cells (CD19+) and natural killer cells (CD56+, CD16+, CD3-) were studied before, during, and after therapy. Expression of the activation marker CD25 on CD3+ T cells, intracellular levels of perforin in CD8+ and CD56+ cells, and interferon-gamma (IFN-gamma) and IL-2 in CD4+ and CD8+ T cells was also measured. Finally, lymphoblast transformation and natural killer (NK) cytotoxic activity were assessed. RESULTS: Both RT and C-RT significantly decreased the mean absolute number of all lymphocyte subsets compared to pretreatment levels (p > 0.001). However, no differences were detected in the characteristics or the magnitude of the lymphopenia induced by the two treatments. Both RT and C-RT increased similarly the percentages of CD25-positive lymphocytes (p > 0.001), and significantly decreased PHA-induced T-cell lymphoblast transformation (p > 0.001) and NK cytotoxic activity against K562 cells (p > 0.001). The percentage of perforin-positive and CD8+ T cells was not altered during either treatment, whereas the percentage of perforin-positive and CD56+ cells was significantly reduced during both treatments, and correlated with reduced cytotoxicity against K562 cells. The percentages of CD8+ IFN-gamma+ and CD4+ IFN-gamma+ T cells as well as that of CD8+ IL-2+ and CD4+ IL2+ T cells were not significantly altered by C-RT compared to RT alone. Finally, with both regimens, NK cells and B-cell numbers showed a more rapid recovery than T-cell numbers. CONCLUSION: Administration of concurrent cisplatinum to radiation may synergistically increase cytotoxic effects of radiation on tumor cells but does not alter the magnitude and the characteristics of radiation-induced immunosuppression.
Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.
BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.
Induction of ovarian tumor-specific CD8+ cytotoxic T lymphocytes by acid-eluted peptide-pulsed autologous dendritic cells.
OBJECTIVE: To evaluate the potential of dendritic cells pulsed with acid-eluted peptides derived from autologous ovarian cancer cells for eliciting a tumor-specific cytotoxic T cell response in women with advanced ovarian cancer. METHODS: CD8+ T lymphocytes derived from peripheral blood mononuclear cells stimulated in vitro with autologous ovarian tumor peptide-pulsed dendritic cells were tested for their ability to induce an HLA class I-restricted cytotoxic T lymphocyte response against autologous tumor cells. To correlate cytotoxic activity by cytotoxic T lymphocytes with T cell phenotype, we used two-color flow cytometric analysis of surface markers and intracellular cytokine expression (interferon-gamma versus interleukin-4). RESULTS: CD8+ cytotoxic T lymphocyte responses against autologous ovarian tumor cells were elicited in three consecutive women who had advanced ovarian cancer. Although cytotoxic T lymphocyte populations from all women expressed strong cytolytic activity against autologous tumor cells, they did not lyse autologous lymphoblasts or Epstein-Barr virus-transformed cell lines, and they showed negligible cytotoxicity against the natural killer-sensitive cell line K-562. Cytotoxicity against the autologous tumor cells was significantly inhibited by anti-HLA class I (W6/32) and anti-HLA-A2 (BB7-2) monoclonal antibodies. CD8+ cytotoxic T lymphocytes expressed variable levels of CD56 and preferentially expressed interferon-gamma rather than interleukin-4. CONCLUSIONS: Peptide-pulsed dendritic cells induced specific CD8+ cytotoxic T lymphocytes that killed autologous tumor cells from women with advanced ovarian cancer. This finding might contribute to the development of active or adoptive immunotherapy for residual or resistant ovarian cancer after standard surgery and cytotoxic treatment.
Quality control in multicentric clinical trials. An experience of the EORTC Gynecological Cancer Cooperative Group.
Data Quality is a central requirement of scientific research and external monitoring is essential in multicentric clinical trials (MCT). A quality control (QC) study was conducted in the main Institutions participating in EORTC-GCCG Protocol number 55863 - randomised phase III trial of vindesine, cisplatin, bleomycin and mitomycin-C (BEMP) versus cisplatin (P) in disseminated squamous cell carcinoma of the uterine cervix - in order to assess the impact of variations in data quality on the conclusions of the trial. The reliability of the different centres in following the protocol was investigated by a questionnaire covering drug prescription, local facilities and the procedure for preparation and administration of chemotherapy. The 'treatment protocol adherence' was evaluated by recalculation of the ideal protocol dose and its comparison with the actual delivered dosage at each cycle of chemotherapy. 'Data quality control' was assessed by comparison of data on case report forms (CRFs) with the corresponding items in the medical records. Eleven centres participating in the trial were visited by the same team of reviewers. Striking differences were noted in the chemotherapy administration procedures and between the type and quality of hospital files. Overall, there was an acceptable level of data quality and protocol compliance. Data accuracy was 81.8% (range: 65. 6-97%) of the 4424 items checked. Incorrect data were found in 7.0% (2.3-14.5%), data were missing on the form in 3.6% of cases (0-12%) and data was on the form but not in the file in 7.6% of cases (0. 7-17.5%). Causes of inaccuracy were analysed. Both problems in data management but also in a lack of clarity of the protocol and/or CRFs were to blame. Training and supervision of data managers, precision in writing protocols, standardisation of some aspects of CRFs and the use of a checklist for chemotherapy data and treatment toxicities would have avoided many of these errors. The need for QC in all collaborative groups performing MCT is emphasised. A literature review on QC in MCT dealing with chemotherapy is included.
A new standard of care for treatment of ovarian cancer.
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Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: an EORTC Gynaecological Cancer Cooperative Group Study.
The objective of this phase II study was to assess the efficacy and toxicity of vinorelbine administered as a single agent in the treatment of chemonaïve cervical cancer patients. 46 patients (41 eligible) with cervical cancer (epidermoid or adenocarcinoma) and measurable metastatic and/or recurrent disease localised outside irradiated areas were treated with weekly intravenous (i.v.) vinorelbine 30 mg/m2 infused over 20 min. No prior chemotherapy was allowed. Median age was 53 years (range: 33-73), and performance status 1 (0-2). 31 patients (76%) had prior radiation therapy. There were 7 partial responders (17, 95% confidence interval (CI) 7-32) and 8 stable diseases (20%). Median duration of response was 5 months (4-11). Granulocytopenia was the major toxicity, with 47% of patients exhibiting grade 3 or 4 toxicity. Dose reduction and/or treatment delay was necessary in 28 patients (78%). Peripheral neuropathy reported in 10 patients was mild (grade 1 in 9 patients and grade 2 in 1 patient). In conclusion, single agent vinorelbine has moderate activity in recurrent or metastatic cervical cancer, but its reduced neurotoxicity warrants further study in combination with cisplatin.
Diagnosis of persistent ovarian carcinoma with three-step immunoscintigraphy.
The diagnosis of recurrent ovarian carcinoma is usually determined at surgical re-exploration since the main non-invasive diagnostic tests have low accuracy. It would be desirable to have a high accuracy non-invasive diagnostic procedure. With this aim, we have assessed the utility of three-step immunoscintigraphy. Thirty patients were intravenously injected with biotinylated monoclonal antibodies MOv18 and B72.3, followed by avidin-streptavidin injection and finally by 111In-biotin. Tumour recurrences were imaged 2 h post radioactivity injection. All patients underwent surgical re-exploration 3-4 days after immunoscintigraphy; the presence of tumour in the area of immunoscintigraphic uptake was evaluated in the biopsied material. Twenty-one patients studied were true-positive, five were true-negative, four were false-positive and none was false-negative. The diagnostic accuracy, positive predictive value and negative predictive value were 87%, 84% and 100% respectively. If these findings are confirmed in a larger number of patients, we expect immunoscintigraphy to be introduced as a cost-effective procedure in the follow-up of patients who have received surgery for ovarian carcinoma, since it promises to reliably identify patients who do not require surgical re-exploration, and guide biopsies when they are indicated.
In vitro induction of tumor-specific human lymphocyte antigen class I-restricted CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients with advanced ovarian cancer.
OBJECTIVE: The purpose of this study was to evaluate the potential of dendritic cells pulsed with whole-tumor extracts derived from autologous ovarian cancer cells in eliciting a tumor-specific cytotoxic T-cell response in vitro from patients with advanced ovarian cancer. STUDY DESIGN: CD8(+) T lymphocytes stimulated in vitro with autologous ovarian tumor lysate-pulsed dendritic cells were tested for their ability to induce a human leukocyte antigen class I-restricted cytotoxic T-lymphocyte response able to specifically kill autologous tumor cells in standard 6-hour chromium 51 cytotoxicity assays. In addition, to correlate cytotoxic activity by cytotoxic T-lymphocytes with a particular lymphoid subset, 2-color flow cytometric analysis of intracellular cytokine expression (interferon gamma and interleukin 4) at the single-cell level was performed. RESULTS: Cytotoxic T lymphocytes specific for autologous ovarian tumor cells were elicited from 3 patients with advanced ovarian cancer. Although cytotoxic T-lymphocyte populations expressed strong cytolytic activity against autologous tumor cells, they did not lyse concanavalin A-stimulated autologous lymphocytes or autologous Epstein-Barr virus-transformed lymphoblastoid cell lines and showed negligible cytotoxicity against the natural killer cell-sensitive cell line K-562. Cytotoxic effect against the autologous tumor cells was inhibited by an anti-human leukocyte antigen class I monoclonal antibody (W6/32). It is interesting that CD8(+) cytotoxic T lymphocytes expressed variable levels of CD56, a marker that may be associated with high cytotoxic activity. Finally, most of the tumor-specific CD8(+) T cells exhibited a T(H)1 cytokine bias, and a high percentage of interferon gamma expressors among cytotoxic T lymphocytes was correlated with higher cytotoxic activity. CONCLUSION: These data show that tumor lysate-pulsed dendritic cells can consistently induce in vitro specific CD8(+) cytotoxic T lymphocytes able to kill autologous tumor cells from patients with advanced stage ovarian cancer. This novel approach may have important implications for the treatment of residual or resistant disease with active or adoptive immunotherapy after standard surgical and cytotoxic treatment.
Ovarial cancer: best timing and applications of debulking surgery.
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Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes.
Interleukin-10 (IL-10) is widely known as an immunosuppressive cytokine by virtue of its ability to inhibit macrophage-dependent antigen presentation, T-cell proliferation, and Th1 cytokine secretion. However, several studies have challenged the perception of IL-10 solely as an immunosuppressive cytokine. As part of an investigation on potentiation of the cytotoxic activity of human papillomavirus E7-specific CD8(+) cytotoxic T lymphocytes (CTL) for adoptive transfusions to cervical cancer patients, we found that IL-10 in combination with IL-2, unlike several other combinations, including IL-2 with IL-12, gamma interferon (IFN-gamma), tumor necrosis factor alpha, and transforming growth factor beta, was able to consistently increase cytotoxicity. This augmentation in cytotoxic activity correlated with a significant increase in the cytoplasmic accumulation of perforin as detected by fluorescence-activated cell sorter. Surface expression of both the alpha and beta chains of the CD8 heterodimeric coreceptor and CD56 molecules was increased by exposure of CTL to IL-10. More importantly, we found that administration of IL-10 in combination with IL-2 after antigen stimulation consistently increased the intracellular expression of Th1 cytokines (i.e., IFN-gamma and IL-2) compared to results for control CD8(+) T cells cultured in IL-2 alone. In kinetic studies, proliferation, intracellular perforin levels, cytotoxic activity, and IFN-gamma expression were consistently elevated in CTL cultures containing IL-10 compared to control cultures, both at early and late time points following stimulation. In contrast, intracellular IL-2 expression was consistently increased only at early time points following stimulation with autologous tumor cells or solid-phase anti-CD3 antibody. Taken together, these data support the use of IL-10 in combination with IL-2 for the in vitro expansion and potentiation of tumor-specific CTL for clinical use in the therapy of cancer.