Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500

OBJECTIVE: We have previously reported the safety, efficient gene transfer, and favorable CA125 responses of individuals with recurrent ovarian cancer treated by p53 gene replacement with the adenoviral vector SCH 58500. The purpose of the present investigation was to evaluate the long-term follow-up of these heavily pretreated patients subsequent to SCH 58500 dosing. METHODS: Patients (n=36) were treated with either single-dose SCH 58500 in the phase I study or with multiple doses (MD) of SCH 58500 over multiple cycles in combination of platinum-based chemotherapy in the phase I/II portion of the study. Five patients were initially treated in the single-dose group and re-enrolled in the MD group. The MD group was evaluated both without the re-enrolled patients as MD1 (n=19), and as MD2 (n=24), which included them. Patients who were only treated on the single-dose arm were designated as SD (n=12). Most patients received additional chemotherapy at the discretion of their physicians on completion of the trial. The current analysis is a retrospective sequential cohort survival analysis. RESULTS: The first patient was treated in March 1997 and the last patient completed SCH 58500 in September 1998. There was no difference in age at diagnosis, Karnofsky performance status, interval between diagnosis to SCH 58500, prior cycles or regimen of chemotherapy, platinum-free interval, percent platinum refractory patients, pretreatment CA125, or largest tumor volume between groups. Both MD groups had a slightly longer chemotherapy-free interval before SCH 58500 than the SD group. Median survival of individuals who received MD SCH 58500 with chemotherapy was 12-13.0 months, compared to only 5 months for those treated with SD SCH 58500. There are 10 long-term survivors more than 20 months after MD treatment for recurrent disease compared to only 2 long-term survivors after SD SCH 58500. CONCLUSION: The 12- to 13.0-month median survival in a heavily pretreated population with recurrent ovarian cancer compares favorably to the 16-month median survival for individuals treated with paclitaxel at the time of initial recurrence of this disease and is more than double the 5-month survival seen with palliative radiotherapy or paclitaxel failure. These data suggest that further study of SCH58500 is clearly indicated.     

Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation.

PURPOSE: To study safety, feasibility, and biologic activity of adenovirus-mediated p53 gene transfer in patients with bladder cancer. PATIENTS AND METHODS: Twelve patients with histologically confirmed bladder cancer scheduled for cystectomy were treated on day 1 with a single intratumoral injection of SCH 58500 (rAd/p53) at cystoscopy at one dose level (7.5 x 10(11) particles) or a single intravesical instillation of SCH 58500 with a transduction-enhancing agent (Big CHAP) at three dose levels (7.5 x 10(11) to 7.5 x 10(13) particles). Cystectomies were performed in 11 patients on day 3, and transgene expression, vector distribution, and biologic markers of transgene activity were assessed by molecular and immunohistochemical methods in tumors and normal bladder samples. RESULTS: Specific transgene expression was detected in tissues from seven of eight assessable patients treated with intravesical instillation of SCH 58500 but in none of three assessable patients treated with intratumoral injection of SCH 58500. Induction of RNA and protein expression of the p53 target gene p21/WAF1 was demonstrated in samples from patients treated with SCH 58500 instillation at higher dose levels. Distribution studies after intravesical instillation of SCH 58500 revealed both high transduction efficacy and vector penetration throughout the whole urothelium and into submucosal tumor cells. No dose-limiting toxicity was observed, and side effects were local and of transient nature. CONCLUSION: Intravesical instillation of SCH 58500 combined with a transduction-enhancing agent is safe, feasible, and biologically active in patients with bladder cancer. Studies to evaluate the clinical efficacy of this treatment in patients with localized high-risk bladder cancer are warranted.     

Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer

A cohort study was designed to evaluate the efficiency of gene transfer and whether biological activity from the expressed therapeutic gene resulted after administration of a recombinant adenovirus containing the human wild-type p53 (p53(wt)) gene (rAd-p53 SCH 58500). The cohort study was conducted in five trial subjects with recurrent ovarian cancer. Each trial subject received multiple cycles of rAd-p53 SCH 58500, each cycle comprised of doses of 7.5 x 10(13) particles on each of five consecutive days. Subjects were treated with rAd-p53 SCH 58500 alone during Cycle 1 and in combination with gemcitabine during the subsequent cycles. Both tumor biopsies and peritoneal aspirates were collected and evaluated for gene transfer and evidence of the biological activities of the expressed p53(wt) gene. Using quantitative PCR and RT-PCR, and in situ PCR, gene transfer and expression were documented in tumor biopsies (four of five patients) collected from Cycle 1. Furthermore, upregulation of p21/WAF1, bax and mdm-2, and downregulation of survivin were observed in these same tumor biopsy samples, suggesting that intraperitoneal administration of rAd-p53 SCH 58500 leads to detectable p53 biological activity in target tumor tissue. In addition, gene transfer and its expression were observed in cells obtained from peritoneal aspirates. These fluids were mainly comprised of polymorphonuclear neutrophils, indicating that successful gene transfer can be achieved by multiple cycle intraperitoneal administration of recombinant adenovirus.     

Intravascular adenoviral agents in cancer patients: lessons from clinical trials

A large number of adenoviral agents are being developed for the treatment of cancer. However, the treatment-related death of a patient with ornithine transcarbamylase deficiency following adenovirus administration by hepatic artery has led to serious concerns regarding the safety of intravascular adenovirus. Both replication-incompetent (rAd.p53, e.g., SCH58500) and replication-selective (dl1520, aka Onyx-015; CG7870) oncolytic adenoviruses, by intravascular administration, are in clinical trials. We review Phases I and I/II results from these clinical trials. dl1520 and rAd.p53 were well-tolerated following hepatic artery infusion at doses of up to 2x10(12) and 2.5x10(13) particles, respectively. At a dose of 7.5x10(13) particles, rAd.p53 was associated with dose-limiting cardiac output suppression; dl1520 dose escalation did not proceed higher than 2x10(12). Intravenous (i.v.) infusions of dl1520 and CG7870 have been well tolerated by i.v. infusion at doses of 2x10(13) and 6x10(12), respectively, without identification of a maximally tolerated dose to date. Mild/moderate transaminitis was demonstrated in some patients on both the hepatic arterial and i.v. trials at doses >or=10(12) particles. Interleukin (IL)-6 and IL-10 were induced in a dose-dependent manner in most patients, but significant interpatient and intrapatient (on repeat doses) variabilities were demonstrated. Evidence of p53 gene expression (Ad.p53) or viral replication (dl1520) was demonstrated in the majority of patients receiving >or=10(12) particles. Over 100 cancer patients have been treated with intravascular adenovirus constructs to date with an acceptable toxicity profile; further clinical trial testing appears appropriate in cancer patients.     

What Is the Benefit of Bevacizumab Combined with Chemotherapy in Patients with Recurrent Ovarian,Fallopian Tube or Primary Peritoneal Malignancies?

Abstract

The aim of this retrospective analysis was to investigate the efficacy and adverse effects of the monoclonal anti vascular endothelial growth factor antibody bevacizumab (Avastin^®) combined with chemotherapeutic agents in non-protocol patients with recurrent ovarian, fallopian tube, or primary peritoneal malignancies. Using our data-bases, we identified patients treated with bevacizumab combination therapy since June2005. Responses were evaluated with Response evaluation Criteria in Solid tumorsand serum CA125 Rustin criteria. Toxicity was assessed according to the Commontoxicity Criteria (CTC) v.3.0. Data from 64 patients were included. The median patient age was 58 years, and they had undergone a median of 4.5 (range, 1-10) prior cyto-toxic chemotherapy regimens. The median length of follow-up was 8 months (range, 2-29). The most commonly used combinations were bevacizumab plus taxanes (26.6%) and plus cyclophosphamide (26.6%). A median of 4 cycles of therapy with a medianbevacizumab dose of 3,600 mg (range, 500-18,240) were administered. An overallresponse rate of 21.3% was observed in 13 patients with partial response, and an-other 42.6% of patients had stable disease. Among the patients with elevated pre-treatment serum CA125 concentration, an overall response rate of 46.3% (25/54) was observed according to modification of the Rustin criteria. Fifteen (23.4%) patients had grades 3 or 4 adverse events. Gastrointestinal perforations occurred in 2 (3.1%) patients. Seventeen (26.6%) patients had improved performance status scores. Beva-cizumab combined with chemotherapy showed promising clinical benefits, with significant response of serum CA125 concentration and moderate adverse effects.     

Gemcitabine salvage chemotherapy for patients with gynecologic malignancies of the ovary, fallopian tube, and peritoneum.

The efficacy and toxicity of gemcitabine salvage chemotherapy was evaluated in 27 heavily pretreated patients with recurrent and progressive ovarian, fallopian tube, or peritoneal cancer. At least one platinum-based chemotherapeutic regimen had failed in each patient. The median number of previous chemotherapy regimens and cycles of chemotherapy was 4 and 23, respectively. A total of 124 cycles of gemcitabine were delivered (median, 3 cycles). Hematologic toxicity included four patients with grade 3/4 thrombocytopenia and two patients with grade 3/4 neutropenia. Thrombocytopenia and neutropenia resulted in eight dose reductions and a single 1-week treatment delay. Nonhematologic side effects were well tolerated and largely self-limiting. No complete responses were observed. Three patients (11%) demonstrated partial responses to therapy. The duration of response was 7 months for two of the responders and 5 months for the third responder. Stable disease was observed in 14 patients (52%), in whom the median progression-free interval was 5 months. In conclusion, among heavily pretreated patients, gemcitabine has limited antitumor activity in platinum-resistant carcinomas of the ovary, fallopian tube, and peritoneum. The role of gemcitabine in the treatment of gynecologic malignancies of the ovary, fallopian tube, and peritoneum will be determined by studies that define the efficacy of multiagent regimens of chemotherapy that include gemcitabine and by studies that include patients who have been less heavily pretreated.     

Combination therapy with SCH58500 (p53 adenovirus) and cyclophosphamide in preclinical cancer models

SCH58500 (ACN53) is a replication-deficient, recombinant adenovirus which expresses human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and it has enhanced activity in combination with many chemotherapeutic drugs. However, the anti-tumor efficacy of SCH58500 combined with the DNA-damaging chemotherapeutic cyclophosphamide has not been previously reported. Cyclophosphamide did not enhance the activity of SCH58500 in three out of four human tumor xenograft models studied. Furthermore, combination therapy with SCH58500 and cyclophosphamide was not any better than single drug treatment in transgenic H-ras mice and in FVB mice bearing syngeneic MidT2-1 tumors. This is in sharp contrast to previous combination studies in these models where SCH58500 had enhanced efficacy when given with the farnesyl protein transferase inhibitor SCH66336, paclitaxel, cisplatin, cisplatin/paclitaxel, or doxorubicin. Further evaluation of this combination is required before it can be recommended for clinical trials in cancer patients.     

Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models

SCH66336 is a p.o.-active, farnesyl protein transferase inhibitor. SCH66336 inhibits farnesylation of RAS and other proteins in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. SCH58500 is a replication-deficient, recombinant adenovirus, which expresses the human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and enhanced activity in combination with many chemotherapeutic drugs. Here we report that combination therapy with SCH66336 and SCH58500 has synergistic or additive antiproliferative effects on a panel of tumor cells lines in vitro. The efficacy of the three-drug combination of SCH66336, SCH58500, and paclitaxel was also examined in vitro. Each two-drug interaction displayed such marked synergy, the addition of a third drug to the statistical model could only yield additivity. Greater combined efficacy for SCH66336 and SCH58500 was also observed in vivo in the DU-145 human prostate and wap-ras/F transgenic mouse cancer models.     

Derivation and initial characterization of a mouse mammary tumor cell line carrying the polyomavirus middle T antigen: utility in the development of novel cancer therapeutics

Here we describe the derivation of novel cell lines from spontaneous mammary tumors that arose in mouse mammary tumor virus-polyomavirus (MMTV-PyV) Middle T (MidT) transgenic mice. Clonal cell lines from four mixed cell populations were tested for adenovirus transducibility and sensitivity to p53 tumor suppressor gene therapy mediated by SCH58500, a replication-deficient adenovirus that expresses human p53. The MidT2-1 cell line was selected for further characterization in vitro and in vivo. This cell line carried the PyV MidT antigen, had wild-type p53 DNA, and was sensitive to suppression of proliferation by MMAC/PTEN tumor suppressor gene therapy. MidT2-1 cells gave rise to highly aggressive tumors in syngeneic FVB mice in both the mammary fat pad and the peritoneal cavity. The histopathology of MidT2-1 tumors closely resembled the histopathology of the primary transgenic tumors. Tumor growth in vivo was inhibited by p53 gene therapy or by MMAC gene therapy. In addition, combination therapy with a number of anticancer agents had synergistic or additive efficacy in vitro. In particular, MMAC gene therapy synergized with SCH58500 or paclitaxel. In the i.p. MidT2-1 tumor model p53 gene therapy enhanced the survival benefits of paclitaxel/cisplatin chemotherapy. Combination therapy has become a mainstay in cancer treatment. In this report, we use a novel transgenic mouse tumor cell line to suggest new combinations that might be explored in clinical cancer care. These include gene therapy using the tumor suppressors MMAC and p53, chemotherapy using farnesyl transferase inhibitors, the microtubule stabilizing taxanes, and the DNA synthesis disruptors gemcitabine and cisplatin. The precise biological mechanisms by which these therapies induce their antitumor effects are not fully elucidated. However, the work presented here suggests that many of these therapeutic approaches have synergistic antitumor activity when used in combination.     

血清CEA、CA125及CA72-4在胃癌腹膜转移中的临床意义

背景与目的:胃癌腹膜转移多处于疾病终末期,但每种肿瘤标志物在胃癌腹膜转移中的临床意义仍不是很明确.该研究探讨血清肿瘤标志物CEA、CA125及CA72-4在胃癌腹膜转移中的诊断价值及其临床意义.方法:收集延边大学附属医院肿瘤科2008年1月—2013年12月间经影像学、手术和病理学等检查确诊、并接受静脉及腹腔灌注化疗的108例胃癌腹膜转移患者为研究对象,分别于确诊时、每次化疗前检测血清CEA、CA125及CA72-4,分析单独、2或3种肿瘤标志物同时检测在胃癌腹膜转移的诊断敏感性,并分析其与临床病理因素、化疗疗效及生存期之间的相关性.结果:在胃癌腹膜转移患者CEA、CA125和CA72-4的阳性率各为20.4%、46.3%和45.4%,联合CEA/CA125、CEA/CA72-4、CA125/CA72-4及CEA/CA125/CA72-4的阳性率分别为54.7%、52.8%、69.5%和79.6%,3种标志物联合检测明显优于单独检测(P<0.05).CEA、CA125和CA72-4水平均与ECOG分级存在相关性(P<0.05).CA125阳性与腹水有关(P<0.001).CA72-4阳性与卵巢转移相关(P<0.05).确诊时血清CEA、CA125和CA72-4阳性患者中位生存期短于CEA、CA125和CA72-4阴性的患者(P<0.05).在3周期化疗后3种肿瘤标志物较治疗前均下降,差异有统计学意义(P<0.05).化疗后CA125下降与腹水量的减少有明显相关性(P<0.05).确诊时肿瘤标志物阳性患者经化疗3个周期后转为阴性的患者生存期明显延长(P<0.001).结论:联合检测血清CEA、CA125和CA72-4可明显提高胃癌腹膜转移的诊断率.     

Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial

The major focus of intrahepatic arterial (IHA) administration of adenoviruses (Ad) has been on safety. Currently, there is little published data on the biological responses to Ad when administered via this route. As part of a Phase I study, we evaluated biological responses to a replication-defective adenovirus encoding the p53 transgene (SCH 58500) when administered by hepatic arterial infusion to patients with primarily colorectal cancer metastatic to the liver. In analyzing biological responses to the Ad vector, we found that both total and neutralizing Ad antibodies increased weeks after SCH 58500 infusion. The fold increase in antibody titers was not dependent on SCH 58500 dosage. The proinflammatory cytokine interleukin-6 (IL-6) transiently peaked within 6 h of dosing. The cytokine sTNF-R2 showed elevation by 24 h post-treatment, and fold increases were directly related to SCH 58500 doses. Cytokines TNF-alpha, IL-1beta, and sTNF-R1 showed no increased levels over 24 h. Predose antibody levels did not appear to predict transduction, nor did serum Ad neutralizing factor (SNF). Delivery of SCH 58500 to tumor tissue occurred, though we found distribution more predominantly in liver tissues, as opposed to tumors. RT-PCR showed significantly higher expression levels (P<0.0001, ANOVA) for adenovirus type 2 and 5 receptor (CAR) in liver tissues, suggesting a correlation with transduction. Evidence of tumor-specific apoptotic activity was provided by laser scanning cytometry, which determined a coincidence of elevated nuclear p53 protein expression with apoptosis in patient tissue. IHA administration of a replication defective adenovirus is a feasible mode of delivery, allowing for exogenous transfer of the p53 gene into target tissues, with evidence of functional p53. Limited and transient inflammatory responses to the drug occurred, but pre-existing immunity to Ad did not preclude SCH 58500 delivery.     

Niraparib: A Review in Ovarian Cancer

Niraparib (Zejula^®), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Approval was based on the results of the randomized, double-blind, placebo-controlled phase III NOVA trial. In NOVA, niraparib significantly prolonged progression-free survival (primary endpoint), chemotherapy-free interval and time to first subsequent therapy compared with placebo in patients with recurrent, platinum-sensitive, high grade serous ovarian, fallopian tube or primary peritoneal cancer. The beneficial effects of niraparib were consistent regardless of BRCA mutation or homologous recombination deficiency (HRD) status. Niraparib had a manageable tolerability profile, with the majority of grade 3 or 4 adverse events being haematologic abnormalities (e.g. thrombocytopenia, anaemia, neutropenia). Adverse events were generally well managed with dose interruption or modification of niraparib. Current evidence suggests that niraparib is an effective new option with a manageable tolerability profile for the maintenance treatment of recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults, with or without BRCA1/2 mutation or HRD.     

A study of ovarian cancer patients treated with dose-intensive chemotherapy supported with peripheral blood progenitor cells mobilised by filgrastim and cyclophosphamide.

We have shown that large numbers of haemopoietic progenitor cells are mobilised into the blood after filgrastim [granulocyte colony-stimulating factor (G-CSF)] alone and filgrastim following cyclophosphamide chemotherapy in previously untreated patients with ovarian cancer. These cells may be used to provide safe and effective haemopoietic rescue following dose-intensive chemotherapy. Using filgrastim alone (10 micrograms kg-1), the apheresis harvest contained a median CFU-GM count of 45 x 10(4) kg-1 and 2 x 10(6) kg-1 CD34+ cells. Treatment with filgrastim (5 micrograms kg-1) following cyclophosphamide (3 g m-2) resulted in a harvest containing 66 x 10(4) kg-1 CFU-GM and 2.4 x 10(6) kg-1 CD34+ cells. There was no statistically significant difference between these two mobilising regimens. We have also demonstrated that dose-intensive carboplatin and cyclophosphamide chemotherapy can be delivered safely to patients with ovarian cancer when supported by peripheral blood progenitor cells and filgrastim. Carboplatin (AUC 7.5) and cyclophosphamide (900 mg m-2) given at 3 weekly intervals with progenitor cell and growth factor support was well tolerated in terms of haematological and systemic side-effects. Double the dose intensity of chemotherapy was delivered compared with our standard dose regimen when the treatment was given at 3 weekly intervals. Median dose intensity could be further escalated to 2.33 compared with our standard regimen by decreasing the interval between treatment cycles to 2 weeks. However, at this dose intensity less than a third of patients received their planned treatment on time. All the delays were due to thrombocytopenia.     

Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: active, but how effective?

Carcinoma of unknown primary (CUP) is characterized by dismal patient survival. The outcome of patients with two favourable risk CUP subsets was studied. Eighty patients diagnosed with either midline lymph node metastases (n=33) or peritoneal carcinomatosis (n=47) were analysed retrospectively. The majority had poorly differentiated adenocarcinoma or undifferentiated carcinoma, treated with platinum-taxane based chemotherapy from 1996 till 2002. Females with peritoneal carcinomatosis also underwent surgical debulking. Objective tumour regression was present in 44% of patients (nodal group 30% versus peritoneal group 53%, p=0.066). Complete responses were seen more often in peritoneal carcinomatosis patients (nodal group 9%, peritoneal group 36%, p=0.008). At a median follow up of 60 months, median progression-free and overall survival were 5 and 10 months respectively in the nodal group, 7 and 15 months in the peritoneal group. Five-year survival was 7% (nodal group 0% vs. peritoneal group 10%, p=0.05). Complete responders fared better than non-CR patients. Fewer than four metastatic sites, elevated CA 125, and normal CA 19-9 levels were favourable prognostic factors for survival. Modern combination chemotherapy has satisfactory activity, with a minority of CUP patients enjoying long-term responses. Research efforts towards complete remission consolidation and molecular profiling are imperative.     

Phase I study and preliminary pharmacology of the novel innate immune modulator rBBX-01 in gynecologic cancers.

PURPOSE: A recombinant protein product, rBBX-01, is the first innate immunostimulator derived from a protozoan (Eimeria protozoan) and has shown potent preclinical in vivo and in vitro activities. This phase I trial was done to determine the safety and basic pharmacology of rBBX-01. EXPERIMENTAL DESIGN: Eligible patients had recurrent incurable gynecologic malignancies. The study was divided into three components: a starting low-dose phase (0.85, 2.0, and 4.0 microg/m2), an intrapatient dose acceleration phase (4.0-1,024.0 microg/m2), and a high-dose phase (1,000 and 2,000 microg/m2). All treatment doses were administered daily for 5 days. Patients were allowed a second cycle of treatment if there was evidence of response. RESULTS: Sixteen patients received a total of 20 cycles of rBBX-01. All patients tolerated the drug well, exhibiting no local or systemic, acute or delayed, adverse reactions. Plasma levels of rBBX-01 were detectable in all patients over the entire dose range, although changes in the pharmacodynamic marker (interleukin-12) exhibited patient-to-patient variability. Of 14 patients with ovarian, primary peritoneal, or endometrial cancer with elevated CA125 biomarkers at the start of treatment, 4 responded with decreased levels of CA125. One patient showed decreasing CA125 levels for 10 months and received no additional chemotherapy for 11 months. Those patients exhibiting reductions in CA125 also exhibited increased levels of plasma interleukin-12 during the week of therapy. CONCLUSION: The immunostimulator rBBX-01 was safe in multidose regimens in heavily pretreated women. Of the 14 patients with elevated CA125 levels, an approximately 30% response rate was detected. rBBX-01 should receive additional testing in the clinical setting.     

Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.     

Primary Peritoneal Serous Papillary Carcinoma: A Clinical and Pathological Study

Primary peritoneal serous papillary carcinoma (PPSPC) is a rare primary tumor of the peritoneum that found predominantly in elderly and post-menopausal women. The aim of our study is to review the clinical and pathologic information of 22 patients, and then try to summarize clinical behavior and pathological characteristics of PPSPC, in order to be better recognized of this entity in future. We retrospectively reviewed the data from 22 patients with PPSPC treated at our hospital from 1992 to 2008. All paraffin blocks were recut for periodic acid-Schiff diastase and immunohistochemical staining for CD15, cytokeratin7(CK7), cytokeratin20(CK20), S-100 protein, carcinoembryonic antigen (CEA), CA125, estrogen receptor(ER) and progesterone receptor(PR). The median age of the patients at the time of surgical staging was 56 years (range, 32–77 years). The most common presenting symptoms were abdominal distension (59.1%) and ascites (63.6%). Pretreatment CA125 levels were significant elevated in 90.5% patients. Optimal debulking was performed in 18 patients. All patients were consequently treated with platinum-based chemotherapy. Response to treatment is promising, and the median overall survival of all patients was 21.0 months (95% CI 16.9, 25.1 months). The positive rate of immunohistochemical staining was CD15 95.5%, CK7 90.9%, S-100 protein 68.2%, CA125 59.1%, CK20 31.8%, ER 31.8%, CEA 27.3% and PR 9.1%, respectively. Gynecologist should be aware of PPSPC when abdominal distension, gross ascites and a raised level of CA125 in women without ovarian enlargement. Immunohistochemical staining might be helpful as accessory criteria for the differential diagnosis among the PPSPC, peritoneal malignant mesothelioma (PMM), primary epithelial ovarian carcinoma (PEOC) and peritoneal carcinomatosis from the gastrointestinal tumors (SPCGT). Cytoreductive surgery combined with pre/postoperative platinum-based chemotherapy may be effective for PPSPC patients.     

A case of nonresected gastric cancer with peritoneal dissemination maintained on TS-1, cisplatin (CDDP) and docetaxel combination chemotherapy with good QOL

A 64-year-old woman was admitted to the hospital for abdominal fullness and constipation. In the pelvic cavity, an abdominal CT scan revealed massive ascites showing malignancy on histological examination. Upper GI endoscopy revealed type 3 gastric cancer from the anglus to the cardia. A barium-enema showed a stenotic lesion at the sigmoid colon due to peritoneal dissemination. An abnormally high CA125(1,400 mg/ml) level was detected in serum. We performed systemic chemotherapy of TS-1, CDDP and peritoneal infusion of docetaxel on the nonresected gastric cancer with peritoneal dissemination. After 2 cycles, cytology of ascites revealed no malignancy, and the serum CA125 value regained its normal level. After 3 cycles, the killer cell effect was recognized by laparoscopic examination and the stenotic change of sigmoid colon had almost disappeared. The patient clinically achieved good QOL by this method, which was very effective for nonresected gastric cancer with peritoneal dissemination.