PROutine: a feasibility study assessing surveillance of electronic patient reported outcomes and adherence via smartphone app in advanced cancer.

BACKGROUND: In advanced cancer, quality of life (QoL) is a major treatment goal. In order to achieve this, the identification of suffering by screening for patient-reported-outcomes (PROs, i.e., symptoms) is of utmost importance. The use of paper-pencil questionnaires is associated with significant shortcomings due to missing data, recall bias and transcription errors. Other than that, the electronic recording of PROs by mobile Health (mHealth) offers a number of advantages. The aim of this study was to test whether the routine assessment of PROs via a newly developed smartphone application (MeQoL®) is feasible. METHODS: A prospective, uncontrolled, multi-center, feasibility trial was performed in adult outpatients with advanced, solid cancer. Patients under anti-cancer therapy and with regular outpatient visits were eligible. Patients daily recorded the degree of perceived distress (NCCN Distress Thermometer®), pain intensity {average and worst [numerical rating scale (NRS), 0-10]}, the number of breakthrough pain episodes (BPE) and ten questions from a modified version of the Edmonton Symptom Assessment Scale (ESAS). Weekly, five questions concerning different domains of QoL from the short-form 8 (SF-8) questionnaire were obtained. Also, patients recorded the intake of their opioid rescue medication. According to the main scope of the trial (feasibility), no primary endpoint was defined. Rather, the following main feasibility criteria were assessed: missing data, drop-out- and acceptance-rate, patient satisfaction, patients' judgement of practicability, patients' and physicians' suggestions for improvement and basic clinical and demographic data of the participating patients. The study was registered in the German Clinical Trials Register (ID: DRKS00008761). RESULTS: In three German cancer centers, 40 patients {female: 28 (70%); average age, 57 years [range, 27-73 years; standard deviation (SD), 12]} were included. As three devices were lost on transport, 37 devices could be evaluated. The median investigation period per device was 99.5 days (SD, 31). Patient adherence in using the smartphone app to document their distress and symptoms was high and missing data were low: In median daily reviews were performed on 70 (SD, 29) of these days (70%) and median weekly recordings were 13 weeks (87%). Most often, patients recorded symptom intensity (89%, MIDOS) and distress (85%, NCCN thermometer). On feedback forms, patients reported a good to very good user friendliness of MeQoL® and a high motivation to use this tool again. CONCLUSIONS: Even though participants were asked to record PROs rather frequently (daily), missing data were low and patient satisfaction was high. Having in mind the findings of other working groups, such routine implementation of mHealth solutions may substantially improve outcomes of cancer therapy and increase the value of trials' findings. For the individual patient, MeQoL® allows for monitoring adherence to pharmacotherapy and can facilitate patient guidance.

Anaplastic pelvic carcinoma secondary to low-grade endometrial carcinoma.

BACKGROUND: Low-grade endometrial carcinoma has an excellent prognosis. The risk of secondary cancer after endometrial carcinoma is moderately increased and is mostly related to the field of postoperative radiation (small intestine, colon, vagina, and urinary bladder). Anaplastic (undifferentiated) pelvic carcinoma (APC) is rare and probably under-reported. To date, only one publication has reported six cases of APC that were secondary to low-grade endometrial carcinoma. CASE REPORT: We have analyzed the fulminant course of APC-preceded by paraneoplastic arthritis-four months after hysterectomy and adnexectomy for low-grade endometrial carcinoma (endometrioid type, moderately differentiated, tumor diameter: 2 cm, infiltration depth 3 of 15 mm). The 73-year-old patient died five weeks after the diagnosis of the second malignancy. CONCLUSION: The prognosis of APC is poor and the limitations of the therapy result from aggressive tumor biology and rapid deterioration of the patients' general condition. Rheumatological symptoms can precede cancer diagnosis. Immunohistochemistry facilitates the differentiation between primary and secondary carcinoma.

Randomized, phase II, placebo-controlled, double-blind study with and without enzastaurin in combination with paclitaxel and carboplatin as first-line treatment followed by maintenance treatment in advanced ovarian cancer.

PURPOSE: Enzastaurin is an oral serine/threonine kinase inhibitor antitumor agent. Our phase II trial tested the efficacy and safety of enzastaurin added to a standard carboplatin/paclitaxel chemotherapy regimen in patients with newly diagnosed advanced ovarian cancer. PATIENTS AND METHODS: This was a randomized, placebo-controlled study in patients with International Federation of Gynecology and Obstetrics stage IIB to IV ovarian, fallopian tube, or peritoneal epithelial carcinoma. Patients were randomly assigned to six cycles of chemotherapy (paclitaxel/carboplatin ± enzastaurin [PCE/PC]) followed by maintenance therapy (enzastaurin/placebo). Primary end point was progression-free survival (PFS). Secondary measures included response rate, safety assessment, and translational research. RESULTS: A total of 142 patients were randomly assigned to PCE (n = 69) or PC (n = 73). Patients in the PCE group had a 3.7-month longer median PFS compared with patients in the PC group; this was not statistically significant (hazard ratio [HR], 0.80; 95% CI, 0.50 to 1.29; P = .37). Safety profiles of the treatment arms were comparable. Frequency of discontinuation because of adverse events was similar (PCE, 11.9%; PC, 9.7%). Multivariate analyses confirmed the importance of optimal debulking with regard to PFS (debulking optimal v suboptimal: HR, 0.51; 95% CI, 0.30 to 0.85; P = .009). HR for covariate stage (stage IIB to IIIB v IIIC to IV) was not statistically significant (0.75; 95% CI, 0.38 to 1.47; P = .40). Translational research of immunohistochemistry protein assays did not identify any markers significantly associated with treatment difference regarding PFS. CONCLUSION: The PCE combination increased PFS, but it was not significantly superior to PC in this phase II study.

A randomized phase II non-comparative study of pemetrexed­carboplatin and gemcitabine­vinorelbine in anthracycline- and taxane-pretreated advanced breast cancer patients.

Pemetrexed-carboplatin and gemcitabine­vinorelbine combination therapies were efficacious in phase II and phase III studies as first-line breast cancer treatment. Thus, Arm A and Arm B combinations were investigated in patients pretreated with anthracycline and taxanes. Women with advanced breast cancer, with ≥1 measurable lesion per RECIST, were stratified by line of treatment (1st, 2nd), visceral disease (yes/no), ECOG PS (0-1 vs. 2) and randomized 1:1 to Arm A (pemetrexed 600 mg/m², D1 i.v. q21; carboplatin, AUC 5, D1 i.v. q21) or Arm B (gemcitabine 1,200 mg/m² D1, D8 i.v. q21; vinorelbine 30 mg/m² D1, D8 i.v. q21). Treatment continued until progression. The primary endpoint was objective response rate (RR). Secondary endpoints were duration of response (DoR), time-to-response (TTR), time-to-progressive disease (TTPD), time-to-treatment failure (TTTF) and safety. A two-stage design was employed independently for each arm. Of 135 randomized patients, 125 (Arm A, n=64; Arm B, n=61) qualified for tumor-response analysis. The mean (standard deviation) number of cycles administered was 6.3 (4.13) in Arm A and 6.2 (4.39) in Arm B. Efficacy in Arm A and Arm B were: RR (95% CI), 26.6 (16.3-39.1) and 29.5 (18.5-42.6); time-to-events (months), DoR 7.7 and 7.5; TTPD, 5.1 and 5.6; TTR, 1.8 and 1.8; TTTF, 4.8 and 5.1; respectively. Most common grade 3/4 adverse events possibly related to study-drug were neutropenia, thrombocytopenia, anemia and leucopenia in Arm A and neutropenia, leucopenia and fatigue in Arm B. In this study, both combinations showed moderate activity as predefined RR was not reached and were well tolerated.

Papillary-serous adenocarcinoma of the uterine cervix during tamoxifen therapy after bilateral breast cancer.

BACKGROUND: Papillary-serous adenocarcinoma (PSCC) is a very rare subtype of cervical cancer. To our knowledge, this is the first report on PSCC of the uterine cervix following bilateral breast cancer. CASE REPORT: A 61-year-old Caucasian woman underwent conserving surgery of both breasts at the age of 57 years, because of bilateral invasive ductal carcinoma. Radiation and tamoxifen treatment followed. Routine surveillance examinations, including pelvic examination, Papanicolaou (Pap) smear, and transvaginal ultrasound, were uneventful. Recently, a small contact-bleeding mass of the cervix was found. The Pap smear was II (reactive); HPV-DNA test was negative. The biopsy of the mass revealed PSCC with a high expression of p53, carcinoembryonic antigen (CEA), and Ki67 (50%). Staining for estrogen receptor (ER), progesterone receptor (PR), and vimentin was negative. The serum carbohydrate antigen 125 (CA-125) reached 159 U/ml. The patient was treated with radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. A poorly-differentiated papillary-serous, non-secretory adenocarcinoma, pT1b1, pN0 (0/44), pM0, G3, R0, V0, L0, was confirmed. According to the German recommendations for early-stage cervical cancer, the patient received no adjuvant treatment. Currently, the patient is free of relapse 38 months after the diagnosis of cervical cancer and 87 months after that of breast cancer. CONCLUSION: Immunohistochemistry is helpful in diagnosing rare entities. This case adds further evidence that the prognosis for early-stage PSCC is probably not poorer than that for other cervical adenocarcinomas.

Taxane-based mono- or combination therapy for managing metastatic breast cancer (MBC) in routine practice: a multinational prospective observational study.

OBJECTIVES: Taxanes are standard for first-line chemotherapy of metastatic breast cancer (MBC), but indications for single-agent versus combination treatment remain controversial. This non-interventional study in 12 different countries explored treatment patterns and progression-free survival (PFS) in routine practice. RESEARCH DESIGN AND METHODS: The prospective study was designed to determine factors associated with the choice of taxane-based regimens for MBC. Data were collected at the start of first-line treatment planned by the physician (baseline), and at subsequent routine practice visits. Patients were followed up until death, disease progression or change of treatment regimen, for a maximum of 8 months. Upon analysis, patients were classified into taxane single-agent (TM) or taxane-based combination (TC) cohorts according to scheduled first-line therapy. Logistic regression was used to investigate the relationship between choice of TM vs. TC and baseline factors. RESULTS: Among the 465 patients enrolled (22.4% HER2+), 160 were prescribed TM (69% docetaxel, 31% paclitaxel) and 305 TC, frequently combined with gemcitabine (39%) or capecitabine (24%). HER2+ status was the only factor associated with choosing TC (p < 0.001). Median PFS [95% CI] was 11.5 [8.7-13.3] months for TM and 10.3 [8.4-14.4] months for TC. Among HER2+ patients (N = 104), only 59% received trastuzumab, none had previous adjuvant trastuzumab. Median PFS was 19.7 [9.3-unestimated] months for TC including trastuzumab, 18.8 [5.0-22.0] months for TC and 6.1 [3.8-13.3] months for TM without trastuzumab. CONCLUSIONS: In patients from 12 different countries treated during routine practice, TCs were prescribed more frequently than single agents. HER2+ status was significantly associated with TC use. 41% of HER2+ patients received no anti-HER2 treatment; PFS results for TC with and without trastuzumab (19.7 and 18.8 months) suggested TCs without trastuzumab might be worth further investigation in these patients. However, the study was not randomized; treatment evaluation bias can therefore not be excluded.

A phase II trial of pemetrexed in combination with carboplatin in patients with recurrent ovarian or primary peritoneal cancer.

OBJECTIVE: Carboplatin-based combinations are commonly used in platinum-sensitive ovarian cancer (PSOC). Pemetrexed in combination with carboplatin has been shown to be feasible in a phase I study in PSOC. The primary objective of this subsequent phase II study was to determine the overall response rate (ORR; defined by Response Evaluation Criteria in Solid Tumors) of this combination in patients with recurrent PSOC. Secondary objectives included progression-free survival (PFS), overall survival (OS), and toxicity. METHODS: Patients with PSOC (defined by recurrence ≥ 6 months after completion of up to two lines of prior platinum-based therapy), measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. Pemetrexed 500 mg/m(2) was administered as a 10-minute infusion followed by carboplatin AUC 6 as a 30-minute infusion on day 1 of a 21-day cycle. RESULTS: Sixty-six patients were treated. Of the 61 patients evaluable for response, there were 20 responders (one complete response and 19 partial responses), for an ORR of 32.8% (95% CI: 21.3%, 46.0%). For the intent-to-treat population (all 66 patients), the median PFS was 9.4 months (95% CI: 8.3, 11.1), with 22.7% censoring. Median OS was not reached due to the high censoring rate. There was one drug-related death (multi-organ failure). The most common drug-related grade 3/4 toxicities were neutropenia (39.4%), thrombocytopenia (24.2%), carboplatin hypersensitivity (9.1%), nausea (6.1%), and vomiting (6.1%). CONCLUSIONS: Carboplatin AUC 6 and pemetrexed 500 mg/m(2) has a low incidence of serious toxicities. Defining the platinum-based combination with the best therapeutic index would require a prospective phase III study.

A phase-I trial of pemetrexed plus carboplatin in recurrent ovarian cancer.

BACKGROUND: Carboplatin-based combinations are established in platinum-sensitive recurrent ovarian cancer. To improve the therapeutic index, new platinum-based combinations are required. Pemetrexed is a multi-targeted antifolate inhibiting thymidylate synthase. The aim of this study was to determine the maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) and to characterize toxicities of the combination of pemetrexed (Pem) and carboplatin (Cb). DESIGN: A standard three-patient cohort dose escalation was performed starting at Cb AUC-5 and Pem 500 mg/m(2). Patients with platinum-sensitive recurrent ovarian cancer were eligible. Two levels of Cb (AUC-5, 6) and five levels of Pem (500, 600, 700, 800, and 900 mg/m(2)) were evaluated. DLTs were based on cycle 1. RESULTS: Twenty patients were enrolled. The median age was 57.4 years (37.3-75.3) and the median platinum-free interval was 26.2 months (7.2-124.4). There was one DLT at dose level 3 in cycle one. No serious adverse events related to the study therapy were observed. The 20 patients completed 112 cycles of Cb (104 were planned) and 115 cycles of Pem (112 were planned). The maximum dose level of Cb AUC-6 and Pem 900 mg/m(2) was well tolerated. Response rates in 19 patients were: CR: 63.2%; PR: 21.1%; SD; 5.3%, PD: 10.5%. CONCLUSIONS: The combination carboplatin and pemetrexed is safe and well tolerated. A multicenter phase-II trial is currently underway.

The role of p53 as a surrogate marker for chemotherapeutical responsiveness in ovarian cancer.

INTRODUCTION: In advanced ovarian cancers (OCs), p53 mutations are frequently observed. The objective of this study was to explore the value of the p53 mutational status, using four different techniques, in advanced OC patients as a predictive marker for responsiveness to platinum-based chemotherapy. METHODS: One hundred and four, mostly serous papillary OC specimens were analyzed, of which all received a platinum containing chemotherapy after optimal cyto-reductive surgery. To verify the p53 mutational status, immunohistochemical staining with monoclonal antibodies, functional yeast assay (FASAY), single-strand conformation polymorphism analysis (SSCP) and genomic sequencing was performed in parallel. RESULTS: Out of ten OC patients [2 low malignant potential (LMP)/8 G1] only two had a mutant p53, whereas eight showed a wild-type p53. 40 out of 63 (G2/3) patients with G2/3 OC showed mutant p53 and 23 patients showed a wild-type pattern. p53 status was significantly different between these two groups (LMP/G1 vs. G2/3) (P = 0.015). A progressive disease after chemotherapy completion was noted in 35.6% of the patients (26 out of 73); in 69.2%, a mutated p53 and in 30.8%, a wild-type p53 was found. Nine (12.3%) patients showed a complete response at the end of the first-line chemotherapy. Out of these nine patients five had a mutated and four a wild-type p53. A partial response was observed in nine (12.3%) patients of whom four had a mutated p53. With respect to response to first-line chemotherapy (six cycles of platinum containing regimen), the p53 status was not predictive; no statistical significance regarding the p53 mutational status was observed when the two extreme groups PD versus PR/CR were compared (P > 0.05). CONCLUSION: In this study, the p53 mutational status was not predictive for responsiveness to platinum-based chemotherapy; but p53 was significantly more frequently mutated in poorly differentiated OCs.

Carboplatin and paclitaxel in combination with oral enzastaurin in advanced ovarian or primary peritoneal cancer: results from a safety lead-in study.

INTRODUCTION: This safety lead-in study examined the pharmacokinetic and adverse event profile of combining enzastaurin with paclitaxel plus carboplatin as first-line therapy for the treatment of advanced-stage ovarian cancer and primary peritoneal carcinoma. The specific objectives of this study were to assess safety and tolerability after 2 cycles of treatment, to determine if enzastaurin alters paclitaxel and carboplatin pharmacokinetics, and to determine if enzastaurin pharmacokinetics is affected by paclitaxel and carboplatin. METHODS: After debulking surgery, patients with previously untreated epithelial ovarian or primary peritoneal carcinoma received sequential paclitaxel (175 mg/m) and carboplatin (area under the curve, 5 mg x min/mL) on day 1 every 3 weeks for 6 cycles. Patients ingested an oral loading dose of 1125 mg enzastaurin on day 4 of cycle 1, followed by oral 500-mg enzastaurin daily until the end of therapy. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0. RESULTS: There were 5 serious adverse events in 4 of 11 patients: soft tissue injury, wound infection, intestinal fistula, clostridial infection, and anemia. Coadministration with enzastaurin did not significantly alter paclitaxel and carboplatin pharmacokinetics (area under the curve ratio of treatment comparison asymptotically equal to 1.05 and 1.06, respectively). Enzastaurin exposures were unchanged (Cav,ss ratio of treatment comparison asymptotically equal to 0.95 for average steady-state total analyte concentrations of enzastaurin and its metabolite). CONCLUSIONS: Adding enzastaurin to paclitaxel plus carboplatin chemotherapy is feasible for advanced ovarian cancer after radical cytoreduction. Enzastaurin did not alter paclitaxel or carboplatin pharmacokinetics, and enzastaurin exposures were not significantly changed by carboplatin and paclitaxel.

Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation.

New strategies in the therapy for malignant diseases depend on a targeted influence on signal transduction pathways that regulate proliferation, cell growth, differentiation, and apoptosis by the activation of serine/threonine kinases. Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase Cbeta (PKCbeta), is one of these new drugs and causes inhibition of proliferation and induction of apoptosis. Pemetrexed, a multitarget inhibitor of folate pathways, is broadly active in a wide variety of solid tumors. Therefore, the effect of enzastaurin and the combination treatment with pemetrexed was analyzed when applied to the drug-sensitive ovarian cancer cell line HEY and various subclones with drug resistance against cisplatin, etoposide, docetaxel, and paclitaxel, as well as pemetrexed, and gemcitabine. In these novel chemoresistant subclones, the expression of the enzastaurin targets PKCbetaII and glycogen synthase kinase 3beta (GSK3beta) was analyzed. Exposition to enzastaurin showed various inhibitory effects on phosphorylated forms of GSK3beta and the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. Cell proliferation experiments identified the cell line-specific half-maximal inhibitory concentration values of enzastaurin and a synergistic inhibitory effect by cotreatment with the antifolate pemetrexed. Induction of apoptosis by enzastaurin treatment was investigated by Cell Death Detection ELISA and immunoblot analyses. Simultaneous treatment with pemetrexed resulted in an enhanced inhibition of proliferation and induction of apoptosis even in partial enzastaurin-resistant cells. Therefore, the combinational effect of enzastaurin and pemetrexed can have promise in clinical application to overcome the fast-growing development of resistance to chemotherapy in ovarian cancer.

Doxorubicin/pemetrexed followed by docetaxel versus doxorubicin/ cyclophosphamide followed by docetaxel as neoadjuvant treatment for early-stage breast cancer: a randomized phase II trial.

BACKGROUND: Microarray gene expression profiling has indicated that complex molecular gene expression signatures might be predictive of outcome after systemic treatment for early breast cancer. Neoadjuvant systemic therapy (NST) with its assessment of pathologic complete response (pCR), so far the best surrogate parameter for cure, provides a unique opportunity to rapidly identify such molecular predictors. PATIENTS AND METHODS: Currently, an international, randomized phase II study of 2 sequential regimens as NST is being conducted in patients with primary invasive breast cancer T2-4a-c N0-2 M0. Patients receive 4 cycles of doxorubicin/pemetrexed, followed by 4 cycles of docetaxel (AP-Doc) or 4 cycles of doxorubicin/cyclophosphamide, followed by 4 cycles of docetaxel (AC-Doc). Tumor, tissue, blood, and serum are collected at baseline and, if available, after 4 cycles of chemotherapy, and at surgery. The clinical objectives are to assess pCR rate, tumor response, rate of histologically negative axillary lymph nodes, disease-free survival, and safety after NST with AP-Doc or AC-Doc. Translational research objectives include the identification of differentially expressed genes predictive for the achievement of pCR after either treatment regimen. RESULTS: As of January 2007, 178 of the 256 patients planned for this study had been enrolled at 12 European centers. The recommendation after a planned interim safety and efficacy analysis was to continue with the trial as planned. CONCLUSION: We anticipate this study will provide a better understanding of the treatment options with pemetrexed in primary breast cancer and give insight into the practical robustness of the new marker sets in response prediction.

An integrated clinical-genomics approach identifies a candidate multi-analyte blood test for serous ovarian carcinoma.

PURPOSE: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood. EXPERIMENTAL DESIGN: We developed an algorithm to identify secreted proteins encoded among approximately 22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression. RESULTS: We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (<0.5- or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls. CONCLUSIONS: Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.

Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential.

Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12,500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2-G3 groups of tumors was highly correlated to patient outcome (chi(2) for equivalence of death rates=7.681189; P=0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular 'meta-signature' in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.

A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer.

BACKGROUND: Despite considerable improvement in the treatment of advanced ovarian cancer, the optimization of efficacy and tolerability remains an important issue. Therefore, we performed a randomized, phase III non-inferiority trial comparing paclitaxel plus cisplatin (PT) with paclitaxel plus carboplatin (TC) in patients with advanced ovarian cancer. METHODS: A total of 798 patients with International Federation of Gynecology and Obstetrics stage IIB-IV were randomly assigned to receive six courses of either PT or TC at 3-week intervals. The primary endpoint was the proportion of patients without progression at 2 years. Secondary endpoints included toxicity, response to treatment, quality of life, and overall and progression-free survival time. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30, version 2.0. Survival curves were calculated using the Kaplan-Meier method, and hazard ratios were estimated using the Cox proportional hazards model. RESULTS: The proportion of patients without progression at 2 years was not statistically significantly different between the two treatment arms (40.0% for PT versus 37.5% for TC, difference = 2.5%, one-sided 95% confidence interval [CI] = - infinity to 8.2%). Median progression-free survival time in the TC arm (17.2 months, 95% CI = 15.2 to 19.3 months) and the PT arm (19.1 months, 95% CI = 16.7 to 21.5 months) were also not statistically significantly different; the same was true of median overall survival time (43.3 months, 95% CI = 37.2 to 47.8 months versus 44.1 months, 95% CI = 40.2 to 49.4 months, for the TC and PT arms, respectively). The TC regimen was associated with a higher frequency of hematologic toxicity, but a lower frequency of gastrointestinal and neurologic toxicity, than the PT regimen. Mean global quality-of-life scores at the end of treatment were statistically significantly better in the TC arm than in the PT arm (65.25 versus 51.97, respectively; difference = -13.28, 95% CI = -18.88 to -7.68). CONCLUSION: The TC regimen achieved comparable efficacy to the PT regimen but was associated with better tolerability and quality of life, and should, therefore, be considered as an important alternative for standard first-line chemotherapy in patients with advanced ovarian cancer.

Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with progressive cervical cancer.

PURPOSE: Cervical cancer, the second most common malignancy in women worldwide, is almost invariably associated with infection by human papillomavirus (HPV). HPV-16 or -18 is commonly present in 70% of cervical cancers. HPV-positive tumor cells present antigens of the viral protein in the context of human leukocyte antigen (HLA) class I that can be recognized by CTLs. We have conducted a study in patients with early-stage cervical cancer to assess the safety and immunological effects of vaccination with TA-HPV, a live recombinant vaccinia virus expressing modified forms of the HPV-16 and -18 E6 and E7 proteins. EXPERIMENTAL DESIGN: Twenty-nine patients with clinical International Federation of Gynecologists and Obstetricians (FIGO) stage Ib or IIa cervical cancer were given two vaccinations with TA-HPV at least 4 weeks apart, starting 2 weeks before radical hysterectomy. Patients were monitored closely for side effects of the vaccination. Serial blood samples were examined for HPV-specific CTLs or changes in levels of antibodies to HPV-16 or -18 E6 and E7 proteins and to vaccinia virus. RESULTS: Vaccination with recombinant vaccinia was well tolerated in all patients with only mild to moderate local toxicity, and no serious adverse events were attributable to the vaccine. After a single vaccination, HPV-specific CTLs were found in four patients (HLA A1, A3, three patients; HLA A1, A24, one patient). Eight patients developed HPV-specific serological responses. CONCLUSIONS: This study confirmed the safety and immunogenicity of the vaccine in a proportion of those patients vaccinated. Additional clinical studies using TA-HPV in combination with an additional experimental vaccine for HPV-16 are currently under way.

Gene therapy of ovarian cancer.

For the treatment of ovarian cancer, gene therapy is increasingly viewed as the fourth therapeutic concept (in addition to surgery, chemotherapy, and irradiation). Many approaches that use viral and nonviral delivery systems have been employed to introduce genes into tumor cells, thus changing their malignant phenotype. The development of tissue-specific promoters has enhanced the specificity of adenoviral transduction, the most commonly used transfer method. Phase I clinical trials (targeting p53, BRCA1, Her2/neu, Bcl-2, MDR, EIA, and HSV-TK genes) have been performed to test the relative safety of different strategies. Further studies are needed to evaluate the effectiveness of these treatments. New studies must evaluate gene therapy alone and in combination with cytostatic regimens because preclinical studies have shown the chemosensitizing effects of several target genes. The increasing knowledge about the genetic background of ovarian cancer will provide many targets for novel gene therapy approaches.

Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial.

Dendritic cell (DC)-based therapy has proven to be effective in patients with malignant lymphoma, melanoma, and renal and prostate carcinoma. In this phase I clinical trial, we have shown that patients with advanced gynaecological malignancies can be effectively vaccinated with DC pulsed with keyhole limpet haemocyanin (KLH) and autologous tumour antigens. Two patients with uterine sarcoma and six subjects with ovarian carcinoma received three to 23 intracutaneous injections of antigen-pulsed DC at 10-day or 4-week intervals. Three patients showed stable disease lasting 25 to 45 weeks, and five experienced tumour progression within the first 14 weeks. KLH- and tumour lysate-specific delayed-type hypersensitivity (DTH) reactions were observed in six and one patient, respectively. Lymphoproliferative responses to KLH and to tumour lysate stimulation were recorded in six patients and in two patients respectively. Tumour antigen-stimulated interferon-gamma (IFN-gamma) secretion by peripheral blood mononuclear cells (PBMC) in one patient was consistent with a T(H) type 1 cytokine bias. The treatment was safe, well tolerated, immunologically active and except for local cutaneous hypersensitivity devoid of significant adverse effects.