Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial.

BACKGROUND: Progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PROs) were significantly improved by adding bevacizumab to chemotherapy for platinum-resistant ovarian cancer (PROC) in the phase III AURELIA trial. We explored treatment outcomes according to primary platinum resistance (PPR) versus secondary platinum resistance (SPR). PATIENTS AND METHODS: Patients were categorized as PPR (disease progression <6 months after completing first-line platinum therapy) or SPR (progression ≥6 months after first platinum but <6 months after second). The exploratory Cox and logistic regression analyses correlated PFS, ORR, overall survival (OS), and PROs with the time to development of platinum resistance. RESULTS: Baseline characteristics were similar in patients with PPR (n = 262; 73%) and SPR (n = 99; 27%), although ascites were more common in the PPR subgroup. In bevacizumab-treated patients (n = 179), SPR was associated with improved PFS (median 10.2 versus 5.6 months in PPR patients; P < 0.001) and OS (median 22.2 versus 13.7 months, respectively; P < 0.001) but not PROs (22% versus 22% with improved abdominal/gastrointestinal symptoms at week 8/9). In multivariate analyses, SPR remained an independent prognostic factor for better PFS [adjusted hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.25-0.67; P < 0.001] and OS (HR 0.49, 95% CI 0.30-0.80; P = 0.005) in bevacizumab-treated patients, but was not statistically significant for either end point in the chemotherapy-alone subgroup. The magnitude of PFS benefit from bevacizumab appeared greater in SPR than PPR patients (HR 0.30 versus 0.55, respectively; interaction P = 0.07) with a similar direction of effect for OS (interaction P = 0.18). CONCLUSIONS: In bevacizumab-treated patients, PFS and OS were more favorable in SPR than PPR patients with equally improved PROs. The PFS and OS benefit from combining bevacizumab with chemotherapy was more pronounced in SPR than PPR PROC. PPR versus SPR should be a stratification factor in future trials evaluating anti-angiogenic therapy for PROC.

Poor concordance between CA-125 and RECIST at the time of disease progression in patients with platinum-resistant ovarian cancer: analysis of the AURELIA trial.

BACKGROUND: Data on CA-125 as a predictor of disease progression (PD) in ovarian cancer come predominantly from patients with platinum-sensitive disease receiving chemotherapy alone. We assessed concordance between CA-125-defined and RECIST-defined PD using data from the Gynecologic Cancer InterGroup (GCIG) randomized phase III AURELIA trial in platinum-resistant ovarian cancer (PROC). PATIENTS AND METHODS: Patients with PROC were randomized to receive single-agent chemotherapy with or without bevacizumab. PD by CA-125 was defined according to GCIG criteria (except that confirmatory CA-125 measurement was not required). This exploratory analysis included patients with RECIST PD and a CA-125 reading ≤28 days before and ≤21 days after RECIST-defined PD. RESULTS: Of 218 eligible patients, only 94 (43%, 95% confidence interval 36% to 50%) had concordant RECIST and CA-125 PD status (42% in the chemotherapy-alone arm; 45% in the bevacizumab combination arm, P = 0.6). There was no evidence of CA-125-defined PD in the remaining 124 patients despite PD according to imaging. There were no significant differences in baseline characteristics between patients with PD defined by both RECIST and CA-125 and those with RECIST-only PD. CA-125 was even less sensitive in detecting PD in patients with early (<8 weeks after randomization) compared with later RECIST-defined PD (69% versus 53%, respectively, not meeting CA-125 criteria; P = 0.053). There was no significant difference in survival after PD in patients with concordant PD by RECIST and CA-125 versus those with PD only by RECIST. We validated our findings in an independent study population of PROC. CONCLUSIONS: In this platinum-resistant population, PD was typically detected earlier by imaging than by CA-125, irrespective of bevacizumab treatment. Disease status by CA-125 at the time of PD was not prognostic for overall survival. Regular radiologic assessment as well as symptom benefit assessment should be considered during PROC follow-up.

A prognostic nomogram to predict overall survival in patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.

Removal of APIs and bacteria from hospital wastewater by MBR plus O(3), O(3) + H(2)O(2), PAC or ClO(2).

The objective of this study has been to develop technologies that can reduce the content of active pharmaceutical ingredients (APIs) and bacteria from hospital wastewater. The results from the laboratory- and pilot-scale testings showed that efficient removal of the vast majority of APIs could be achieved by a membrane bioreactor (MBR) followed by ozone, ozone + hydrogen peroxide or powdered activated carbon (PAC). Chlorine dioxide (ClO(2)) was significantly less effective. MBR + PAC (450 mg/l) was the most efficient technology, while the most cost-efficient technology was MBR + ozone (156 mg O(3)/l applied over 20 min). With MBR an efficient removal of Escherichia coli and enterococci was measured, and no antibiotic resistant bacteria were detected in the effluent. With MBR + ozone and MBR + PAC also the measured effluent concentrations of APIs (e.g. ciprofloxacin, sulfamethoxazole and sulfamethizole) were below available predicted no-effect concentrations (PNEC) for the marine environment without dilution. Iodinated contrast media were also reduced significantly (80-99% for iohexol, iopromide and ioversol and 40-99% for amidotrizoateacid). A full-scale MBR treatment plant with ozone at a hospital with 900 beds is estimated to require an investment cost of €1.6 mill. and an operating cost of €1/m(3) of treated water.

Pelvic exenteration for vulvar cancer: Postoperative morbidity and oncologic outcome - A single center retrospective analysis.

BACKGROUND: Pelvic exenteration may be the only curative treatment for some patients with primary advanced or recurrent vulvar cancer but is associated with high morbidity. This study evaluated the clinical outcome of patients treated at a centralized service in Norway. METHODOLOGY: This retrospective study included patients treated with pelvic exenteration for primary locally advanced or recurrent vulvar cancer between 1996 and 2019 at Oslo University Hospital, Norway. Complications were coded according to the contracted Accordion classification. Relapse free survival (RFS), cancer specific survival (CSS) and overall survival (OS) were estimated with the Kaplan Meier method. RESULTS: The 30 patients were followed for a median of 4.94 years (95%CI: 3.37-NR). Exenteration due to primary vulvar cancer was carried out in 16 (53%) patients, 14 (47%) had recurrent vulvar cancer. Free histopathological margins were achieved in 28 (93%) patients. The 90 days morbidity for grade 3 complications was 63%, predominantly wound/surgical flap infections, 7% had no complications. 90 days mortality was 3%. Five-year RFS was 26% (95% CI 8-48%), OS was 50% (95%CI: 29-69%) and CSS was 64% (95% CI 43-79%). There was no significant difference in survival between patients with primary vs recurrent disease. The 3-year CSS for patients with negative lymph nodes and positive lymph nodes was 70% (95% CI 47-84%) and 30% (95% CI 1-72%), respectively. CONCLUSIONS: Acceptable oncologic outcomes after pelvic exenteration for primary and recurrent vulvar cancer can be achieved if surgery is centralized. Careful patient selection is imperative due to significant postoperative morbidity and considerable risk of relapse.

Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours.

BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m(-2) q3w, paclitaxel 80 mg m(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m(-2) q3w. The primary endpoint was safety/tolerability. RESULTS: A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ≥3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; ≥225 mg, 33%), and grade ≥3 neutropenia occurred more commonly at doses ≥225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w. CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.

Prognostic importance of DNA ploidy and DNA index in stage I and II endometrioid adenocarcinoma of the endometrium.

BACKGROUND: We evaluated the prognostic importance of DNA ploidy in stage I and II endometrioid adenocarcinoma (EAC) of the endometrium with a focus on DNA index. PATIENTS AND METHODS: High-resolution DNA ploidy analysis was carried out in tumor material from 937 consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) stage I and II EAC of the endometrium. RESULTS: Patients with diploid (N = 728), aneuploid tumor with DNA index ≤ 1.20 (N = 118), aneuploid tumors with DNA index >1.20 (N = 39) and tetraploid tumor (N = 52) had 5-year recurrence rates 8%, 14%, 20% and 12%, respectively. Patients with aneuploid tumor with DNA index >1.20 had a poorer 5-year progression-free survival (67%) and overall survival (72%) compared with the patients with aneuploid tumor with DNA index ≤ 1.20 (81% and 89%, respectively). Aneuploid tumors with DNA index ≤ 1.20 relapsed mainly in the vagina and pelvis, whereas aneuploid tumors with DNA index >1.20 relapsed predominantly outside pelvis. CONCLUSIONS: The recurrence risk for the patients with aneuploid tumor is higher than the patients with diploid tumor in EAC of the endometrium. Based on DNA index with cut-off 1.20, aneuploid tumors can be separated into two subgroups with different recurrence pattern and survival.

First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)--a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG.

BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.

The prognostic value of DNA ploidy in a total population of uterine sarcomas.

BACKGROUND: The diagnosis of uterine sarcoma is associated with poor outcome for the patient and there is a need for reliable prognostic markers. Most previous studies on the prognostic value of DNA ploidy include few uterine sarcomas and report conflicting results. MATERIALS AND METHODS: We examined the prognostic value of DNA ploidy and its association with clinicopathological parameters and crude survival in a total population of 354 sarcoma. RESULTS: In univariate analyses, we observed significantly better crude survival for endometrial stromal sarcomas (ESS) and adenosarcoma (AS) patients with diploid as compared with nondiploid tumors, but not for patients with leiomyosarcomas (LMS). In Cox multivariate analyses, DNA ploidy was the only significant predictor of survival for patients with AS. In LMS, mitotic index (MI), tumor size, tumor extent and tumor margins, whereas for ESS, MI, tumor extent and tumor necrosis obtained independent significance of survival. DNA ploidy was a significant predictor of survival for LMS patients in Cox regression analyses when excluding MI. CONCLUSION: DNA ploidy might be useful as a prognostic marker in patients with LMS and AS.

Hyperbaric oxygen therapy for late radiation tissue injury in gynaecological patients.

BACKGROUND: Pelvic radiation therapy is an important element of curative therapy for gynaecological cancers. Serious radiation-related complications developing months or years after treatment are known as late radiation tissue injury (LRTI). METHODS: We investigated the possible pain reducing effect of hyperbaric oxygen treatment (HBOT) in a study of 16 patients with LRTI after radiation for gynaecological malignancy. The 16 patients were registered prospectively, underwent HBOT for 21 consecutive days and were followed for a 6-month period after treatment using the Brief Pain Inventory, Montgomery and Aasberg Depression Rating Scale, as well as registration of global patient scores, analgesic consumption and magnetic resonance imaging (MRI) findings. RESULTS: HBOT was shown to have insignificant effect on pain, pain characteristics, daily function, the use of analgesics and MRI-related tissue injury. Fifty percent of the patients still reported some or good effect of the treatment. CONCLUSION: It is not possible to conclude from our study if gynaecological patients with pelvic pain will benefit from HBOT. The application of HBOT to selected patients may be justified, but further research with adequate sample size, as well as the timing of HBOT related to the development of LRTI, is required to establish the optimum patient selection.

Rare ovarian tumours: Epidemiology, treatment challenges in and outside a network setting.

PURPOSE OF THE REVIEW: More than 50% of all gynaecological cancers can be classified as rare tumours (defined as an annual incidence of <6 per 100,000) and such tumours represent an important challenge for clinicians. RECENT FINDINGS: Rare cancers account for more than one fifth of all new cancer diagnoses, more than any of the single common cancers alone. Reviewing the RARECAREnet database, some of the tumours occur infrequently, whilst others because of their natural history have a high prevalence, and therefore appear to be more common, although their incidence is also rare. Harmonization of medical practice, guidelines and novel trials are needed to identify rare tumours and facilitate the development of new treatments. Ovarian tumours are the focus of this review, but we comment on other rare gynaecological tumours, as the diagnosis and treatment challenges faced are similar. FUTURE: This requires European collaboration, international partnerships, harmonization of treatment and collaboration to overcome the regulatory barriers to conduct international trials. Whilst randomized trials can be done in many tumour types, there are some for which conducting even single arm studies may be challenging. For these tumours alternative study designs, robust collection of data through national registries and audits could lead to improvements in the treatment of rare tumours. In addition, concentring the care of patients with rare tumours into a limited number of centres will help to build expertise, facilitate trials and improve outcomes.

Chronic fatigue and its correlates in long-term survivors of cervical cancer treated with radiotherapy.

OBJECTIVE: To describe the prevalence of chronic fatigue (CF) and associated variables in locoregional cervical cancer survivors (CCSs) surveyed > 5 years after radiotherapy. Demographic, clinical and psychological characteristics of the CCSs were compared with normative data. DESIGN: Cross-sectional study. SETTING: Department of Gynaecologic Oncology at Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway. POPULATION: Seventy-nine CCSs aged < or = 79 years, treated between 1994 and 1999, representing 62% of those invited. Normative data were based on various population studies of Norwegian women. METHODS: Data were collected by means of a mailed questionnaire, which included demographic variables and instruments covering fatigue, mental distress, sexual functioning, somatic impairments and quality of life (QOL). MAIN OUTCOME MEASURES: Self-reported fatigue score and caseness of CF based on the fatigue questionnaire. RESULTS: CCSs showed 30% CF versus 13% reported in the general population (P= 0.001). CCSs with CF had a significantly lower QOL, higher levels of anxiety and depression and more physical impairments than those without CF. In a multivariable regression model, depression was the only variable significantly associated with CF in CCSs. CONCLUSIONS: More CCSs have CF than age-matched women in the general population. CF should be of clinical concern since these women also frequently have treatable mental and physical problems.

Expression of apoptosis-related proteins is an independent determinant of patient prognosis in advanced ovarian cancer.

PURPOSE: The present study was undertaken to investigate the prognostic and predictive relevance of the expression of apoptosis-related proteins Bax, Bcl-X(L), and Mcl-1 in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsies from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for the expression of Bax, Bcl-X(L) and Mcl-1 proteins. Their prognostic relevance was examined in a uni- and multivariate survival analysis. RESULTS: Sixty-six percent of cancer cases expressed Bax, 62% Bcl-X(L), and 53% Mcl-1. The expression of Bax correlated with tumor differentiation (P: =.016) and less residual disease after surgery (P <.0001). In univariate analysis, Bax expression was associated with improved (P =.0004) prognosis and Mcl-1 expression with poorer (P =.011) prognosis. None of the factors studied was of independent prognostic significance by itself, but when Bax and Bcl-2 expression data were considered together, this combined variable was of independent prognostic significance (P =.0115), together with residual disease status (P =.0016), differentiation grade (P =.0014), and the presence of ascites (P =.0122). Patients with a long median survival (104 months) could be discriminated from those with a short one (16 months) by combining the individual patients' expression data for p53, Bax, and Bcl-2 with their residual disease status (P <.00001). None of the factors studied was able to predict response to chemotherapy. CONCLUSION: The expression of selected apoptosis-related proteins is of independent prognostic significance and may be helpful in a molecular substaging of patients with stage III ovarian cancer.

Phase I/II trial of the multidrug-resistance modulator valspodar combined with cisplatin and doxorubicin in refractory ovarian cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of doxorubicin when given in combination with cisplatin and the multidrug-resistance (MDR) modulator valspodar and the remission rate induced by this combination in patients with platinum- and anthracycline-resistant ovarian cancer. PATIENTS AND METHODS: Fifty-nine patients who had failed prior platinum- and anthracycline-based chemotherapy were enrolled. During the dose-finding phase, patients received a loading dose of valspodar (1.5 or 2 mg/kg) via 2-hour intravenous (IV) infusion on day 1 and continuous IV infusion (CIVI) of valspodar (2, 4, or 10 mg/kg/d) over 3 days. Doxorubicin (starting from 20 up to 50 mg/m(2)) and cisplatin (50 mg/m(2)) were administered via 15- to 20-minute IV infusions on day 3. During the efficacy phase, patients received at least two treatment cycles unless toxicity was unacceptable, and responding patients and those with stable disease received four to six cycles. RESULTS: All patients completed at least one cycle of combined treatment. The MTD of doxorubicin was determined to be 35 mg/m(2) when administered with valspodar at 2 mg/kg loading dose and 10 mg/kg/d CIVI plus 50 mg/m(2) cisplatin. At these doses, valspodar blood concentrations known to reverse MDR in vitro were reached in all patients. Valspodar was well tolerated at all dose levels. Dose-limiting toxicities of the combination were primarily hematologic and included febrile neutropenia and prolonged leucopenia. The addition of valspodar to the treatment did not worsen cisplatin-related toxicity. Among 33 patients treated at the MTD for doxorubicin, one (3%) had a complete response, and four (12%) had a partial response. An additional seven patients experienced a stabilization of their previously progressive disease. The survival rates at 6 and 12 months were 59% and 19%, respectively. CONCLUSION: Valspodar can be safely coadministered with doxorubicin and cisplatin. Although the regimen used in this trial produced renewed responses in patients with heavily pretreated, refractory ovarian cancer, the value of valspodar in reversing resistance mediated by P-glycoprotein remains to be determined.

Clinical significance of apoptosis-related factors p53, Mdm2, and Bcl-2 in advanced ovarian cancer.

PURPOSE: To investigate the prognostic and predictive relevance of p53, Mdm2, and Bcl-2 protein expression in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsy specimens from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for expression of p53, Mdm2, and Bcl-2 proteins. Both uni- and multivariate analyses of prognostic factors were performed, and correlations with classical clinicopathologic parameters and response to chemotherapy were examined. RESULTS: Forty-nine percent and 39% of cases were considered positive for expression of p53 and Bcl-2, respectively. p53 expression was correlated with loss of histologic differentiation and Bcl-2 expression with smaller residual disease after primary surgery. The absence of p53 expression and the presence of Bcl-2 expression were associated with improved survival but not with overall response to chemotherapy, although a positive correlation was found between Bcl-2 expression and the possibility of obtaining a completely negative second-look laparotomy. Expression of Mdm2 was found in 17% of cases. Although correlations were found with known favorable clinicopathologic factors, no prognostic significance was demonstrated for Mdm2 in this patient group. In multivariate analyses, histologic type, degree of differentiation, residual disease, and p53 alone or combined with Bcl-2 expression were found to be independently associated with overall survival. CONCLUSION: p53, and especially the combination of p53 and Bcl-2 expression data, represents an independent prognostic predictor in stage III ovarian cancer. Despite their role in the apoptotic process, p53 and Bcl-2 do not seem to be clinically useful predictors of response to combination chemotherapy in these patients.

Randomized trial of recombinant human interleukin-3 versus placebo in prevention of bone marrow depression during first-line chemotherapy for ovarian carcinoma.

PURPOSE: To determine whether recombinant human interleukin-3 (rhIL-3) reduces bone marrow depression and improves chemotherapeutic schedule adherence in ovarian cancer patients receiving first-line combination chemotherapy. PATIENTS AND METHODS: In a randomized multicenter study, 185 patients received carboplatin (dose based on projected area under the concentration-time curve [AUC]=4) and cyclophosphamide (750 mg/m2) day 1, every 3 weeks for six cycles. Patients were randomized to receive rhIL-3 (5 microg/kg) or placebo once daily subcutaneously on days 3 to 12. RESULTS: Adherence to chemotherapeutic regimen, mean chemotherapy cycle length, tumor response rate, and median survival at 24 months did not differ between groups. The number of side effects-primarily allergic reactions, flu-like symptoms and fever-were higher in the rhIL-3 group, which resulted in 21 discontinuations compared with one in the placebo group. Compared with placebo, the rhIL-3 group had higher platelet counts day 1 of cycles 2 to 6. The number of patients with World Health Organization (WHO) grade IV thrombocytopenia or number of platelet transfusions did not differ. Leukocyte counts differed only in cycles 1 and 2 between groups. The leukocyte nadir occurred earlier in the rhIL-3 (day 12) than in the placebo group (day 15, P=.006). Leukocytes and neutrophils were only higher in the rhIL-3 group day 1 of cycle 2. In cycles 4 and 5, more patients with WHO grade IV neutropenia received rhIL-3 (P < .005). Eosinophil counts were higher day 1 of cycles 2 to 6 in the rhIL-3 group (P < .0001). CONCLUSION: rhIL-3 had stimulatory hematopoietic effects. This did not result either in reduction of platelet transfusions or in improvement of chemotherapeutic schedule adherence. There were more side effects in the rhIL-3 group than in the placebo group. rhIL-3 at 5 microg/kg/d is, therefore, not of clinical benefit in this chemotherapeutic regimen.

Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial.

BACKGROUND: Despite improvements in the treatment of ovarian cancer, most patients develop recurrent disease within 3 years of diagnosis. There is no agreed second-line treatment at relapse. We assessed paclitaxel plus platinum chemotherapy as such treatment. METHODS: In parallel international, multicentre, randomised trials, between January, 1996, and March, 2002, 802 patients with platinum-sensitive ovarian cancer relapsing after 6 months of being treatment-free were enrolled from 119 hospitals in five countries. Patients were randomly assigned paclitaxel plus platinum chemotherapy or conventional platinum-based chemotherapy. Analysis was by intention to treat, except for toxic effects. FINDINGS: With a median follow-up of 42 months, 530 patients have died. Survival curves showed a difference in favour of paclitaxel plus platinum (hazard ratio 0.82 [95% CI 0.69-0.97], p=0.02), corresponding to an absolute difference in 2-year survival of 7% between the paclitaxel and conventional treatment groups (57 vs 50% [95% CI for difference 1-12]), and median survival of 5 months (29 vs 24 months [1-11). 717 patients developed progressive disease or died. The progression-free survival curves show a difference in favour of paclitaxel plus platinum (hazard ratio 0.76 [0.66-0.89], p=0.0004), corresponding to an absolute difference in 1-year progression-free survival of 10% (50 vs 40% [4-15]) and in median progression-free survival of 3 months (13 vs 10 months [1-5]). INTERPRETATION: Paclitaxel plus platinum chemotherapy seems to improve survival and progression-free survival among patients with relapsed platinum-sensitive ovarian cancer compared with conventional platinum-based chemotherapy.

Markers of apoptosis in stage IB squamous cervical carcinoma.

AIMS: To examine the prognostic relevance of the expression of the Bcl-2, Bcl-xL, and Bax proteins in stage IB squamous cervical carcinoma (SCC). METHODS: In total, 220 patients who underwent radical hysterectomy and bilateral lymphadenectomy at the Norwegian Radium Hospital for stage IB SCC between 1987 and 1993 were studied. Immunohistochemistry using monoclonal antibodies against Bcl-2, Bcl-xL, and Bax was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls. RESULTS: Cytoplasmic expression of Bcl-2, Bcl-xL, and Bax was low (< 5% positive cells) in 159 of 220 (73%), 193 of 220 (87%), and 39 of 220 (18%) tumours, respectively, and high (> or = 5% positive cells) in 61 of 220 (27%), 27 of 220 (13%), and 181 of 220 (82%) tumours, respectively. In univariate analysis, all classic clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival. CONCLUSION: Bcl-2, Bcl-xL, and Bax were not independently associated with prognosis in stage IB SCC.

Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study.

The eukaryotic cell cycle is controlled by protein complexes consisting of cyclin-dependent kinases and cyclins. The cyclin-dependent kinases are in turn negatively regulated by a family of cyclin-dependent kinase inhibitors, comprising, among others, the p21 and p27 proteins. p21 and p27 have been shown to be of prognostic significance in a broad array of human tumors. Using immunohistochemistry, the frequency of expression and the possible prognostic and predictive significance of these proteins were examined in a series of 185 uniformly treated patients with stage III ovarian cancer. We found p21 to be overexpressed in 48% of cases. No significant correlation was found between the expression of p21 and p53 proteins (P = 0.273). A low level of p27 was demonstrated in 48.5% of cases. p21 overexpression correlated with lower Fédération Internationale des Gynaecologistes et Obstetristes substage, lower patient age, and absence of ascites, but neither p21 nor p27 expression was of prognostic significance for the whole group of patients. Only a trend toward reduced survival (P = 0.092) was noticed for the small subgroup of patients (6%), whose tumors lacked p27 expression completely. A clear positive correlation could be found between p21 and p27 protein expression (P = 0.012). Despite the suggested role of the 21 and p27 proteins in determining drug sensitivity, they were not found to be predictive for response to chemotherapy, as assessed by second-look laparotomy in this large group of patients with advanced ovarian cancer.