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Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p

This study aims to evaluate oncological outcomes in women affected by locally advanced cervical cancer (LACC) treated by neoadjuvant chemotherapy before radical surgery (NACT + RS) or concurrent chemo-radiotherapy (CCRT).This was a multicenter retrospective analysis of data related to women with LACC (FIGO stage IB2-IVA), who were treated by NACT + RS or CCRT between November 2006 and January 2018. The first endpoints were the evaluation of disease-free survival (DFS) and overall survival (OS); univariate and multivariate analyses were performed for identifying the prognostic factors independently associated with these oncological outcomes.Overall, 106 women were included in the analysis; 55 of them (51.9%) underwent NACT + RS and 51 (48.1%) CCRT, respectively. Patients in the NACT + RS group had a significant better five-year DFS and five-year OS than those in the CCRT group (77.4% vs. 33.4%,This retrospective study demonstrated an improved survival outcome for patients undergoing NACT + RS compared with those undergoing CCRT. Our findings seem to support the use of NACT before RS as an effective alternative option to CCRT standard therapy.

Paraganglioma is one of the rarest neoplasms involving the ovary, with only 10 previous reports. We present a case of peritoneal carcinomatosis from primary ovarian paraganglioma and a systematic review of the literature. Clinical information was retrieved from medical records, and a systematic review of the literature was performed according to meta-analysis of observational studies in epidemiology guidelines. A 33-year-old woman presented with a 12-month history of hypertension and weight loss. She was diagnosed with ovarian paraganglioma and was treated with extensive debulking surgery to no residual disease after three cycles of neoadjuvant chemotherapy. She recurred after 6 months and was started on somatostatin-analogue. Following further disease progression with bone metastasis (treated with palliative radiotherapy), a trial with Sunitinib was started. The patient died 30 months after initial diagnosis. Of the cases reported to date, only one had peritoneal metastasis at presentation but none of them had such an ominous prognosis. Ovarian paraganglioma is an extremely rare condition. We report the first case of primary malignant ovarian paraganglioma with an exceptionally aggressive behavior. Clinicopathological correlation with immunohistochemistry is essential to avoid misdiagnosis. A standard treatment is not recommended yet but cytoreductive surgery seems to be a favorable approach to prolong survival.

Hidradenocarcinoma (HC) is a very rare disease. This case report illustrates a successful treatment of a 60-year-old woman with vulvo-vaginal localization of hidradenocarcinoma treated with external beam radiotherapy delivered by helical tomotherapy with a simultaneous integrated boost (SIB), followed by brachytherapy. External beam radiotherapy dose prescription was 50.4 Gy in 28 fractions, five fractions per week to whole pelvis (planning target volume 1 – PTV1), 60.2 Gy in 28 fractions to SIB1 (fundus of uterus and right inguinal node), and 58.8 Gy in 28 fractions to SIB2 (lower/middle third of vagina, paraurethral region and right inguinal lymph nodes). Brachytherapy dose prescription was 28 Gy in 4 fractions for cervix, fundus of uterus and upper third of vagina (HR-CTV1), and 22 Gy in 4 fractions to middle third of vagina and paraurethral region (HR-CTV2). D90 for whole treatment was 91.9 Gy and 86.0 Gy for HR-CTV1 and HR-CTV2, respectively. Patient remained 12-months disease-free without treatment related side effects.

Background Brain metastases (BM) from epithelial ovarian cancer (EOC) are considered a rare and unfavourable event. There is no consensus regarding the best management of these patients. Methods A multicenter retrospective analysis of patients with BM from EOC treated between 1997 and 2014 in 18 institutions of the MITO (Multicenter Italian Trials in Ovarian cancer) group was conducted. Univariate and multivariate analysis were performed. Results A total of 174 women were identified as having BM from EOC. The median time interval between primary diagnosis of EOC and occurrence of BM was 26months (range 2–129months). The median overall survival from primary EOC diagnosis was 48months (95% CI 39.5–56.4months) and from diagnosis of BM was 12months (95% CI 9.6–14.3months). The majority of enrolled women (81.7%) were classified as sensitive to platinum-based chemotherapy. Four variables were significantly associated with poor overall survival in multivariate analysis: multiple BM [HR: 1.86 (95% CI: 1.22–2.84)], presence of extracranial disease [HR: 1.77 (95% CI: 1.11–2.83)] age [HR: 1.74 (95% CI: 1.17–2.59)], and monotherapy [HR: 2.57 (95% CI: 1.64–3.86)]. On the contrary, residual tumor at primary surgery, FIGO stage at primary diagnosis and platinum sensitivity were found to have no significant impact on survival from diagnosis of brain lesions. Conclusions Our results suggest that BM is a rare and late manifestation of EOC, with a 12-month life-span expectation. Multiple approach is a positive independent prognostic factor and should be proposed to carefully selected patients.

BACKGROUND In this randomized phase 2 study, the authors assessed the efficacy and safety of intravenous aflibercept at 2 different doses (2 mg/kg or 4 mg/kg) in patients with recurrent, platinum-resistant ovarian, peritoneal, or fallopian tube cancer who developed disease progression after receiving topotecan and/or pegylated liposomal doxorubicin. METHODS Patients were randomized to receive intravenous aflibercept at a dose of either 2 mg/kg or 4 mg/kg every 2 weeks until they developed disease progression or significant toxicity. The primary endpoint was to evaluate Response Evaluation Criteria in Solid Tumor response rates (overall response rate [ORR] = complete responses plus partial responses) and to test the null hypothesis (ORR, >5%). Secondary endpoints included time to tumor progression, safety, progression-free survival/overall survival, drug pharmacokinetics, and immunogenicity. In total, 67 evaluable patients per cohort were planned based on a Simon 2-stage design, and, if those patients responded, then enrollment could extend to 200 patients. Tumor radiographic response was assessed by investigators and by an independent review committee. RESULTS After the first 84 evaluable patients, 8 unconfirmed partial responders were noted (ORR, 10%) across both arms; the Independent Data Monitoring Committee recommended continuing blinded accrual. At study completion, 215 evaluable patients were accrued, including 1 responder of 106 patients (0.9%) in the 2-mg/kg cohort and 5 responders of 109 patients (4.6%) in the 4-mg/kg cohort according to the independent review committee. The clinical benefit rate (ORR plus stable disease >6 months) was 12.3% and 11% in the 2-mg/kg and 4-mg/kg cohorts, respectively. Treatment-related grade 3 and 4 adverse events included hypertension (25.5% and 27.5% in the 2-mg/kg and 4-mg/kg cohorts, respectively), proteinuria (9.4% and 7.3%, respectively), and fatigue (5.7% and 3.7%, respectively). The gastrointestinal perforation rate was low (3 patients; 1.4%). CONCLUSIONS Aflibercept at a dose of either 2 mg/kg or 4 mg/kg was generally well tolerated but did not meet the primary endpoint for response. Cancer 2014;120:335–343. © 2013 American Cancer Society.

OBJECTIVE: The recombinant fusion protein, aflibercept binds and neutralizes vascular endothelial growth factor (VEGF) A, B and placental growth factor (PlGF). Aflibercept inhibits ascites formation and reduces tumor burden in an ovarian cancer model. This open-label, single-arm, multicenter phase II study assessed the efficacy and safety of aflibercept in patients with advanced chemo-resistant epithelial ovarian cancer and symptomatic malignant ascites. METHODS: Patients who required≥3 previous paracenteses at 1-4 paracenteses per month received intravenous aflibercept 4mg/kg every 2weeks. The primary endpoint was repeat paracentesis response rate (RPRR), with response defined as at least a two-fold increase in time to repeat paracentesis compared with the baseline interval. RESULTS: Ten out of 16 enrolled patients achieved a response; the RPRR was 62.5% (95% CI 35.4%-84.8%). Aflibercept was considered effective based on a hypothesis that the RPRR was ≥60%. Median time to repeat paracentesis was 76.0 (95% CI 64.0-178.0) days, which was 4.5 times longer than the baseline interval (16.8days). Median progression-free survival was 59.5 (95% CI 41.0-83.0) days. Twelve patients experienced adverse events considered related to aflibercept treatment including hypertension (7 patients), headache, anorexia, and dysphonia (3 patients each). Two patients experienced Grade 3/4 treatment-related adverse events (Grade 3 hypertension and weight loss in one patient, Grade 3 intestinal perforation in one patient). CONCLUSION: Aflibercept 4mg/kg every 2weeks was effective at controlling malignant ascites, reducing the interval between repeat paracenteses. The safety profile was consistent with that reported for anti-VEGF agents. Objective: The recombinant fusion protein, aflibercept binds and neutralizes vascular endothelial growth factor (VEGF) A, B and placental growth factor (PlGF). Aflibercept inhibits ascites formation and reduces tumor burden in an ovarian cancer model. This open-label, single-arm, multicenter phase II study assessed the efficacy and safety of aflibercept in patients with advanced chemo-resistant epithelial ovarian cancer and symptomatic malignant ascites. Methods: Patients who required ≥ 3 previous paracenteses at 1-4 paracenteses per month received intravenous aflibercept 4 mg/kg every 2 weeks. The primary endpoint was repeat paracentesis response rate (RPRR), with response defined as at least a two-fold increase in time to repeat paracentesis compared with the baseline interval. Results: Ten out of 16 enrolled patients achieved a response; the RPRR was 62.5% (95% CI 35.4%-84.8%). Aflibercept was considered effective based on a hypothesis that the RPRR was ≥ 60%. Median time to repeat paracentesis was 76.0 (95% CI 64.0-178.0) days, which was 4.5 times longer than the baseline interval (16.8 days). Median progression-free survival was 59.5 (95% CI 41.0-83.0) days. Twelve patients experienced adverse events considered related to aflibercept treatment including hypertension (7 patients), headache, anorexia, and dysphonia (3 patients each). Two patients experienced Grade 3/4 treatment-related adverse events (Grade 3 hypertension and weight loss in one patient, Grade 3 intestinal perforation in one patient). Conclusion: Aflibercept 4 mg/kg every 2 weeks was effective at controlling malignant ascites, reducing the interval between repeat paracenteses. The safety profile was consistent with that reported for anti-VEGF agents. © 2012 Elsevier Inc. All rights reserved.

Objectives The aim of the present report is to support the feasibility and the safety of a new fertility-sparing treatment in young women affected by bulky cervical cancer. Methods Between February 2007 and October 2010, seven patients presenting large IB–IIA1 tumors (30–45mm) were scheduled for conservative treatment. All patients underwent neoadjuvant chemotherapy (NACT) followed by laparoscopic pelvic lymphadenectomy and vaginal radical trachelectomy (VRT). Results One patient presented hematological toxicity during NACT (grade 3). All patients showed complete disappearance of tumor (n=4/7) or partial response (a 50% or more decrease in total tumor size, n=3/7) to neoadjuvant treatment, and they were all treated with pelvic lymphadenectomy and VRT. Additional treatment (interstitial brachytherapy) was offered to only one woman because of a persistent parametrial tumoral lesion. After a mean follow up of 22months (range 5–49), no relapse was observed. To date, only one woman in our study attempted to conceive and she is currently pregnant. Conclusions Neoadjuvant chemotherapy for fertility sparing treatment is an innovative approach which is potentially quite interesting for many young women affected by bulky cervical cancer. These women, i.e. those with tumors larger than 2cm (2–5cm), are traditionally not offered fertility sparing treatment, thus the preliminary data we report here might have a promising impact. Nevertheless, for these patients it may be suitable to use the more radical, and time-tested, conservative surgical approach to allow for a complete and conservative excision of the residual tumor after neoadjuvant treatment. Studies with a larger number of patients and adequate follow-up are required to validate this conservative approach and to define clearly the good indications for this treatment.

Background: asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF), an agent selectively damaging the tumour vasculature, showed a biphasic dose–response curve in preclinical models. Previous phase I trials of NGR-hTNF indicated 0.8 and 45 μg/m2 as optimal biological and maximum-tolerated dose, respectively. Patients and methods: Two sequential cohorts of 12 colorectal cancer (CRC) patients who had failed standard therapies received NGR-hTNF 0.8 or 45 μg/m2 in combination with capecitabine–oxaliplatin (XELOX). Results: Median number of prior treatment lines was 3 in the low-dose and 2 in the high-dose cohort. Overall, 21 patients had been pretreated with oxaliplatin-based regimens. No grade 3–4 NGR-hTNF-related toxicities were observed. Grade 1–2 chills were reported in 43% and 40% of cycles in the low-dose and high-dose cohorts, respectively. In the low-dose cohort, one patient achieved a partial response and five had stable disease for a median of 4.6 months. In the high-dose cohort, six patients had stable disease for a median of 3.6 months. Three-month progression-free survival (PFS) rates were 50% and 33% in the low-dose and high-dose cohort, respectively. Three patients in low-dose cohort experienced PFS longer than PFS on last prior therapy. Conclusions: Both NGR-hTNF doses were safely combined with XELOX in pretreated CRC patients. Hint of activity was apparent only with low-dose NGR-hTNF.

Background: The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is active in heavily pretreated patients with metastatic colorectal cancer (mCRC) both in monotherapy and in combination with chemotherapy (CT). This study assesses the antitumor activity of single-agent cetuximab in CT-naive patients. Patients and methods: Phase II clinical trial was used. Patients were EGFR positive by immunohistochemistry and were not candidate for radical surgery, even in the case of substantial tumor shrinkage. Cetuximab was administered weekly. Results: Thirty-nine patients were treated and evaluated. The most common adverse event was skin toxicity (89% any grade; 48% grade 1; 31% grade 2; 10% grade 3). One patient had a complete response and three obtained partial responses (10% overall response rate). Thirteen patients had stable disease (34%). Twenty-two patients experienced progressive disease (56%). Overall median time to progression (TTP) was 2 months, and the responders individual TTP was 12, 9, 9, and 6 months. Conclusions: Even in chemo-naive patients, cetuximab as single agent is active only in a small fraction of mCRC, similarly to what has been reported for heavily pretreated patients. The extent of benefit when response occurs is, however, such that it is mandatory to intensify the search for the predictive markers of response to cetuximab therapy.

A re-evaluation of the status of fishes in Kansas suggests that 54 of the 116 native species should be assigned special conservation status due to substantial declines in distribution or abundance and/or their rarity in the state. Nine species are recommended for retention in their existing status of endangered, threatened, or species in need of conservation. We recommend elevated conservation status for 44 additional species, and provide information on trends in distribution and abundance for these taxa. A single species, the Arkansas River Shiner, Notropis girardi, is considered to be extirpated recently from Kansas.

BACKGROUND The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well. METHODS In the current study, 202 patients with MBC were randomized to receive either the combination of epirubicin at a dose of 90 mg/m2 plus paclitaxel at a dose of 200 mg/m2 for 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94). RESULTS The authors rejected the null hypothesis that the sequential treatment is less active than the standard concomitant regimen (ORRs: concomitant = 58.5%, sequential = 57.6%). The median progression-free and overall survival periods were 11.0 months (95% confidence interval [95% CI], 9.7–12.3) and 20.0 months (95% CI, 17.2–22.6), respectively, in the concomitant arm and 10.8 months (95% CI, 7.9–13.6) and 26 months (95% CI, 18.1–33.8), respectively, in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 (according to the World Health Organization grading system) neutropenia (62.2% of courses vs. 50.62%; P = 0.003) and Grade ≥ 2 neuropathy (45.5% vs. 30.4% of patients; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity according to New York Heart Association criteria. QOL analyses failed to provide clear differences. CONCLUSIONS The sequential administration of epirubicin and paclitaxel at full doses was found to be as active as their association. Therefore, both the sequential and the combined administration were acceptable options. Cancer 2004. © 2004 American Cancer Society.

To assess the potential impacts of impoundments on sensitive stream species, such as the Topeka shiner (Notropis topeka) and hornyhead chub (Nocomis biguttatus), I conducted a review of existing scientific literature. A substantial body of literature indicates that construction of dams has a negative impact on native stream fishes. In general, an impoundment can reduce the quantity and quality of stream habitat, alter reproductive and feeding behavior of fishes, and increase the number and sizes of predatory fish within a stream system. These impacts suggest a negative relationship between impoundments and obligate stream species, such as the Topeka shiner and hornyhead chub.

Background/Aims: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino - IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. Methods: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. Results: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counselling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). Conclusions: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice.

Haemorrhagic cystitis (HC) is a recognised complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). This study evaluates the incidence and severity of HC in patients undergoing allogeneic HSCT during hospitalisation and within the first 100 days following transplant, looking at the use of prophylaxis, management of HC, outcomes at 100 days post transplant, and to identify any correlations between development of HC and the different conditioning regimens for transplant or HC prevention methods used. Results Four hundred and fifty patients (412 adult and 38 paediatric) were enrolled in this prospective, multicentre, and observational study. HC was observed in 55 patients (12.2%) of which 8/38 were paediatric (21% of total paediatric sample) and 47/412 adults (11.4% of total adult sample). HC was observed primarily in the non-related HSCT group (45/55; 81.8%, p= 0.001) compared to sibling and myeloablative transplant protocols (48/55; 87.3%; p= 0.008) and with respect to reduced intensity conditioning regimens (7/55;12.7%). In 33 patients with HC (60%), BK virus was isolated in urine samples, a potential co-factor in the pathogenesis of HC. The median day of HC presentation was 23 days post HSCT infusion, with a mean duration of 20 days. The most frequent therapeutic treatments were placement of a bladder catheter (31/55; 56%) and continuous bladder irrigation (40/55; 73%). The range of variables in terms of conditioning regimens and so on, makes analysis difficult. Conclusions This multi-centre national study reported similar incidence rates of HC to those in the literature. Evidence-based guidelines for prophylaxis and management are required in transplant centres. Further research is required to look at both prophylactic and therapeutic interventions, which also consider toxicity of newer conditioning regimens.

Spotted bass Micropterus punctulatus are popular sport fish in streams and reservoirs throughout the southeastern United States. Despite their popularity, there is a paucity of information on population characteristics and habitat requirements of spotted bass in streams. The purpose of this study was to document the factors that influence spotted bass populations in Kansas streams. Study sites were selected throughout the native range of spotted bass in Kansas. Spotted bass were sampled by electrofishing, and 31 habitat variables were measured at 16 study sites. Linear regression analyses (single and multiple) were used to determine relationships between habitat variables and spotted bass density (number/ha), biomass (kg/ha), catch per effort (CPE; number per minute of electrofishing), relative weight (Wr ), and growth. Variability in density of spotted bass 180 mm or longer was best explained by rootwad area (m2/ha). However, variability in biomass and CPE of spotted bass 180 mm or longer was be...

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-α2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m 2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-α 25 × 10 6 U Day 1 + ip carboplatin 400 mg/m 2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3–4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever ( P = 0.000) and flu-like syndrome ( P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1–72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-α does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Background: While ovarian cancer is one of the most sensitive cancers to cytotoxic drugs, with objective response rates of 60-80% routinely being reported in previously untreated pa

We have carried out a phase II trial to evaluate the efficacy and toxicity of a combination therapy consisting of mitoxantrone 10 mg/sqm i.v. on day 1, levo-leucovorin 250 mg/sqm administered over 2 hours and 5-fluorouracil 500 mg/sqm i.v. push after the first hour of levo-leucovorin infusion, on days 15–16 (MFL) in patients aged more than 65 years. 24 patients with advanced breast cancer entered the study: 16 aged 65–70 yrs, 4 patients 70–75 yrs, and 4 > 75 yrs. Median PS was 1 (range 0–2); sites of metastases were: bone 14 patients, viscera 14 patients, soft tissue 11 patients, and CNS 1 patient. A median number of 6 cycles (range 3–9) was administered. All patients were evaluable for response and toxicity; partial response was obtained in 12 (50%) patients (95% C.I 30–70), stable disease was observed in 9 patients (37.5%), while 3 patients (12.5%) progressed. Median progression-free survival and survival were 9 months (range 2–14) and 14 months (range 5–36), respectively. Toxicity was generally mild and the most frequently observed side-effects were WHO gr. 1–2 leukopenia in 6/24 (25%) patients and gr. 1–2 emesis in 10/24 (41.6%) pts. 1 patient pretreated with doxorubicin cumulative dose of 240 mg/sqm showed clinical signs of congestive heart failure (NYHA grade 1) after the fifth cycle of treatment. MFL is a well tolerated regimen and could represent a safe and effective treatment in older advanced breast cancer patients.

Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer.This review summarizes the available evidence on the use of PEM in the treatment of OC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to November 2011. Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of PEM in the treatment of recurrent OC are described.Eight trials evaluated the use of PEM in OC patients. Studies using PEM in combination with carboplatin in platinum-sensitive OC suggested that the response rate is similar to other combination therapies. However, based on the absence of randomized trials comparing this doublet with currently used combination treatments, it is difficult to draw conclusions on the efficacy of PEM regimens in these patients. In platinum-resistant OC patients, two studies suggested that PEM alone might have equivalent activity to other single-agent treatment. Further pharmacogenomic and clinical data are warranted to better define the role of PEM in the treatment of recurrent OC.

87 patients with high risk of recurrence FIGO stage I and II ovarian carcinoma were treated with adjuvant chemotherapy consisting of cisplatin 50 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every 28 days for 6 courses. Toxicity and efficacy of the regimen was evaluated after a median follow-up of 45 months. Treatment-related toxicity was mild and reversible, consisting chiefly of acute WHO grade 2 myelosuppression (10% of patients) and controllable grade 3 emesis (55%). No late toxicity was observed. Actuarial 7-year survival and relapse-free survival (RFS) were 76% and 61%, respectively; a statistically significant difference in outcome was observed for undifferentiated grade tumour (G1 vs. G2 vs. G3: P less than 0.01) but not for FIGO stage disease (stage I vs. stage II). In our opinion, short-term chemotherapy including the most active single agent, i.e. cisplatin, appears a tolerable and effective treatment which deserves further evaluation in large randomised trials.

The efficacy of the serotonin antagonist ondansetron (GR 38032F) was evaluated in the prevention of nausea and vomiting induced by CMF chemotherapy in 29 breast cancer patients. At their first treatment course of CMF, all given IV on day 1 q 21 days, patients were given oral antiemetic treatment as follows: ondansetron 8 mg, 2 h prior to CMF, repeated after 5 and 10 h the day of chemotherapy and then 8 mg tds for a minimum of 3 days to a maximum of 5 days following chemotherapy. At first course of CMF, complete protection from emesis and nausea was observed in 86.2% and 62% of patients, respectively. At subsequent CMF courses with ondansetron, complete control of emesis was observed in 80% of patients. Side effects were mild and no dystonic reactions were observed. Ondansetron represents an effective, safe, and easily administered outpatient regimen. The addition of a corticosteroid to ondansetron could further improve control of CMF-induced emesis.

With ageing, function preservation and maintenance of quality of life represent a major goal in an increasing proportion of patients. Life expectancy is a function of age, comorbidity, disability and cancer type and stage. Decision-making involves a delicate balance among all these factors, evaluation of treatment related complications of the overall effects of cancer and cancer treatment on the patients' quality of life. Despite several instruments for the assessment of quality of life being validated, none have been calibrated to the special requirements of the older patients. The structured interview administered by a trained clinician represents a standard approach for geriatric research and even for clinical practice because of the frailty of the older population. The combination of this approach with the self-administered questionnaire appears the most effective way to minimise missing data in collecting information for patients unable to complete the form.

While ovarian cancer is one of the most sensitive cancers to cytotoxic drugs, with objective response rates of 60-80% routinely being reported in previously untreated patients, the majority of individuals with advanced disease ultimately relapse. Paclitaxel, a new and novel antimicrotubule agent, has shown activity as a salvage therapy in epithelial ovarian cancer. More importantly, in a prior study, it has been shown to be active in tumors that have displayed resistance to platinum compounds, with a reported response rate of 20%. Ifosfamide has shown activity in the treatment of patients who previously demonstrated clinical resistance to a platinum-cyclophosphamide combination. Recently, a synergistic activity of Taxol combined with ifosfamide has been reported in ovarian cell lines. Based on these data, a phase I/II study of a combination treatment with paclitaxel and ifosfamide was performed.Thirty-one patients with recurrent ovarian cancer or ovarian cancer refractory to cisplatin (CDDP)-containing regimens were treated with paclitaxel at a dose of 135 mg/m2 on day 1; ifosfamide was administered at 1 g/m2 on days 2 and 3 for the first cycle and 1.5 and 2 g/m2 with the same schedule in cycles 2 and 3, respectively. In the absence of toxicity, the dose of ifosfamide was maintained at 2 g/m2 for the last three cycles. Cytotoxic therapy was repeated every 3 weeks.A 30% overall objective response rate was achieved in the 30 patients assessable for response. Among 21 platinum-resistant patients, 4 partial responses (19%) were observed, while in the 9 platinum-sensitive patients 2 complete responses and 3 partial responses (55%) were observed. Myelosuppression was the predominant toxicity. Leukopenia (WHO grade 3-4) occurred in 10% of patients who received ifosfamide at a dose of 1 g/m2 and in 18% of patients treated with ifosfamide at 1.5 g/m2.Our results confirmed a low activity of paclitaxel in platinum-resistant patients. The results of this combination treatment with paclitaxel-ifosfamide in our platinum-sensitive patients support further investigations in a randomized study of the combination regimen against paclitaxel alone or retreatment with organoplatinum compounds.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-alpha2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-alpha 25 x 10(6) U Day 1 + ip carboplatin 400 mg/m2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3-4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P = 0.000) and flu-like syndrome (P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1-72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-alpha does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Encouraging results with Paclitaxel are reported in ovarian cancer patients relapsing and progressing after platinum-based chemotherapy; however, the two populations have different probabilities of a response to a second-line treatment. Here we report the results achieved in 39 patients with platinum-refractory ovarian cancer, treated with Paclitaxel 175 mg/qm2 (or 135 mg/m2 if heavily pretreated) using 3-hour intravenous infusion every 3 weeks, in an attempt to verify the activity of this drug in platinum-resistant patients. The toxicity was mild to moderate and primarily hematologic and neurologic. The objective response rate is 12.8% with no complete responses. The response duration was brief and the median survival 6 (range 1-17) months. An accurate cost-benefit balance is necessary before routinely use of Paclitaxel in platinum-refractory patients. Further research is needed to determine the optimal role of Paclitaxel in the whole therapeutic strategy for ovarian cancer.

PURPOSE The aim of the study was to compare high-versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin as primary chemotherapy for suboptimal stage III and IV ovarian cancer. PATIENTS AND METHODS One hundred forty-five patients were randomized to receive six courses of cisplatin 50 or 100 mg/m2 plus epidoxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. The two treatment arms were well balanced; all patients had greater than 2 cm and 37.2% had greater than 5 cm of residual disease; 29.6% had stage IV disease. RESULTS Patients in the high-dose arm received a double dose-intensity and double total dose of cisplatin. The high-dose regimen induced significantly more episodes of leukopenia (47.8% v 32.8%, P = .05), thrombocytopenia (21.7% v 3.2%, P = .003), anemia (37.6% v 12.5%, P = .002), nephrotoxicity (six v one patient), and neurotoxicity (30.4% v 6.3%, P = .002). There were no significant differences in efficacy in terms of clinical response rate (high-dose 57.5% v low-dose 61.1%), pathologic complete response (CR) (9.6% v 18.1%), median survival times (29 v 24 months), and median progression-free survival (18 v 13 months). CONCLUSION This study shows that doubling the dose-intensity and total dose of cisplatin in combination with epidoxorubicin and cyclophosphamide has significant toxic effects and does not improve clinical outcome in patients with suboptimal ovarian cancer.

Based on experimental findings suggesting that 5-fluorouracil (FUra) may have different mechanisms of action depending on the schedule of administration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific. We thus tested the activity of a hybrid regimen consisting of two biweekly cycles of FUra bolus (600 mg/m2) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). Thirty-three consecutive patients with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study from February 1992 to August 1993. They were treated with two biweekly cycles of FUra bolus (600 mg/m2) preceded by (24-h interval) methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). The median Eastern Cooperative Oncology Group performance status was 1; the liver was the only metastatic site in 17 patients. Treatment outcome was evaluated by computed tomographic scan in all patients, except for two. Three complete and 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%). Performance status (Eastern Cooperative Oncology Group) influenced clinical response. The combined complete response and partial response rate was 69%, 33%, and 25% in patients with an Eastern Cooperative Oncology Group performance status of 0, 1, and 2, respectively (chi2, 4.6, P = 0.032, two-tailed Mantel test for trend). After a median follow-up time of 26 months, 10 patients are still alive. The median progression-free survival and overall survival were 9.5 and 20.2 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3%, and vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen.

We have evaluated the efficacy and toxicity of a chemotherapy consisting of methotrexate, mitoxantrone, 5-Fluorouracil and leucovorin in 21 advanced breast cancer patients. Among 20 evaluable patients, objective response was obtained in 6 patients (30%) with two complete responses, stable disease in 4 patients (20%), while 10 patients (50%) progressed. Median progression-free survival and survival were 10 and 15 months, respectively. The most frequently observed side-effects were myelosuppression and emesis; one patient, who had previously received doxorubicin at the maximum dose-limiting cardiac toxicity, died of congestive heart failure after the third cycle. This treatment is moderately effective for advanced breast cancer patients.

An incidence of cerebral metastases secondary to epithelial ovarian cancer as high as 11.6% has been reported in small series and related to the prolonged survival of ovarian cancer patients treated with platinum compounds (Hardy, J. R., and Harvey, V. J. Gynecol. Oncol. 33, 296-300, 1989). A review of the histories of 413 ovarian cancer patients, treated from 1981 to 1989 with platinum-based combination chemotherapy according to the protocols of the Gruppo Oncologico Nord Ovest (GONO) (North West Oncology Group), showed that only 9 patients (2.2%) developed clinical evidence of cerebral metastases. Six of 9 patients had FIGO Stage IIIc disease and 1 each with FIGO Stages Ic, IIc, and IV. All these patients had received cisplatin or carboplatin-based combination chemotherapy. Clinical response to initial cytotoxic therapy was as follows: complete response, 3 patients; partial response, 4 patients; stable disease, 1 patient; progressive disease, 1 patient. Cerebral metastases occurred at a median of 19 months (range 3-36) from diagnosis and median survival of patients with central nervous system (CNS) metastasis was 26 months (range 10-81) from diagnosis of primary disease and 8 months (range 1-45) from diagnosis of CNS involvement. The incidence of CNS metastases in our series is similar to that reported in the past and significantly lower than figures reported by the above mentioned paper. On the basis of our data we do not agree with Hardy and Harvey about the relationship possibly existing between prolonged survival and incidence of CNS metastases and, particularly, about the need for prophylactic cranial irradiation.

It has been demonstrated that the prognosis of ovarian cancer is influenced by the dose intensity of cytotoxic treatment. The impact of received dose intensity of platinum-based combination chemotherapy on disease outcome was analysed in 226 stage III-IV ovarian cancer patients entered into two prospective randomised trials. All patients received either cisplatin or carboplatin and cyclophosphamide with or without doxorubicin for six courses after primary surgery. The impact of the received dose intensity of each drug (RDI), the average received dose intensity of the treatment regimen (ARDI) and the relative total drug dose (RTD) on progression-free survival (PFS) and survival were analysed. In the 198 patients receiving the full six courses of treatment, RDI of cisplatin or carboplatin, ARDI and RTD were0.76 in 74.2, 61.1 and 65.1% of cases, respectively. Although the differences were not significant, pathological complete response was more frequently observed in the group of patients with ARDI0.75, whereas the partial response rate was higher in the ARDIor = 0.76 group. Median survival and PFS were 19 and 13 months; 22 and 10 months; 23 and 13 months for the groups of patients receiving chemotherapy at a ARDI of0.75,or = 0.76-0.99 and1.00, respectively (P = not significant). It appears that modest dose modifications and brief treatment delays during first-line platinum-based chemotherapy do not affect response rate, survival and PFS in advanced ovarian cancer patients.

In 221 patients with FIGO stage I and II endometrial carcinoma, the impact on survival of age at diagnosis, menopausal status, FIGO stage, myometrial invasion, tumor grade and histology was evaluated by univariate and multivariate analysis. At a median follow-up of 50 months (range 45-210), 42 patients had died, and therefore overall survival was 81% (179/221). Univariate analysis showed that age, menopausal status and histology did not influence survival, whereas FIGO stage, myometrial invasion and tumor grade were important prognostic factors. Multivariate analysis showed that tumor grade had a significant and independent impact on survival and confirmed that FIGO stage is the most important parameter influencing survival.

14598 Background: Aflibercept, has demonstrated the ability to reduce formation of ascites in preclinical models of EOC, as well as in advanced EOC patients. Aflibercept, a potent angiogenesis inhibitor fusion protein, is comprised of portions of human vascular endothelial growth factor VEGF receptor R1+R2 (Flt-1, KDR) extracellular domains and fused to the Fc-portion of human IgG. Aflibercept binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor. Methods: Aflibercept, 4 mg/kg, i.v. was administered every 2 weeks, in pts with advanced EOC and symptomatic ascites requiring frequent paracentesis (pct). Eligibility criteria included resistance to prior platinum based therapy and topotecan and/or liposomal doxorubicin, ECOG performance status of 0–2, normal organ function, no proteinuria (

Fifty-seven patients who had progressed during or relapsed after randomized first-line combination chemotherapy containing cisplatin or carboplatin were entered into a crossover study in which the analog not previously assigned was administered alone as salvage treatment. Carboplatin and cisplatin were administered at doses of 400 and 100 mg/m 2 , respectively, every 28 days. Among the 24 patients enrolled in the cisplatin arm, 6 (25%) objective responses (ORs) (3 complete, 3 partial) were observed, whereas 3 partial responses were obtained in the 33 carboplatin-treated patient (9%). Analysis of results, according to response to first-line chemotherapy, demonstrated that the patients who progressed were sensitive only to cisplatin second-line treatment (OR: 312), with no responders among carboplatin-treated patients (OR: 011). All patients were treated on an outpatient basis and therapy-related toxic effects were mild, consisting chiefly of myelosuppression, and more frequent in the carboplatin group. In our opinion, carboplatin 400 mg/m 2 per cycle is scarcely effective in patients with refractory or relapsed ovarian cancer pretreated with cisplatin regimens, whereas cisplatin 100 mg/m 2 per cycle appears to be an effective salvage therapy even in patients not responding to carboplatin. The dose of carboplatin should be further escalated especially in refractory patients.

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.

3757 Background and methods: We evaluated 53 patients with advanced colorectal cancer within a phase II trial of first line CT consisting of 3 sequential parts: a) MTX (days 1 and 15) l-OHP + FU (d...

sation of hypothyroidism. The following evidence supports a neoplastic TSH origin: (a) an elevated a subunit level [l]; (b) residual intrasphenoidal tumour; (c) absence of 24 h TSH cycle. Cases of TSH-secreting adenoma, in which bromocriptine or octreotide produce a persistant decrease in TSH and cx subunit secretion, have been reported [2-71. The octreotide escape phenomenon has been reported in cases with ectopic adrenocorticotropic hormone [8]. In our case, the escape phenomenon could be due to the disappearance of sensitive receptors present on the TSH-secreting adenoma [9,10] or to the presence of different cell clones with a different sensitivity to inhibition by somatostatin and/or bromocriptine.

county records and provided new information on the distribution of nine fish species and one hybrid darter in the state. The occurrence of Catostomus commersoni in Cherokee County was verified and a range extension for Etheostoma whipplei in the United States was documented. Fishes were collected in the summer of 1995 during a survey of the basin's tributary streams conducted by the Kansas Department of Wildlife and Parks.

40 N ≥ 10 b.c. pts (median age: 46 yrs, range 31–56; median number of involved nodes: 13, range 10–33) were entered so far into a pilot trial to evaluate the feasibility of an adjuvant H.D. CT program without the use of stem cell support. Pts were given 3 cycles of CYC 600 mg/m2 d. 1, EPIDOX 60 mg/m2 d. 1, 5-FU 600 mg/m2 d. 1, q. 3 wks, followed by H.D. CT, administered in protect environment as needed, with CYC 2500 mg/m2 dd. 1,2; VP 16 500 mg/m2 dd. 1–3; CDDP 50 mg/m2 dd. 1–3. Granulocyte-colony stimulating factor (G-CSF) was administered in all patients beginning on day 5 from H.D. CT and continued until leukocyte count reached 10 × 109/L. Median duration of granulocytopenia

Paclitaxel activity with or without ifosfamide was investigated as salvage therapy in patients (pts) with a.o.c. Group I (n = 20 evaluable) pts received taxol alone 175 mg/m 2 , over 3 hours, every 3 weeks. Group II (n = 13 evaluable pts) received taxol 135 mg/m 2 as in Group I; escalating doses of ifosfamide (1; 1.5; 2 gr/m 2 ) was administered on days 2–3 with mesna rescue. In absence of severe toxicity, ifosfamide was administered at 2 gr/m 2 for the last three cycles. The average number of courses was respectively 4 in Group I (range 1–8) and 3 in Group II (range 1–6). Overall, 3 PR were observed in 15 pts with primary platinum resistant disease, 2 PR were observed in 8 pts with platinum sensitive disease while no response was observed in 10 pts with secondary platinum resistant ovarian cancer. Our results, although preliminary, suggest that taxol ± ifosfamide show a moderate but definite activity in so heavily pretreated category of pts. As expected the activity in platinum sensitive pts was twofold the activity achieved in platinum resistant pts, showing respectively 25% of PR vs 12% of PR. However, was to note that a 20% of activity was observed in primary platinum resistant pts. Moreover taxol plus ifosfamide association seems not to achieve better results than taxol alone, while it showed a higher haematologic toxicity. It is concluded that the number of previous therapeutic lines rather than the intrinsic sensitivity to cisplatin front line treatment is probably the major determinant of taxol activity when employed as salvage treatment.