Janina Markowska

A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma

OBJECTIVES Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented. METHODS Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS). RESULTS Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ≥ grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%). CONCLUSIONS Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations.

TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

BackgroundTaxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.MethodsWe compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Coxs and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].ResultsThe advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.ConclusionOur results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.

Does Metformin affect ER, PR, IGF-1R, β-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer?

ObjectiveDiabetes mellitus, as a risk factor for endometrial cancer (EC), causes an increase in insulin and IGF-1 concentrations in the blood serum. The increase in insulin and IGF-1 are considered mitogenic factors contributory to cancer development. Studies suggest that metformin has preventive activity, decreasing mortality and the risk of neoplasms. Since estrogen (ER), progesterone (PR) and IGF-1 (IGF-1R) receptor expression and β-catenin and PAX-2 mutations are significant in the development of endometrial cancer, it was decided to study these factors in patients with endometrial cancer and type 2 diabetes mellitus (DM2), and to establish the effects of metformin on their expression.MethodsThe expression of ER, PR, IGF-1R, β-catenin and PAX-2 have been immunohistochemically investigated in 86 type I endometrial cancer specimens. Patients were grouped according to the presence of DM2 and the type of hypoglycemic treatment administered.ResultsComparing EC patients with DM2 and normal glycemic status, we found increased IGF-1R expression in women with DM2. A decrease in ER expression was noted in women with EC and DM2 receiving metformin as compared to women treated with insulin (p = 0.004). There was no statistically significant difference in PR, IGF-1R, β-catenin and PAX-2 expression among women receiving metformin and other hypoglycemic treatment.ConclusionAlthough epidemiological studies suggest the beneficial role of metformin in many human cancers, there are still few studies confirming its favorable effect on endometrial cancer. Decreased ER expression in patients receiving metformin needs further research to allow evaluation of its clinical significance.

Signalling pathways in endometrial cancer.

Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/β-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to β-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or Akt result in increased transmission in the PI3K/Akt pathway, apoptosis inhibition, intensive cell division, mTOR excitation. In non-endometrioid cancers, key mutations include suppressor gene TP53 responsible for repairing damaged DNA or apoptosis initiation. Irregularities in gene P16, encoding a protein forming the p16-cyclinD/CDK-pRb have also been described. Understanding the complex relations between specific proteins taking part in signal transduction of the abovementioned pathways is key to research on drugs used in targeted therapy.

ESGO Statement on the Role of CA/125 Measurement in Follow-Up of Epithelial Ovarian Cancer

T he recent publication of the OV05/EORTC 55955 study on the use of Cancer Antigen 125 (CA-125) in the followup of patients with ovarian cancer after primary treatment has challenged the assumed advantage of early detection of recurrent disease on the basis of a CA-125 rise. This study suggests that despite earlier initiation of second-line treatment, there is no survival benefit. Publication and subsequent review of these European data gave rise to a generalized conclusion that CA-125 monitoring should be abandoned routinely for disease monitoring after treatment. In an accompanying paper in this issue, a European Society of Gynaecological Oncology (ESGO) consensus group has reviewed current data on the use of CA-125 in the follow-up of patients with ovarian cancer. As the conclusions of the OV05/EORTC 55955 study are only applicable for a particular group of patients with ovarian cancer, there is a danger that the conclusion that CA-125 follow-up does more harm than good is also extended to patients that would or could possibly benefit from CA-125 follow-up. The ESGO therefore advises that the use of CA-125 should not be universally abandoned in the routine follow-up of all patients with ovarian cancer. We recommend to consider CA-125 follow-up in the following cases: Patients after complete response on primary treatment for epithelial ovarian cancer who: & have been or are being treated as part of a clinical trial; & are considered for (future) studies on second-line treatment; & will not have routine (3 monthly) follow-up including regular imaging; and & are eligible for secondary surgery at recurrence.

Angiogenesis and cancer stem cells: New perspectives on therapy of ovarian cancer

Failure in ovarian cancer therapy, following cytoreduction and chemotherapy, is related to the presence of cancer stem cells - a small subpopulation of cells resistant to chemotherapy and irradiation - in the tumour which may cause cancer relapse and manifestation of metastases. Therapies targeted at Cancer Stem Cells (CSCs), such as those employing metformin (a drug used in the treatment of diabetes type II) and salinomycin, an antibiotic isolated from Streptococcus albus bacteria, seem promising. Anti-angiogenic therapy with bevacizumab was found to be effective in all phases of ovarian cancer treatment. The presence of CSCs has been associated with angiogenesis. Several CSC biomarkers correlate with the markers of angiogenesis and some signalling pathways, e.g. Notch, and are used by both CSCs and by pro-angiogenic factors.

Training in Bowel and Upper Abdominal Surgery in Gynaecological Oncology European Society of Gynecological Oncology (ESGO) Statement

To the Editor: I n contrast with the treatment of other gynecological malignancies, the radicality of surgery for advanced ovarian cancer is increasing. The significance of complete cytoreduction for survival has been well documented in many observational studies, and recently, the principle has been confirmed by prospective randomized trials.3,4 The achievement of no residual disease in the pelvis and abdomen requires extensive debulking of upper abdominal disease in more than one third of the patients and bowel resections in up to 60% of them. Making high-quality surgery accessible to all patients currently presents an important challenge for gynecological oncology. The situation about the quality and complexity of surgical treatment of advanced ovarian cancer shows a high degree of variation across Europe.7 Existing differences are well presented in a survey, which is published in this issue.8 Colorectal resections, splenectomies, or procedures on diaphragm are already performed by gynecological oncologists in growing proportion of the centers without well-established postgraduate training. Postgraduate training should always reflect relevant evidence-based data and development in clinical practice. Surgical training in gynecological oncology must take into account new requirements for the treatment of ovarian cancer and implement training in selected procedures of bowel and upper abdominal surgery. In large gynecological on cology centers, it is currently easier to offer an adequate volume of bowel resections for postgraduate training than it is in performing radical hysterectomies or pelvic exenterations, the latter procedures being required by current logbooks. In the United States, the American Board of Obstetrics and Gynecology already presents the list of procedures required for training in gynecological oncology, including 12 gastrointestinal procedures, among them resections and re-anastomosis of small and large bowel (http://www.abog.org/ publications). Traditional curricula in European countries without a training program in extended abdominal surgical procedures constitute a significant barrier to the development of the discipline and to achieving ultimate quality care. Training in selected bowel and upper abdominal procedures should be part of the gynecological oncology curriculum. This process will rather stimulate than replace the interdisciplinary cooperation, which shall always be necessary in complex cases. This statement represents an opinion of the ESGO Council. It reflects recent changes in the requirements for the surgical treatment of advanced ovarian cancer. It promotes the introduction of selected bowel and upper abdominal procedures into the postgraduate training in gynecological oncology and supports the role of gynecological oncologist in its performance.

Noble metals in oncology

Worldwide research groups are searching for anticancer compounds, many of them are organometalic complexes having platinum group metals as their active centers. Most commonly used cytostatics from this group are cisplatin, carboplatin and oxaliplatin. Cisplatin was used fot the first time in 1978, from this time many platinum derivatives were created. In this review we present biological properties and probable future clinical use of platinum, gold, silver, iridium and ruthenium derivatives. Gold derivative Auranofin has been studied extensively. Action of silver nanoparticles on different cell lines was analysed. Iridium isotopes are commonly used in brachyterapy. Ruthenium compound new anti-tumour metastasis inhibitor (NAMI-A) is used in managing lung cancer metastases. Electroporation of another ruthenium based compound KP1339 was also studied. Most of described complexes have antiproliferative and proapoptotic properties. Further studies need to be made. Nevertheless noble metal based chemotherapheutics and compounds seem to be an interesting direction of research.

Evaluation of leptin serum concentrations during surgery and first-line chemotherapy in primary epithelial ovarian cancer patients.

Aim of the study The available data on serum leptin levels in ovarian cancer present contradictory results. The majority of authors report lower leptin levels in those patients in comparison to healthy individuals. However, there is no data regarding leptin concentrations during therapy in women with primary epithelial ovarian cancer. Material and methods Blood samples were collected at the time of diagnosis, after initial surgery, and after first-line chemotherapy. Leptin serum concentrations were analysed using ELISA technique. Additionally, parallel measurements of CA125 levels were performed. Results Fifty-three patients with primary epithelial ovarian cancer met the inclusion criteria and were included in our study. Our analysis revealed a significant difference in mean preoperative serum leptin concentrations between early and advanced ovarian cancer patients (p < 0.0001). We identified statistically significant elevation of mean serum leptin levels (p < 0.001) after complete macroscopic cytoreduction and after first-line chemotherapy in advanced ovarian cancer cases. Discussion In this cohort, a significant elevation of postoperative serum leptin levels after complete macroscopic cytoreduction were shown. Moreover, elevation of leptin levels corresponded with remission after chemotherapy. Further studies are needed to determine if leptin can be a potential marker of surgery completeness as well as a marker in chemotherapy response evaluation.

Ten years of anti-HPV vaccinations: what do we know?

Human papillomavirus (HPV) is one of the most important carcinogens in humans. Vaccines against HPV are now considered the first anti-cancer vaccinations. Since 2007, in many developed countries, there have been recommendations present for preventive vaccines against HPV. At present, the degree of implementation of these recommendations depends on a number of country-specific factors such as the health care system organization or the ways of funding. HPV vaccines are primarily to prevent the development of cervical cancer and other genital cancers. Therefore, only their long-term effectiveness can be measured, when a correspondingly large cohort of vaccinated teenagers reaches the age of the greatest incidence of these cancers. However, great care should be taken in assessing the results of vaccinations due to the possibility of misinterpretation and possible erroneous data. Undoubtedly, teenagers are the target population of HPV vaccines. However, vaccinating young sexually active women is also justified from an individual point of view. A 9-valent vaccine has been registered in the USA and in Europe – including Poland – as one of the three preventive vaccines. It is recommended to vaccinate women between 13 and 26 and men between 13 and 21, previously unvaccinated. It is also recommended to vaccinate men aged 26 years or less who have sexual relations with other men and people with reduced immunity, including HIV-positive people who have not been vaccinated previously.