Editorial: Pseudomyxoma Peritonei: More Questions Than Answers (appendix/ovarian

JCO: Pseudomyxoma Peritonei: More QuestionsThan Answers

"Chances are, if you ask most physicians and surgeons about
pseudomyxoma peritonei (PMP), they will respond with more questions
than answers. The confusion that surrounds PMPis not surprising
because the origin, pathology, treatment, prognosis, and very
definition of PMP are still under debate. PMP is a clinical syndrome
that is characterized by mucinous ascites that result from rupture of a
mucin-producing neoplasm, typically of appendiceal origin....."

"...The appendix is the primary cause of PMP; the ovaries are typically
only secondarily involved...."

VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5

VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5

Objective 
To evaluate the role of VEGF-dependent Claudin 5 production for the development of ascites via influencing endothelial permeability in peritoneal tissue of ovarian cancer patients.

Conclusion 
VEGF induces ascites in ovarian cancer patients. This instance happens due to increased peritoneal permeability, caused by downregulation of the tight junction protein Claudin 5 in the peritoneal endothelium.

abstract: Widespread endometriosis mimicking ovarian malignancy: A case report

Widespread endometriosis mimicking ovarian malignancy: A case report.

Abstract

A 26 year old Nigerian nulliparous woman who presented in the medical emergency unit of a teaching hospital was referred after two weeks of management to the gynecology casualty with a diagnosis of malignant left ovarian cyst, because of the ascites, massive haemorrhagic pleural effusion, a left ovarian mass and an elevated C-125 marker.

However, exploratory laparotomy, cytologic and histological examination of the pleural fluid and biopsied specimens revealed endometriosis. We present a case of intra and extra-pelvic endometriosis which simulated a malignant ovarian lesion and was histologically confirmed by cytology of the haemorrhagic pleural effusion and biopsy of the ovarian mass and peritoneal deposits obtained at laparotomy.

This is to draw the attention of clinicians to endometriosis as a cause of pleural effusion, ascites and groin swelling which can simulate ovarian cancer.

abstract: Lymphatic ascites following pelvic and paraaortic lymphadenectomy procedures for gynecologic malignancies

 Blogger's Note: the abstract does not differentiate types of gyn cancers, journal is subscriber based ($$$)

Lymphatic ascites following pelvic and paraaortic lymphadenectomy procedures for gynecologic malignancies

Objective 
Lymphatic ascites is an unusual complication in patients with cancer. In the gynecologic oncology patient population, the most common etiology is operative lymph node dissection. The purpose of this study was to explore the incidence, presenting symptoms, methods of diagnosis and treatment modalities utilized for lymphatic ascites in patients undergoing lymph node dissection for gynecologic cancers.

Methods 
This observational study retrospectively reviewed the charts of patients who underwent lymphadenectomy as part of the surgical management for a gynecologic cancer. Patients that developed postoperative lymphatic ascites between January 2000 and December 2010 were included for analysis. Data extracted from the medical records included tumor pathology, number of harvested lymph nodes, postoperative course, method of diagnosis and treatment.

Results
From a total of 300 surgical staging procedures, 12 patients with lymphatic ascites were identified (4%). The most common reported symptom was leakage of clear fluid per vagina (7, 58%), followed by abdominal distension (4, 33%). The median interval from surgery to development of symptoms was 12.5 days (range 0–22days). 5 patients had complete resolution of symptoms with dietary modifications alone while 7 patients required paracentesis. The median time from surgery to resolution of symptoms was 44days (range 9–99).

Conclusion 
Lymphatic ascites is an under recognized and infrequently reported postoperative complication. Although it usually resolves spontaneously or with conservative management without sequelae, this condition can significantly prolong postoperative recovery and cause patient discomfort. To our knowledge this is the largest group of patients undergoing gynecologic surgical staging procedures to be reviewed for the occurrence of lymphatic ascites.

A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites

A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites

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.

Outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC)

Outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC):

Objective 
To describe the outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC) so as to define the criteria for patient selection for palliative surgery. Methods 90 women with relapsed EOC underwent palliative surgery for bowel obstruction between 1992 and 2008.

Conclusion 
Surgery for bowel obstruction in relapsed EOC is associated with a high morbidity and mortality rate especially in emergency cases when compared to other gynaecological oncological procedures. Palliation can be achieved in almost two thirds of cases, is equally likely in elective and emergency cases but is less likely in those with ascites.

Humoral response to catumaxomab correlates with clinical outcome: Results of the pivotal phase II/III study in patients with malignant ascites. (compared to paracentesis)

Humoral response to catumaxomab correlates with clinical outcome: Results of the pivotal phase II/III study in patients with malignant ascites.

The trifunctional antibody catumaxomab is a targeted immunotherapy for the intraperitoneal treatment of malignant ascites.

In a Phase II/III trial in cancer patients (n = 258) with malignant ascites, catumaxomab showed a clear clinical benefit vs. paracentesis and had an acceptable safety profile. Human antimouse antibodies (HAMAs), which could be associated with beneficial humoral effects and prolonged survival, may develop against catumaxomab as it is a mouse/rat antibody. This post hoc analysis investigated whether there was a correlation between the detection of HAMAs 8 days after the fourth catumaxomab infusion and clinical outcome. HAMA-positive and HAMA-negative patients in the catumaxomab group and patients in the control group were analyzed separately for all three clinical outcome measures (puncture-free survival, time to next puncture and overall survival) and compared to each other. There was a strong correlation between humoral response and clinical outcome: patients who developed HAMAs after catumaxomab showed significant improvement in all three clinical outcome measures vs. HAMA-negative patients. In the overall population in HAMA-positive vs. HAMA-negative patients, median puncture-free survival was 64 vs. 27 days (p < 0.0001; HR 0.330), median time to next therapeutic puncture was 104 vs. 46 days (p = 0.0002; HR 0.307) and median overall survival was 129 vs. 64 days (p = 0.0003; HR 0.433).

Similar differences between HAMA-positive and HAMA-negative patients were seen in the ovarian, nonovarian and gastric cancer subgroups.

In conclusion, HAMA development may be a biomarker for catumaxomab response and patients who developed HAMAs sooner derived greater benefit from catumaxomab treatment.

abstract: Microparticles From Ovarian Carcinomas Are Shed Into Ascites and Promote Cell Migration (EpCAM/assay/benign ascites/small study)

Abstract

Objective: Microparticles are cellular-derived vesicles (0.5-1.0 [mu]m) composed of cell membrane components, which are actively shed from the surface of various cells, including epithelial cells. We compared microparticles in ascites between women with ovarian carcinoma and women with benign ovarian pathology, and isolated tumor-derived (epithelial cell adhesion molecule [EpCAM]-positive) microparticles for functional analysis and proteomics.

Results: Microparticles in benign pelvic fluid were similar to early and advanced-stage ascites (2.4 vs 2.8 vs 2.0 x 106 microparticles/mL). Advanced stage had a greater proportion of EpCAM-positive microparticles than early or benign disease (13.3% vs 2.5% vs 2.1%; P = 0.001), and serous histology had more than endometrioid (13.2% vs 1.8%; P = 0.01).......
Conclusions: Ascites from advanced-stage and serous ovarian carcinomas contain large numbers of tumor-derived microparticles. In vitro, these microparticles bind to cancer cells and stimulate migration. Tumor-derived microparticles in ascites could mediate the predilection for peritoneal spread in serous ovarian carcinomas.

open access: Commentary: VEGF Trap for the treatment of malignant ascites : The Lancet Oncology

"About 10% of all cases of ascites are caused by a malignant disease. In developed countries the most common neoplasm associated with ascites is ovarian cancer. The pathophysiology of malignant ascites is multifactorial, and its molecular pathogenesis is only poorly understood. Ascites formation can result from obstruction of lymph vessels by tumour cells, resulting in incomplete absorption of intraperitoneal fluid and protein,1 especially in patients with lymphoma or breast cancer. Since malignant ascites is usually an exsudate with a high protein concentration, an increased vascular permeability has been implicated in its pathogenesis.2 In addition to mechanical obstruction and cytokines, the pathophysiology of malignant ascites includes hormonal mechanisms. Because of the accumulation of ascites caused by obstructed lymph vessels, the circulating blood volume is reduced, which results in activation of the renin-angiotensin-aldosterone system that is followed by sodium retention.

Unlike the established therapeutic options for the underlying malignancy, there is no generally accepted gold standard for the management of malignant ascites...."

"...With respect to the clinical implications of the results (Walter Gotlieb and colleagues7 in The Lancet Oncology), symptom relief has to be weighed against discomfort and potentially life-threatening adverse events (three patients had fatal gastrointestinal complications in the aflibercept group vs one in the placebo group), since the treatment is applied to patients in a highly palliative situation. Careful patient selection could reduce the incidence of gastrointestinal perforations. However, before a general recommendation of aflibercept for the treatment of malignant ascites can be made, further studies, including comparative effectiveness research,8 are needed to compare the effectiveness of the different therapeutic strategies in daily clinical practice."

Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study : The Lancet Oncology

links to article/commentary/blogger's notes: Intravenous Aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study : The Lancet Oncology

Blogger's Note:  reposted from Jan 20th due to Lancet Editorial and reference - paper is open accdess

• pay specific attention to patient safety/adverse events; 

  • related article on the (beneficial) use of Aflibercept in colorectal cancer patients (Aflibercept Improves Survival In Metastatic Colon Cancer - December 2011)

Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study Aflibercept

 Interpretation

This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit—risk balance should be thoroughly discussed for each patient.

 Commentary: 

VEGF Trap for the treatment of malignant ascites

Gerhild Becker, Hubert E Blum

"In view of the important pathogenetic role of VEGF in ascites formation, the efficacy of VEGF inhibitors have also been assessed in patients with symptomatic malignant ascites. Confirming the results of a recent open-label single-arm phase 2 trial,6 the randomised double-blind placebo-controlled study by Walter Gotlieb and colleagues7 in The Lancet Oncology shows the efficacy of aflibercept in patients with malignant ascites associated with advanced ovarian cancer and can be interpreted as proof of concept. The intervention and the control groups were homogenous, confounding variables controlled, and bias reduced. Therefore, the study has a high internal validity and shows the efficacy of aflibercept. With respect to the clinical implications of the results, symptom relief has to be weighed against discomfort and potentially life-threatening adverse events (three patients had fatal gastrointestinal complications in the aflibercept group vs one in the placebo group), since the treatment is applied to patients in a highly palliative situation. Careful patient selection could reduce the incidence of gastrointestinal perforations. However, before a general recommendation of aflibercept for the treatment of malignant ascites can be made, further studies, including comparative effectiveness research,8 (Blogger's Note: AND patient safety) are needed to compare the effectiveness of the different therapeutic strategies in daily clinical practice."

short abstract: Gynecological cancer: True progress in ovarian cancer or just the tip of the iceberg?

Blogger's Note:  requires subscription to view full text ($$$)

 Gynecological cancer: True progress in ovarian cancer or just the tip of the iceberg?

Lisa Hutchinson

"Abstract

Development of malignant ascites is common in patients with ovarian cancer, and few therapeutic options exist for women with ascites whose tumors become resistant to chemotherapy. Furthermore, in such patients symptom palliation options are limited, and the few available treatments are unpleasant and can result in the need for paracentesis."

Medical News: Mixed Results With (Aflibercept) Eyelea in Ovarian Cancer - in Clinical Context, Ovarian Cancer from MedPage Today

Medical News: Mixed Results With Eyelea in Ovarian Cancer - in Clinical Context, Ovarian Cancer from MedPage Today


Action Points  

---

• The angiogenesis inhibitor aflibercept led to a decreased need for drainage of malignant ascites in patients with advanced ovarian cancer.



• Aflibercept treatment increased the likelihood of fatal bowel perforations in patients whose disease was progressing

Ottawa press release: (drug GAP-107B8 / ascites) PharmaGap Sees Positive Results from In Vivo Ovarian Cancer Models at the Ottawa Hospital Research Institute

Note: in research  

OTTAWA, ONTARIO--(Marketwire - April 18, 2011) - PharmaGap Inc. (TSX VENTURE:GAP)(OTCBB:PHRGF) ("PharmaGap" or "the Company") today announced initial results from preclinical testing at the Ottawa Hospital Research Institute ("OHRI"). Initial results from this study are positive and provide evidence that a peptide formulation of PharmaGap's lead cancer drug GAP-107B8 administered via the intraperitoneal route can reduce tumour burden (19%) and significantly suppress ascites formation (73%) relative to controls. The test was undertaken at OHRI in collaboration with Dr. Barbara Vanderhyden. Dr. Vanderhyden, upon initial review of the data commented "The reduction in ascites volume is very interesting in its own right, because this is a notable cause of morbidity in women with ovarian cancer. There is currently no drug therapy that is effective against ovarian cancer-associated ascites accumulation. Paracentesis, the removal of abdominal ascites, is commonly used to alleviate symptoms and prolong survival of women with ovarian cancer.......

.........In this study two formulations of GAP-107B8 peptides were tested in an established intraperitoneal xenograft model in immune-deficient mice and evaluated for tumour burden and accumulation of malignant ascites (excess fluid containing cancer cells in the abdominal cavity). The cell line selected for testing (OCC-1 human ovarian cancer) is of a phenotype characterized by the production of peritoneal ascites with growth of multiple small solid tumours......

Oncology Videos - ASCO 2010 Highlights (American Society of Clinical Oncology) Dr. Bradley Monk MD of the University of California Irvine talks about gynecological oncology, GOG 218, ovarian cancer, and angiogenesis

Note: Ascites/Avastin as single agent and or chemo GOG 218

Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells

Note: ACOR members see notes from Chicago

Abstract (in research/technical):

"Our findings highlight the possible confounding events that may affect the usefulness of RNAi in a therapeutic setting for disrupting EOC cell survival in ascites."

PennMed Clinical Trial: Phase 1/2a Study of DTA-H19 (IP) in Advanced Stage Ovarian Cancer With Symptomatic Ascites

Description This study is designed to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy for ascites palliation of DTA-H19 administered intraperitoneally (IP) in subjects with advanced stage ovarian cancer who have evidence of symptomatic ascites

Investigators George Coukos, M.D., Ph.D., Principal Investigator University of Pennsylvania Medical Center Philadelphia, Pennsylvania 19104-6142

2010 full free access: The prosurvival activity of ascites against TRAIL is associated with a shorter disease-free interval in patients with ovarian c

( highly technical )The prosurvival activity of ascites against TRAIL is associated with a shorter disease-free interval in patients with ovarian cancer

Intraperitoneal VEGF Inhibition Using Bevacizumab: A Potential Approach for the Symptomatic Treatment of Malignant Ascites?

"THE NECESSITY FOR CLINICAL TRIALS EVALUATING BEVACIZUMAB TREATMENT IN PATIENTS WITH MALIGNANT ASCITES
Based on the preclinical and clinical data outlined above, we strongly suggest that the efficacy and safety of the i.p. application of bevacizumab for the treatment of malignant ascites be assessed in stringently designed clinical studies. Bevacizumab is generally well tolerated and has an acceptable toxicity profile consisting primarily of hypertension and proteinuria. Other rare but important adverse effects, however, include delayed wound healing, arterial thrombosis, and bleeding [118]. Finally, a potentially serious adverse effect of bevacizumab is gastrointestinal perforation and, although comparably infrequent, this potentially life-threatening complication has generated significant clinical interest. Overall, gastrointestinal perforation was found to be an uncommon but well-documented side effect of treatment in the phase III trials of bevacizumab, as well as in subsequent surveillance trials, with a reported incidence of 1%–2% [106, 107, 109, 119]. Though strong evidence identifying specific risk factors is lacking, investigators have urged caution when treating patients with known bowel implants or a large tumor burden, prior radiation, and recent surgery or bowel obstruction [106, 119, 120]."