Is Renal Thrombotic Angiopathy a Potential Problem in the Chronic Treatment of Ovarian Cancer?

UNC Kidney Center:  thrombotic microangiopathy
                           ~~~~~~~~~~~~~~~~~~

Is Renal Thrombotic Angiopathy a Potential Problem in the Chronic Treatment of Ovarian Cancer?

"Treatments for recurrent ovarian cancer result in clinical
benefit and prolongation of survival times. However, our findings suggest that platinums, PLD (in large cumulative doses), bevacizumab, and possibly gemcitabine may result in cumulative kidney damage. Awareness of these long-term complications should open the way for studies on treatment strategies designed to minimize renal complications."

Abstract

Abstract Background and Objective

Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.

(Kidney damage was defined by pathologic abnormalities
or markers of damage, including abnormalities on blood
and urine tests and radiologic studies.)

Patients and Methods. 

Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997–2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002–2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m² for >3 months and were staged according to the National Kidney Foundation guidelines.

Results. 

Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy. 

Conclusions. 

CKD (chronic kidney disease) is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

• Chronic kidney disease
• Ovarian cancer
• Pegylated liposomal doxorubicin
• Renal thrombotic microangiopathy

paywalled - Gynecologic Oncology - Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer

ScienceDirect.com - Gynecologic Oncology - Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer

Objective

To identify factors that increase the risk of neutropenic events in women with advanced ovarian carcinoma receiving initial chemotherapy.

Methods

Multi-center retrospective study of women with FIGO stage III–IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy from 1995 to 2008. Outcomes were severe (SN; absolute neutrophil count [ANC] < 500/mm³) and febrile neutropenia (FN; ANC < 1000/mm³ and temperature > 38.1 °C). Cumulative risk of neutropenic events was estimated by Kaplan Meier method. Multivariate analysis was by Cox proportional hazard regression.

Results

Three hundred twenty-six patients met inclusion criteria. There were 251 SN events among 140 (43%) patients and 24 FN events among 22 (7%) patients. Univariate predictors of SN were body surface area < 2.0 m² (p = 0.03), body mass index (BMI) < 30 kg/m² (p < 0.01), Caucasian race (p < 0.01), treatment on research protocols (p < 0.01), non-carboplatin-containing regimens (p < 0.01), and planned relative dose intensity (RDI) > 85% of standard (p = 0.02). Women over age 60 were more likely to develop FN (p = 0.05). Multivariate predictors of SN were treatment on research protocols (hazard ratio [HR] 1.93; p < 0.01), Caucasian race (HR 2.13; p = 0.01), and planned RDI > 85% (HR 1.69; p = 0.05); predictors of FN were age > 60 (HR 2.84; p = 0.05) and non-carboplatin containing regimens (HR 4.06; p < 0.01).

Conclusion

While SN is fairly common, FN occurs infrequently in women with EOC undergoing taxane and platin-based chemotherapy and primary prophylactic growth factor support is not indicated. However, women older than 60 years of age receiving non-carboplatin containing regimens are at higher risk for FN and warrant closer surveillance.

Healthnewsreviews blog: The marketing of anemia drugs - a story we shouldn't forget (including comments)

The marketing of anemia drugs - a story we shouldn't forget

 "In an opinion piece on TheScientist.com, Daniel W. Coyne writes, “Amgen’s incomplete report on an early major trial of epoetin misled the medical community about the anemia drug’s risks and benefits—and helped make Amgen rich.”
In the book, “How We Do Harm,” Otis Brawley, MD, chief medical and scientific officer of the American Cancer Society, writes quite a bit about hemoglobin-building drugs.  He discusses:.....

FAQ: Adverse Events(search by drug name)

FAQ: Adverse Events

About Us

Adverse Events, Inc. (AEI) is a provider of up-to-the-minute, critical, potentially life-saving information regarding side effects associated with FDA-approved prescription medications. AEI has created a unique set of online tools that are optimized to provide un-paralleled access to adverse event information on over 4,000 drugs, in an easy to understand and navigate format. AEI’s tools give control over treatment plans back to patients and their doctors, while providing an immediate view of potential trends and problems in the drug industry to pharmaceutical, healthcare, insurers, financial institutions and media.
RxFilter™ is a proprietary 17-step data refinement process developed by AdverseEvents, Inc. that standardizes and normalizes the Federal Drug Administration (FDA) Adverse Events Reporting System (AERS) database. Combining complex computer algorithms with hands-on data analysis by highly trained researchers, the RxFilter process is the most thorough optimization procedure ever applied to the FDA's drug safety database. It accurately measures and tracks adverse events associated with medications reported to the FDA.

Top 10 Drugs with the Highest Number of Adverse Events Reported

Browse all by letter: example: Cisplatin    5,107 (number of adverse events reported)

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paywalled: Evaluation of prevalent and incident ovarian cancer co-morbidity : British Journal of Cancer

Access : Evaluation of prevalent and incident ovarian cancer co-morbidity : British Journal of Cancer

British Journal of Cancer , (1 May 2012) | doi:10.1038/bjc.2012.164

Evaluation of prevalent and incident ovarian cancer co-morbidity

Abstract

Background:

The peak in incidence of ovarian cancer occurs around 65 years and concurrent increasing risk by age for a number of diseases strongly influence treatment and prognosis. The aim was to explore prevalence and incidence of co-morbidity in ovarian cancer patients compared with the general population.

Methods:

The study population was patients with ovarian cancer in Sweden 1993–2006 (n=11 139) and five controls per case (n=55 687). Co-morbidity from 1987 to 2006 was obtained from the Swedish Patient Register. Prevalent data were analysed with logistic regression and incident data with Cox proportional hazards models.

Results:

Women developing ovarian cancer did not have higher overall morbidity than other women earlier than 3 months preceding cancer diagnosis. However, at time of diagnosis 11 of 13 prevalent diagnosis groups were more common among ovarian cancer patients compared with controls. The incidence of many common diagnoses was increased several years following the ovarian cancer and the most common diagnoses during the follow-up period were thromboembolism, haematologic and gastrointestinal complications.

Conclusion:

Women developing ovarian cancer do not have higher overall morbidity the years preceding cancer diagnosis. The incidence of many common diagnoses was increased several years following the ovarian cancer. It is crucial to consider time between co-morbidity and cancer diagnosis to understand and interpret associations.

press release: Risks of mixing drugs and herbal supplements: What doctors and patients need to know

Risks of mixing drugs and herbal supplements: What doctors and patients need to know

open access: Oxaliplatin-related thrombocytopenia

Oxaliplatin-related thrombocytopenia

Abstract/Full Text:

Oxaliplatin is a third generation platinum compound that inhibits DNA synthesis, mainly through intrastrandal cross-links in DNA. Most of the experience with the clinical use of this drug is derived from colorectal cancer but it is also used in other tumor types such as ovary, breast, liver and non-Hodgkin's lymphoma. Thrombocytopenia is a frequent toxicity seen during oxaliplatin treatment, occurring at any grade in up to 70 % of patients and leading to delays or even discontinuation of the chemotherapy. Although myelossupression is recognized as the main cause of oxaliplatin-related thrombocytopenia, new mechanisms for this side-effect have emerged, including splenic sequestration of platelets related to oxaliplatin-induced liver damage and immune thrombocytopenia. These new pathophysiology pathways have different clinical presentations and evolution and may need specific therapeutic maneuvers. This article attempts to review this topic and provides useful clinical information for the management of oxaliplatin-related thrombocytopenia. 

conclusions

Oxaliplatin-related thrombocytopenia can prevent the administration of the optimal dose and schedule of this important chemotherapy agent and limit its benefits in the adjuvant or metastatic setting. Mild to moderate bone marrow suppression is the main cause of thrombocytopenia during and after treatment with oxaliplatin. In this setting, patients present thrombocytopenia concomitant to anemia and neutropenia usually 1–2 weeks after treatment. Therapeutic approaches will include dose delays or reduction and consideration of platelet-stimulating agents. However, novel mechanisms of oxaliplatin-related thrombocytopenia should promptly be recognized by physicians and include an immune-dependent mechanism, as well as portal hypertension related to sinusoidal injury yielding splenic sequestration of platelets.

OIIT usually presents a sudden and isolated drop in platelet counts minutes to hours after oxaliplatin administration, leading to acute hemorrhagic events. Female patients with advanced CRC and prior oxaliplatin exposure are more likely to develop this consequence. Prompt immunological testing documenting oxaliplatin-mediated platelet destruction leads to definitive diagnosis. Platelets counts will improve after discontinuation of treatment and transfusions may be necessary during the acute phase. Other measures such as corticoid or immunoglobulin administration are controversial and patients with documented OIIT should not be rechallenged with oxaliplatin.

Hepatic sinusoidal injury is a well-known complication of oxaliplatin treatment and can lead to portal hypertension and hypersplenism. Thrombocytopenia in this setting demonstrates a different natural history, with moderate but prolonged reductions in platelet counts. Splenomegaly and other complications of portal hypertension are recognized in these patients. Platelet recovery is slow and usually takes 2–3 years to be complete after treatment discontinuation. When a fast platelet recovery is wanted, splenic embolization might be considered as a therapeutic measure.

An improvement in the recognition of these mechanisms of oxaliplatin-related thrombocytopenia will permit a better documentation of them and help to understand possible risk factors associated with this complication in different settings. This information may help the development of new preventive and therapeutic approaches and allow for a more rational management of cancer patients treated with oxaliplatin that present thrombocytopenia.

Potentially Dangerous Complementary and Alternative Medicine (CAM) Use by Ovarian Cancer Patients | Abstract

Potentially Dangerous Complementary and Alternative Medicine (CAM) Use by Ovarian Cancer Patients

Abstract

Objective: 

The use of complementary or alternative medicine (CAM) has increased greatly over the last decade. Although many CAM activities are unlikely to increase a patient's risk for adverse events with conventional treatment for cancer, this is not necessarily true of ingestible CAM treatments such as herbal remedies, teas, and other supplements. This study surveyed women with ovarian cancer in order to evaluate the use of herbs and supplements that might place them at increased risk at the time of their surgery for ovarian cancer.  

Methods: 

A total of 219 women with ovarian cancer, who had received care from one of two participating oncology practices, were surveyed. 

Results: 

Of the women who reported having had surgery to treat their ovarian cancer (n=209), 65 (31%) reporting using one or more herbs or supplements that have been hypothesized to increase their risk for adverse outcomes. In almost all cases the risks associated with these substances were elevated risks for excessive bleeding.  

Conclusions: 

The use of herbs and supplements that might increase risks associated with excessive bleeding during gynecologic cancer surgery is common. Further research is needed to better understand the risks associated with use of herbs and supplements among women approaching surgery

. (J GYNECOL SURG 28:1)

abstract - Gynecologic Oncology - Outcome of immediate re-operation or interval debulking after chemotherapy at a gynecologic oncology center after initially incomplete cytoreduction of advanced ovarian cancer

Gynecologic Oncology - Outcome of immediate re-operation or interval debulking after chemotherapy at a gynecologic oncology center after initially incomplete cytoreduction of advanced ovarian cancer

Background

Prognosis in advanced ovarian cancer is largely determined by completeness of tumor resection achieved during primary surgery. Incomplete initial debulking occurs frequently in non-specialized centers and there is an ongoing discussion about the best time for re-surgery after referral to tertiary centers.

Methods

Patients with advanced epithelial ovarian cancer (FIGO IIIB-IV) admitted between 1999 and 2007 who had primary incomplete surgery including those with initiated chemotherapy at outside institution were included. Surgical results, morbidity and prognosis were evaluated in patients with immediate re-operation before chemotherapy and those with interval debulking.

Results

48 eligible patients were identified in our tumor registry. Self-referral by patient was the most frequent mode of admission (n = 21, 43.8%). 22 patients (45.8%) patients underwent immediate re-surgery and 26 patients (54.2%) had an interval debulking after chemotherapy. In 12 patients (54.5%), macroscopically complete tumor removal could be achieved by immediate re-operation and in 17 patients (65.4%) after chemotherapy. Major complications were observed more frequently in patients with interval debulking (26.9 vs. 9.1%, p = 0.324). Median overall survival time was 53 and 34 months (p = 0.110) after immediate and delayed re-operation, respectively.

Conclusions

Upfront re-operation before start of chemotherapy is feasible and successful in an expertise referral centre in more than half of patients with incomplete primary surgery elsewhere. Complete resection even after initial incomplete debulking could improve outcome. Therefore, referral to expertise centers in those patients should be considered. Progression-free survival and overall survival showed a non-significant trend and complication rate a remarkable advantage in favor of upfront re-operation.

Keywords

• primary ovarian cancer;
• cytoreductive surgery;
• interval debulking surgery

abstract: Incontinence after colonoscopy - an unrecognized and preventable problem. A cross-sectional study from the Gastronet quality assurance program

 Abstract

"Female patients had a higher risk of incontinence than men."

Background: 
Colonoscopy requires insufflation of gas for visualization of the bowel wall. Worldwide, this is usually done using air. The aim of the present study was to assess the risk of post colonoscopy incontinence, and to investigate whether insufflation of CO₂ instead of air may reduce this risk, since it is easily absorbed through the bowel mucosa.
 

Conclusion:
About every 20th patient undergoing colonoscopy using standard air insufflation experiences post examination incontinence. This proportion can be reduced by 60 % by converting from air insufflation to insufflation with the absorbable CO₂.

abstract: Assessing residents' disclosure of adverse events: traditional objective structured clinical examinations versus mixed reality.

Assessing residents' disclosure of adv... [J Obstet Gynaecol Can. 2012] - PubMed - NCBI

J Obstet Gynaecol Can. 2012 Apr;34(4):367-73.

Department of Obstetrics and Gynecology, University of Ottawa, Ottawa ON.

Abstract

Objective: 
The skill of disclosing adverse events is difficult to assess. Assessment of this competency in medical trainees is commonly achieved via the objective structured clinical examination (OSCE) using a standardized patient (SP). We hypothesized that the addition of a simulated clinical adverse event prior to the SP encounter could increase trainees' engagement and empathy, thereby improving performance. The objective of this study was to explore whether experiencing a simulated adverse event prior to an SP encounter alters resident performance on a disclosure OSCE.


Conclusion: 
The assessment of adverse event disclosure was not enhanced by the addition of a simulated experience. Study participants reported that the simulation did not provide the contextual information required to elicit empathy and a sense of being emotionally invested in the adverse event.

AACR: Selumetinib Controlled Recurrent Low-grade Serous Ovarian Cancer

Selumetinib Controlled Recurrent Low-grade Serous Ovarian Cancer:

• Selumetinib controlled the disease in 81 percent of patients.
• Median progression-free survival was 11 months.
• Patients experienced minimal side effects.

CHICAGO — Selumetinib, a small-molecule MEK inhibitor, demonstrated the ability to control low-grade serous ovarian or peritoneal cancer, according to phase II study results presented at the AACR Annual Meeting 2012, held here March 31 – April 4.
The first line of defense against low-grade serous ovarian cancer is surgery, followed by cytotoxic chemotherapy. However, this is a slow-growing cancer and does not respond well to traditional chemotherapies, which target fast-growing cells.
Seeking a more rational treatment approach, Gynecologic Oncology Group (GOG) researchers led by John Farley, M.D., a professor at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center in Omaha, Neb., used selumetinib to target the MEK-1/2 protein kinase in the MAPK pathway, which is known to mutate in this form of cancer.
GOG researchers assigned 52 women to 100-mg doses of selumetinib orally twice daily in four-week cycles; 33 percent underwent 12 or more cycles. Prior to the study, 58 percent of patients had received three or more rounds of chemotherapy.
Selumetinib controlled the disease in 81 percent of patients. Specifically, eight patients had complete or partial responses to treatment, and 34 had stable disease. The median survival rate without cancer progression was 11 months, and 63 percent of patients had progression-free survival longer than six months. In addition, selumetinib was well tolerated, with three patients experiencing grade 4 adverse events.
“The results were striking,” said Farley. “Many of the patients in the study had received multiple rounds of chemotherapy and were running out of options. By using these tumors’ historical inherent molecular aberrations to select patients for a treatment that in theory could exploit these abnormalities, we took an important step toward individualized cancer therapies.”
In addition to studying the impact of selumetinib on this type of ovarian cancer, investigators were also interested in how patients with RAS/RAF mutations responded to the drug. The team analyzed the tumor DNA from 34 patients, 62 percent of whom had some form of RAS/RAF mutation. Ultimately, they found that RAS/RAF mutations had no impact on patient response.
The study was funded by the National Cancer Institute.

abstract: Does long-term treatment with Doxil(®) predispose patients to oral cancer?

Does long-term treatment with Doxil(®) predispose patients to oral cancer?

Abstract

We present a possible adverse reaction related to long-term use of Doxil(®) in female patients. We believe that long-term use of Doxil(®) may predispose female patients to oral squamous cell carcinoma. The patients in this report were not exposed to the common risk factors related to oral cancer formation such as smoking or alcohol consumption.  

Both patients were 59-year-old females.

The first patient was diagnosed in 2001 with stage IIIC ovarian cancer. Seven years following treatment with Doxil(®), she was diagnosed with stage III squamous cell carcinoma of the right maxilla.

The second patient was diagnosed with Kaposi's sarcoma with evidence of spread to the lungs. Four years following treatment with Doxil(®) she was diagnosed with stage I squamous cell carcinoma of the left maxilla.

A literature review did not reveal any report on Doxil(®) and predisposition to oral cancer; however, we found an abstract that was presented at the last annual meeting of the American Society of Clinical Oncology (ASCO) by Cannon et al.

When we combine the data from Cannon et al. and the data presented here, a total of six female patients developed an epithelial carcinoma of the oral cavity following long-term treatment with Doxil(®).

We believe that a large-scale study should be initiated on patients that were treated with Doxil(®) for more than 3 years, since these patients might be at risk for developing secondary cancer of the oral cavity.

abstract: Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery - Variability of Poly (ADP-Ribose) Polymerase Activity.

Wiki:  Poly ADP ribose polymerase: Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

                   ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery - Variability of Poly (ADP-Ribose) Polymerase Activity.

Abstract

Purpose: 

The aim of this study was to evaluate the feasibility of phase 0 trials in the setting of a routine surgical procedure. Logistic considerations, tissue sampling and handling, and variability of a biomarker during surgery, in here activity of poly(ADP-ribose) polymerase, were evaluated. 

Experimental design: 

Patients with highly suspicious or proven diagnosis of advanced ovarian cancer, planned for debulking surgery were asked to allow sequential tumor biopsies during surgery. Biopsies were frozen immediately and poly (ADP-ribose) polymerase activity was measured subsequently. 

Results: 

Baseline biopsies were obtained from eight patients after a median time of 88 minutes (minimum of 50 to maximum of 123 minutes). Second and third biopsies were obtained after a median of 60 (32-96) and 101 (79-130) minutes, respectively. Mean tumor load was 44% (5%-100%), with a cellular viability of 98% (85%-100%). Median baseline PARP activity was 1035 pg/ml (range: 429-2663 pg/ml). The observed inter-patient variability at baseline was large: standard deviation was 769 before and 0.59 after natural log transformation. 

Conclusions: 

Conducting phase 0 trials during surgery seems to be feasible in terms of logistic considerations. In preparation of a phase 0 trial during surgery, a feasibility study like this should be conducted to rule out major interactions of the surgical intervention with respect to the targeted biomarker.

Medco Study Finds Many Patients on Newer Oncology Treatments Are at Risk for Drug Interactions - PRNewswire

Medco Study Finds Many Patients on Newer Oncology Treatments Are at Risk for Drug Interactions -- WASHINGTON, March 16, 2012 /PRNewswire/ --

abstract: Phase 1 Dose-Escalation Study of Aflibercept Plus Docetaxel

Phase 1 Dose-Escalation Study of Aflibercept Plus Docetaxel:

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.

Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m²) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.

Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data.
Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).

Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study


Objective 
To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II–IV ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods 
Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60mg/m² on day 8. A standard 3+3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment.

Results 
Patients were treated with paclitaxel 175mg/m² IV and carboplatin IP from AUC 5–7 on day 1 and paclitaxel 60mg/m² IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), >2week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135mg/m² IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4cycles with one DLT (grade 3 hyponatremia).

Conclusions 
Paclitaxel at 175mg/m² IV, carboplatin AUC 6 IP day 1 and paclitaxel 60mg/m² IP day 8 yield 18–56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.

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.

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."

open access: Ports and complications for intraperitoneal chemotherapy delivery (ovarian cancer)

"Intraperitoneal access ports are essential to the delivery of chemotherapy agents into the peritoneal cavity of women with ovarian cancer, but their malfunction and adverse effects are frequently responsible for the failure to complete planned therapy. Complications, such as obstruction of the catheter, infection, leakage, rotation, retraction, and pain, together with bowel and vaginal perforation, cause delays in treatment, patient suffering and the expenditure of medical resources. A wide variety of ports have been used, including vascular access devices and intraperitoneal access devices. This paper reviews the development and use of ports for intraperitoneal chemotherapy, their complications and reported methods of prevention...."

(Blogger's Note: tables are included in the text of the paper)

Table 2.   Reported complications of ports used for IP access 
(years 1984 through to 2010)

Table 3.   Percentage of cases where IP chemotherapy was discontinued because of the port 
(years 1994 through to 2010)

Table 4.   Port complications causing the discontinuation of IP chemotherapy* 
(years 1991 through to 2010)

	Influence of surgeon and team experience "There is a lack of information in the literature with regard to the effect of the expertise of the surgeon placing the ports, and the experience of the support team (including doctors and nurses) in managing the ports and patients to reduce complications and improve completion rates...."

		Conclusion:

Port complications are significant, and overall, 15% (210/1945) of patients discontinued IP chemotherapy as a result of a port complication, with obstruction (37.6%) and infection (31.4%) being the most common reasons.

Complications such as leakage, retraction of the catheter, rotation of the portal, difficulties with access and perforation of the bowel can be kept to a minimum with careful technique, but they are still not completely avoidable. Although infection may theoretically be reduced by the avoidance of placement during grossly contaminated surgeries, hard data on the influence of associated bowel surgery at the time of placement are lacking, and there is no proven method of preventing the adhesions that cause obstruction to flow. There does not appear to be a difference in the rates of complications between fenestrated or unfenestrated ports, and the choice of port should be at the surgeon’s discretion.

Despite almost 30 years of experience, it remains difficult to identify which patients are going to experience port complications that impact on the completion of IP therapy. More effective methods of preventing complications and improving tolerability, and thus reducing discontinuation rates, are needed.