Cisplatin plus paclitaxel and maintenance of (Avastin) bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models

Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models:
 July 2012  doi:10.1038/bjc.2012.261

Background:

Bevacizumab is being incorporated as first-line therapy with standard-of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models.

Methods:

Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models.

Results:

Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft.

Conclusion:

Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression.

paywalled: Bevacizumab-induced perforation of the gastrointestinal tract: clinical and radiographic findings in 11 patients

Bevacizumab-induced perforation of the gastrointestinal tract: clinical and radiographic findings in 11 patients:

Abstract

Aim

To present the gastrointestinal (GI) complications associated with bevacizumab therapy and their findings on abdominal imaging studies.

Methods 

A computerized search identified 11 patients with GI complications of bevacizumab therapy on abdominal CT (n = 11) and fluoroscopic GI contrast studies (n = 4) who met our study criteria (including five patients with ovarian cancer, five with colon cancer, and one with cervical cancer). The medical records and imaging studies were reviewed to determine the clinical and radiographic findings in these patients.

Results  

All 11 patients had findings of GI perforation on CT, or CT and GI contrast studies. CT revealed a localized extraluminal collection containing gas, fluid, and/or contrast material in eight patients (73%) with focal perforation, and free abdominal air and fluid in three (27%) with free perforation The imaging studies also revealed seven fistulas, including two colovaginal, one rectovaginal, one enterocutaneous, one colocutaneous, one gastrocolic, and one colorectal fistula. Eight (73%) of the 11 patients died within 1 year of the development of GI perforation, and the perforation was felt to be the cause of death in four patients (36%).

Conclusion  

Abdominal CT and fluoroscopic GI contrast studies are useful imaging tests for the diagnosis of potentially life-threatening GI perforation as a complication of bevacizumab therapy. When GI perforation is detected on abdominal imaging studies, treatment with bevacizumab should immediately be discontinued.

Clinical Care Options - OCEANS: PFS Improvement of 4 Months With the Addition of Bevacizumab to Carboplatin/Gemcitabine in Patients With Platinum-Sensitive Recurrent Ovarian Cancer ASCO 2011

 Blogger's Note: requires registration (free) to view

Clinical Care Options - Oncology CME - OCEANS: PFS Improvement of 4 Months With the Addition of Bevacizumab to Carboplatin/Gemcitabine in Patients With Platinum-Sensitive Recurrent Ovarian Cancer

CCO Independent Conference Coverage of the 2011 American Society of Clinical Oncology Annual Meeting*

*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

OCEANS: PFS Improvement of 4 Months With the Addition of Bevacizumab to Carboplatin/Gemcitabine in Patients With Platinum-Sensitive Recurrent Ovarian Cancer

Posting Date: June 15, 2011

• OCEANS: randomized, double-blind, placebo-controlled phase III trial^[1]

Summary of Key Conclusions

• Addition of bevacizumab to carboplatin/gemcitabine yielded significant benefits vs carboplatin/gemcitabine alone in patients with platinum-sensitive recurrent ovarian cancer
  • Median PFS improved by 4 months
  • Objective response improved by 21%
  • Median duration of response improved by 3 months
  • Trend toward improved OS
    • Data not yet mature
• Safety profile of bevacizumab plus carboplatin/gemcitabine consistent with previous reports
  • No new safety signals observed
  • No gastrointestinal (GI) perforations reported

Background

• Carboplatin/gemcitabine US Food and Drug Administration approved in 2006 for treatment of platinum-sensitive recurrent ovarian cancer based on improvement in PFS vs carboplatin alone in phase III clinical trial^[2]
• Bevacizumab: humanized anti-VEGF monoclonal antibody
  • Demonstrated single-agent activity in recurrent ovarian cancer^[3,4]
• Current study assessed carboplatin/gemcitabine chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer...............cont'd

Roche will report new data on important progress for people with advanced cancers at ASCO 2012 - AURELIA trial ovarian/Avastin+

Roche will report new data on important progress for people with advanced cancers at ASCO 2012

Data from AURELIA, the first Phase III study of Avastin plus chemotherapy in people with platinum-resistant recurrent ovarian cancer will be presented. This study will be highlighted as part of ASCO’s official press program.

Multiple VEGF Family Members are Simultaneously Expressed in Ovarian Cancer: a Proposed Model for Bevacizumab Resistance

Multiple VEGF Family Members are Simultaneously Expressed in Ovarian Cancer: a Proposed Model for Bevacizumab Resistance.:


Curr Pharm Des. 2012 May 14;

Abstract
Objective Insight into the expression of multiple vascular endothelial growth factor (VEGF) family members can support the implementation of anti-angiogenic therapy. This study aimed to assess VEGF family member expression in ovarian cancers and related omental metastases.

Methods Tissue microarrays encompassing 270 primary cancers and 112 paired metastases were immunostained for VEGF-A, VEGF-B, VEGF-C and VEGF-D. Staining intensities were categorized as absent, weak, moderate or strong. Expression was related to clinicopathological characteristics and survival.

Results Immunohistochemical positivity (defined as moderate or strong expression) was observed for VEGF-A in 90%, VEGF-B in 4%, VEGF-C in 41% and VEGF-D in 55% of the primary ovarian cancers. ....... VEGF family member expression showed no independent prognostic significance in multivariate survival analysis.

Conclusion VEGF-A, VEGF-C and VEGF-D are widely and often simultaneously expressed in ovarian cancer, which may contribute to bevacizumab resistance. Measuring their expression could support a rational, individualized choice of anti-angiogenic therapy and might be of predictive value. Studies are warranted to determine whether combinatorial analysis of VEGF family member expression can be used to predict anti-angiogenic drug efficacy.

The role of bevacizumab in advanced epithelial ovarian cancer.

The role of bevacizumab in advanced epithelial ovarian cancer.:

The role of bevacizumab in advanced epithelial ovarian cancer.
Curr Pharm Des. 2012 May 14;

Abstract
Background: There is a strong rationale for usage of anti-angiogenic agents in epithelial ovarian cancer. Bevacizumab is the most widely investigated anti-VEGF agent and has shown promising results in recent clinical trials.

Objective: To review the rationale and usage of bevacizumab in advanced epithelial ovarian cancer; as mono-therapy, in combination with chemotherapy both as first line and for recurrent ovarian cancer as well as in combination with other targeted therapies.

Results: In epithelial ovarian cancer, angiogenesis promotes tumor growth, ascites formation and metastasis. Targeting VEGF in ovarian cancer patients may have indirect and direct cytotoxic effects. Results of placebo controlled phase III trials, the GOG-218 and ICON7, of carboplatin-paclitaxel alone or combined with bevacizumab in chemo-naive patients and the OCEAN trial comparing carboplatin-gemcitabine with or without bevacizumab in women with recurrent platinum-sensitive epithelial ovarian cancer all suggest a benefit for the addition of bevacizumab on progression free survival. Additionally, bevacizumab in combination with other targeted therapies, such as sorafenib and everolimus are under investigation in phase II trials and the current knowledge of molecular predictors is discussed.

In conclusion: Until now no survival benefit has been observed, but bevacizumab is the first anti-angiogenic agent demonstrating a progression free survival benefit in addition to standard chemotherapy regimens in advanced epithelial ovarian cancer, both in the upfront and recurrent setting. Mature overall survival data and the search for predictive biomarkers are important for the future role of bevacizumab in epithelial ovarian cancer.

ASCO '12 Abstract Dump: Cancer Stocks in Focus - TheStreet (financial)

ASCO '12 Abstract Dump: Cancer Stocks in Focus - TheStreet

.....While investors were flooded with new cancer drug data Wednesday, ASCO did hold back some of the some important and potentially stock-moving research for a more high-profile release at the meeting itself. 

Key cancer drug data that remains under wrap include results from a phase III study of Johnson & Johnson's(JNJ_) Zytiga in "pre-chemo" prostate cancer patients; a phase III study of Bayer and Onyx's regorafenib in advanced gastrointestinal stromal tumors; several Roche/Genentech(RHHBY) studies, including Avastin in ovarian cancer and TDM-1 in breast cancer (partnered with Immunogen(IMGN_)); melanoma data from GlaxoSmithKline's(GSK_) targeted drug dabrefenib; and a new targeted PD-1 immunotherapy from Bristol-Myers Squibb(BMY_).
The following pages summarize new and important cancer drug data released tonight by ASCO from research abstracts for its upcoming annual meeting.......

paywalled: Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.:

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Hepatogastroenterology. 2012 Jul-Aug

Abstract
Background/Aims:
We conducted a phase I trial of IP oxaliplatin and paclitaxel with IV paclitaxel and bevacizumab in patients with peritoneal carcinomatosis.

Methodology:
Patients received IV bevacizumab (2.5mg/kg) over 1 hour (day 1), then IV paclitaxel (110mg/m2) 24-hr-infusion (day 1) and IP oxaliplatin (25-40mg/m2) (day 2), and IP paclitaxel (30-60mg/m2) (day 8 from cycle 2 onwards). A '3+3' design was used.

Results:
Nineteen patients were treated (median age 60 years; 10 women, 9 men; median number of prior therapies 3). Primary tumors were colorectal (n=9), signet ring carcinoma (n=2), gastric (n=2), ovarian (n=2) and others (n=4). The maximum tolerated doses (MTD) of IP oxaliplatin and IP paclitaxel were 25mg/m2 and 60mg/ m2, respectively. Nine (47%) patients reported no toxicities >grade 2. Two patients receiving IP oxaliplatin 40mg/m2 and IP paclitaxel 60mg/m2 had dose limiting toxicities (DLT) of grade 3 diarrhea/dehydration and febrile neutropenia. Toxicities included abdominal pain (n=14), nausea (n=10) and constipation (n=7). Of 12 patients restaged at 2 months, 7 (58%) had stable disease (SD) including 2 (17%) who had SD for >4 months.

Conclusions: 
IP paclitaxel and IP oxaliplatin can be given safely at 60mg/m2 and 25mg/m2, respectively.

PMID: 22580643 [PubMed - in process]

Medscape: Bevacizumab Benefits Patients With Recurrent Ovarian Cancer (bevacizumab plus carboplatin and gemcitabine followed by bevacizumab)

Bevacizumab Benefits Patients With Recurrent Ovarian Cancer

Correspondence: Bevacizumab in Neoadjuvant Treatment for Breast Cancer — NEJM

Blogger's Note:  correspondence/author's reply/references; while this is specific to Avastin/breast cancer,  future trial protocols may take note

Bevacizumab in Neoadjuvant Treatment for Breast Cancer — NEJM

PLoS ONE: Effect of Angiogenesis Inhibitor (Avastin) Bevacizumab on Survival in Patients with Cancer: A Meta-Analysis of the Published Literature

 Blogger's Note: indicates which cancer patients did/did not show PFS/OS; limited to combo therapies (lack of monotherapy trials); read limitations to the analysis (eg. individual patient data/meta-analysis...); notes serious side effects

PLoS ONE: Effect of Angiogenesis Inhibitor Bevacizumab on Survival in Patients with Cancer: A Meta-Analysis of the Published Literature

Add-on bevacizumab slows progression of recurrent ovarian cancer - - ModernMedicine

Add-on bevacizumab slows progression of recurrent ovarian cancer - - ModernMedicine


(from Reuters) "....Dr. Aghajanian and colleagues note that overall survival data from the trial are not yet available; information on clinicaltrials.gov indicates a predicted study completion date of October 2013.
For now, say the researchers, "The data from OCEANS demonstrate that the addition of BV (bevacizumab) to GC (gemcitabine and carboplatin) can improve outcomes, and ongoing studies will assess whether this ability to add benefit is universal to other platinum-based combinations."
OCEANS is supported by Genentech, which markets bevacizumab as Avastin.

paywalled: Vascular disrupting agents: a delicate balance between efficacy and side (safety) effects

Vascular disrupting agents: a delicate balance between effi... : Current Opinion in Oncology

Current Opinion in Oncology:

May 2012 - Volume 24 - Issue 3 - p 305–315

doi: 10.1097/CCO.0b013e32835249de

INNOVATIVE EARLY CLINICAL TRIALS METHODOLOGY AND NEW THERAPEUTICS IN CANCER: Edited by Ahmad Awada

Abstract

Purpose of review: 

Targeting the tumor vasculature is an attractive approach for cancer therapy. Vascular disrupting agents (VDAs) are compounds that directly target tumor blood vessels and create central tumor necrosis. The current review aims to summarize the clinical development (i.e. safety and efficacy) of this class of compounds.

Recent findings: 

VDAs have demonstrated signs of clinical activity in different tumor types [e.g. anaplastic thyroid carcinoma (ATC), nonsmall cell lung carcinoma (NSCLC), ovarian cancer, sarcoma]. However, the lack of predictive biomarkers to identify patients with a high probability of response to VDAs, places this class of compounds at a high risk of failure. This has recently been exemplified by several negative phase II/III trials in NSCLC, ATC, and castration-refractory metastatic prostate cancer.

Summary: 

VDAs represent a unique class of anticancer compounds. Their clinical development is hampered by cardiovascular, neurological toxicities as single agent and by hematological toxicity in combination with chemotherapy. Molecular predictors of their efficacy are crucial for further development. As single agent, only few objective responses have been observed in a variety of solid tumors. However, VDAs have failed to demonstrate a survival advantage in several phase II/III trials especially in combination with chemotherapy.

phase 2: Vargatef (Nintedanib) in Addition to First Line Chemotherapy With Interval Debulking Surgery in Patients With Ovarian Cancer - Full Text View - ClinicalTrials.gov - France) (treatment/placebo/note: Avastin...)

Vargatef in Addition to First Line Chemotherapy With Interval Debulking Surgery in Patients With Ovarian Cancer - Full Text View - ClinicalTrials.gov

This study is not yet open for participant recruitment.

Verified April 2012 by ARCAGY/ GINECO GROUP

First Received on April 19, 2012.   Last Updated on April 23, 2012   History of Changes

Sponsor:	ARCAGY/ GINECO GROUP
Information provided by (Responsible Party):	ARCAGY/ GINECO GROUP
ClinicalTrials.gov Identifier:	NCT01583322

  Purpose

Patients with extensive and bulky disease are often those whose initial surgery is delayed after 3 or 4 cycles of neo-adjuvant chemotherapy.

In that case, there is, indeed, some concern to administer bevacizumab during the chemotherapy surrounding the interval debulking surgery due to the long half life (14- 21 days) of this monoclonal antibody and the interference of anti angiogenic agents with wound healing.

Vargatef® (Nintedanib) might offer a better alternative to bevacizumab in the neo-adjuvant setting. Vargatef® (Nintedanib) has a much shorter half-life of 7 to 19 hours. Preliminary experience in cancer did not show a trend for increased incidence of fistula or bowel perforation. For more details please refer to the investigator drug brochure for Vargatef® (Nintedanib).

This trial will compare progression-free survival and surgical complications of 188 patients with FIGO stage IIIC/IV treated in first line with either neo-adjuvant chemotherapy (carboplatin & paclitaxel) and interval debulking surgery or the same treatment + Vargatef® (Nintedanib).

open access: JCO - OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

• Submitted January 26, 2012; accepted
  February 17, 2012; published online
  ahead of print at www.jco.org on April
  23, 2012.
• Supported by Genentech.
• Presented in part at the 47th Annual
  Meeting of the American Society of
  Clinical Oncology, June 3-7, 2011,
  Chicago, IL.

Table 1. Baseline Patient Demographics and Disease Characteristics: 
(see actual table for further details; see other tables for adverse/safety event comparisons; )

Histology subtype #'s

Serous 202
Mucinous 1
Endometrioid 16
Transitional cell 2
Clear cell 6
Mixed 5
Other 10



 The limitations of OCEANS include a lack of quality-of-life data
and specimen collection for biomarker analysis. The strengths of
OCEANS, however, lie in the robustness of the primary end point,
with strict adherence to RECIST-defined progression and its supportive
IRC analysis, and to the schedule of assessments. The median
increase of 4 months in PFS is well above the frequency of radiologic
reassessments (9 weeks).24,25 TheOCEANS data demonstrate that GC
plus BV followed by BV until progression provides benefit over GC
alone in ROC. OCEANS, GOG 218, and ICON7 represent three
positive phase III trials of BVadded to chemotherapy in the treatment
of ovarian cancer.

Medscape: (Avastin) Bevacizumab: First-Line Therapy in Ovarian Cancer?: Evidence for First-Line Therapy Dr's Markman, Burger, Swenterton

Bevacizumab: First-Line Therapy in Ovarian Cancer?: Evidence for First-Line Therapy

Editor’s Note:
 
Two phase 3 trials published in the New England Journal of Medicine on December 29, 2011, found bevacizumab to be active as first-line therapy in advanced ovarian cancer. Although both trials showed an increase in progression-free survival [PFS], not enough time has elapsed to determine whether the drug extends overall survival. Furthermore, it is unclear whether bevacizumab in ovarian cancer is best used as first-line or second-line therapy. Recently, Drs. Robert Burger and Kenneth Swenerton participated in a Medscape virtual debate via email to address this question: "Should bevacizumab be used as first-line therapy in patients with advanced ovarian cancer?" Dr. Maurie Markman served as moderator. What follows is their conversation......

open access: PLoS ONE: Proteins from Avastin® (bevacizumab) Show Tyrosine Nitrations for which the Consequences Are Completely Unclear

PLoS ONE: Proteins from Avastin® (bevacizumab) Show Tyrosine Nitrations for which the Consequences Are Completely Unclear

"......A major finding indicating pathogenetic or toxic properties of nitrated proteins was presented recently: assembly of alpha-synuclein and fibrinogen were deteriorated by nitration of only a small fraction of proteins [25], [32]. As for fibrinogen, nitration is accelerating the rate of fibrin clot formation [33]. It cannot be ruled out, therefore, that nitration of Avastin® may lead to side effects based upon probable disturbed protein-protein interactions as aggregations that in turn may lead to a series of complications as listed in the drug information sheet.
As to the underlying cause of tyrosine nitration it remains open, whether it can be considered as a post-translational modification of the immunoglobulin Avastin® or technical in nature, or both [34]-[38].
Taken together, it remains unclear if the observed nitrations and other PMs detected on Avastin® may be responsible for different biological or pharmacotoxicological properties and effects. Quantification of nitrations and their presence in several batches of the product has to be taken into considerations on probable toxicity as well, but corresponding in vivo analyses based upon these findings should be carried out by the manufacturers to probably save this protein drug that may have strong potential in tumor therapy."

abstract: Sequential Bevacizumab and Oral Cyclophosphami... [Gynecol Oncol. 2012] - PubMed - NCBI

Sequential Bevacizumab and Oral Cyclophosphamide for Recurrent Ovarian Cancer.

Abstract

OBJECTIVE:

Test the safety and efficacy of sequentially blocking angiogenesis by adding oral cyclophosphamide to bevacizumab following cancer progression on bevacizumab in patients with recurrent ovarian cancer.

METHODS:

Eligibility included≤2 lines of treatment for recurrence and measurable cancer by RECIST 1.0. Patients received bevacizumab (15mg/kg every 3weeks IV) and upon RECIST progression, oral cyclophosphamide (50mg orally daily) was added. Objectives included safety, toxicities, 3- and 6-month PFS rates, response rate, PFS, and OS.

RESULTS:

20 patients were enrolled. Overall response rate was 10%, and 65% of patients had confirmed stable disease (SD). Thirteen of 20 patients received oral cyclophosphamide added to bevacizumab upon bevacizumab progression. Of these 13 patients, 1 patient subsequently achieved a PR (this patient had SD as best response during bevacizumab) and 3 patients had a confirmed SD. For all patients, median PFS was 8.41 months, 6 month PFS rate was 65%, duration of response (DOR) 7.3 months, and median OS was 22.72 months. Median DOR for patients receiving both bevacizumab and cyclophosphamide was 8.4months. Most toxicities were grade 1 and 2 and manageable. Grade 3 and grade 4 toxicities included 1 myocardial infarction, 1 gastrointestinal perforation (GIP), and 12/20 patients (60%) developed grade 3 HTN.

CONCLUSIONS:

Addition of oral cyclophosphamide to bevacizumab at the time of cancer progression on bevacizumab appears to have continued anti-cancer effects in a subgroup of patients and appears to be safe. Randomized trials testing combination versus sequential anti-angiogenic therapy for recurrent ovarian cancer are warranted.

Drug Formulary - Avastin - Cancer Care Ontario (compared to Australia) - see notes

 Blogger's Notes: 

incidence rates ovarian cancer:
Australia: 1,488 (2015 projection)
Canada:  2,600 (annual estimates)

1. Australia population (census) 22 million
2. Canada population (census) 34 million
3. Ontario population (census) 13 million

 
Drug Formulary - Ontario

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BEVA Gastrointestinal - Colorectal Advanced Regimen category: Standard	Drug(s) used: Bevacizumab (with fluoropyrimidine-based chemotherapy)	Regimen Monograph	2011-12-16
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1-2 of 2  result(s)


(CCS) Clinical Trials - Canada: ovarian cancer/Avastin

	Recruiting in 1 of 2 locations
A Study of the Addition of Avastin (Bevacizumab) to Carboplatin and Paclitaxel Therapy in Patients With Ovarian Cancer	Recruiting in 2 of 4 locations

(first line treatment approved) - New treatment (Avastin) option for ovarian cancer in Australia - News

New treatment option for ovarian cancer in Australia - News

"Australian women with advanced ovarian cancer have a new treatment option for their disease. The anti-cancer treatment, Avastin (bevacizumab), is now approved by the Therapeutic Goods Administration (TGA) in combination with chemotherapy (carboplatin and paclitaxel) for the treatment of patients with newly diagnosed (first-line) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer......