Letter: Bevacizumab in Ovarian Cancer — NEJM

Bevacizumab in Ovarian Cancer — NEJM

Correspondence

Bevacizumab in Ovarian Cancer

N Engl J Med 2012; 366:1256-1258  March 29, 2012

Article

To the Editor:

In their article on the findings of the Gynecologic Oncology Group study GOG-0218 (ClinicalTrials.gov number, NCT00262847), Burger et al. (Dec. 29 issue)1 state, as have others in a similar context,2 that the potential to see differences in overall survival in an ovarian cancer trial is limited by post-progression therapies, including crossover to the experimental agent bevacizumab. Post-progression therapies will attenuate differences in overall survival that would be seen if such therapies did not exist, but the observed attenuated differences are the correct measure of clinical benefit for the patients provided that standard-of-care post-progression therapies are used in both treatment groups.3,4

This would seem to be the case in the Gynecologic Cancer InterGroup (GCIG) International Collaboration on Ovarian Neoplasms (ICON7) bevacizumab trial (NCT00483782) reported by Perren et al. (also in the Dec. 29 issue),5 in which less than 4% of the patients in the control group received post-progression antiangiogenic treatments. To interpret the GOG-0218 results, one would need to know how many patients received post-progression antiangiogenic treatments. However, if one considered bevacizumab a standard treatment for progressing (recurrent) ovarian cancer given that it has shown activity, is recommended by National Comprehensive Cancer Network guidelines, and is covered by Medicare, then the observed difference in overall survival seen in the GOG-0218 and ICON7 trials1,5 is the appropriate estimate of clinical benefit for overall survival, regardless of post-progression treatments.

Edward L. Korn, Ph.D.
Boris Freidlin, Ph.D.
Jeffrey S. Abrams, M.D.
National Cancer Institute, Bethesda, MD
korne@ctep.nci.nih.gov

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.

no abstract: Sudden Death Related to Toxicity in a Patient on Capecitabine and Irinotecan Plus Bevacizumab Intake: Pharmacogenetic Implications

Sudden Death Related to Toxicity in a Patient on Capecitabine and Irinotecan Plus Bevacizumab Intake: Pharmacogenetic Implications:

Laetitia Dahan, Joseph Ciccolini, Alexandre Evrard, Litaty Mbatchi, Jack Tibbitts, Pauline Ries, Emmanuelle Norguet, Cedric Mercier, Athanassios Iliadis, L''Houcine Ouafik, Bruno Lacarelle, Jean-Francois Seitz
Feb 1, 2012; 30:41-44
DIAGNOSIS IN ONCOLOGY

media: Benefits of Bevacizumab in Ovarian Cancer Clarified - Michael J. Birrer, MD, PhD

"Bevacizumab (Avastin) has failed to demonstrate statistically significant improvements in overall survival (OS) for women with recurrent ovarian cancer in 2 recent clinical trials, but those results may be affected by factors not related to the drug’s efficacy, according to Michael J. Birrer, MD, PhD......

updated - link to full free paper: Review: Therapeutic strategies in epithelial ovarian cancer (references clear cell ovarian)

 Blogger's Note: numerous references to clear cell ovarian cancer as per Japanese historical ovarian cancer research



direct link to pdf file 

 "In summary, it appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas are, in fact, secondary.

Previous data support the view that serous tumors develop from the fimbria, the most distal part of the fallopian tube, endometrioid and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact to the peritoneum.

Although the data suggesting that epithelial ovarian carcinoma arises in extra-ovarian sites and involves the ovaries secondarily are compelling, low- and high-grade serous carcinomas involve the ovaries and other pelvic and abdominal organs, such as the omentum and mesentery, much more extensively than the fallopian tubes. Similarly, although endometrioid carcinomas develop from endometriosis, which frequently involves multiple sites in the pelvis, these tumors are usually confined to the ovaries.

It is likely that the predisposition for
growth in the ovary is multifactorial but the precise reasons for this are unknown."

Clinical Oncology News - Finding an Avastin (Bevacizumab) Biomarker: An Elusive Target

"On a basic level, it is still somewhat unclear why bevacizumab works on some cancers and not on others because seemingly, all tumors need to be fed by blood vessels."

abstract: Treatment of bevacizumab-induced hypertension by amlodipine. Invest New Drugs. 2012

update with specific locationst: Avastin (bevacizumab): Counterfeit Product - FDA Issues Letters to 19 Medical Practices California, Illinois, Texas

 The U.S. Food and Drug Administration is warning healthcare professionals and patients that a counterfeit version of Avastin (bevacizumab) 400mg/16mL was purchased and may have been used by 19 medical practices — 16 in California , 1 in Illinois, and 2 in Texas

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From: FDA MedWatch
Date: 02/14/2012
Subject: FDA MedWatch - Avastin (bevacizumab): Counterfeit Product - FDA Issues Letters to 19 Medical Practices

Avastin (bevacizumab): Counterfeit Product - FDA Issues Letters to 19 Medical Practices

AUDIENCE: Oncology, Pharmacy, Patient

ISSUE: The FDA is warning healthcare professionals and patients about a counterfeit version of Avastin 400mg/16mL, which may have been purchased and used by some medical practices in the United States. The counterfeit version is labeled as Avastin, manufactured by Roche and does not contain the medicine's active ingredient, bevacizumab, which my have resulted in patients not receiving needed therapy. 19 medical practices in the United States purchased unapproved cancer medicines from Quality Specialty Products (QSP), a foreign supplier that may also be known as Montana Health Care Solutions. Volunteer Distribution in Gainesboro, Tennessee is a distributor of QSP’s products. 

BACKGROUND: Avastin is an injectable medicine used to treat cancer and is administered to patients in clinics, hospitals, and doctors' offices. Roche is the company that manufactures Avastin approved for marketing outside of the United States. Roche conducted laboratory tests that confirmed the counterfeit version of Avastin. Packages or vials may be counterfeit if they:

• are labeled with Roche as the manufacturer
• display batch numbers that start with B6010, B6011 or B86017  

The only FDA-approved version of Avastin for use in the United States is marketed by Genentech (a member company of Roche). The FDA-approved version does not include the Roche logo on the packaging or vials. FDA approved versions of these medicines are available in adequate supply to meet demand.

RECOMMENDATION: Medical practices that have obtained products from Volunteer Distribution and QSP should stop using them and contact the FDA. These products should be retained and securely stored. To report suspect counterfeit products and other suspect products obtained from Volunteer Distribution or QSP/Montana Health Care Solutions:

• Call FDA's Office of Criminal Investigations (OCI) at 800-551-3989,
• Visit OCI's Web site (www.accessdata.fda.gov/scripts/email/oc/oci/contact.cfm), or
• Email - DrugSupplyChainIntegrity@fda.hhs.gov

Healthcare professionals and patients are encouraged to report adverse events related to the use of suspect injectable cancer medications to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including links to the FDA Counterfeit Statement, letters to medical practices, and the company Press Release, at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm291968.htm

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Genentech: Newsroom: Press Statement: GENENTECH STATEMENT ON COUNTERFEIT DRUG LABELED AS AVASTIN® (BEVACIZUMAB) IN THE UNITED STATES

GENENTECH STATEMENT ON COUNTERFEIT DRUG LABELED AS AVASTIN® (BEVACIZUMAB) IN THE UNITED STATES
SOUTH SAN FRANCISCO, Calif. -- February 14, 2012 -- Roche and Genentech have been informed that a counterfeit product, labeled as Avastin (bevacizumab), has been distributed in the United States.
The counterfeit product is not safe or effective and should not be used. Chemical analyses of the counterfeit vials tested to date have confirmed the product does not contain the active ingredients for Avastin.
Patient safety is Roche and Genentech's primary concern. We are working with the U.S. Food and Drug Administration (FDA) and law enforcement to aid their evaluations, determine the source of the counterfeit drug, and prevent its further distribution...."

abstract: (Avastin) Bevacizumab-Associated Fistula Formation in Postoperative Colorectal Cancer Patients - adverse events

Blogger's Note: adverse events are worth noting albeit other types of cancers; full text of paper would be required to properly assess the conclusions of this particular study

           ~~~~~~~~~~~~~~~~~~~~

Conclusions

Bevacizumab is the most common antiangiogenesis agent used for treatment of metastatic CRC. Previous adverse events associated with bevacizumab treatment include venous thromboembolism, poor wound healing, and spontaneous bowel perforation. In this report, late postoperative development of fistulas occurred relatively soon after initiation of bevacizumab and usually spontaneously resolved with cessation of bevacizumab treatment. Based on the timing of fistula development relative to operation and initiation of bevacizumab, fistulas are likely secondary to bevacizumab therapy rather than postsurgical complications. Bevacizumab-induced fistulas occur in a small, but significant proportion of CRC patients and must be recognized early.

abstract: Predictive value of serum CA-125 levels in patients with persistent or recurrent epithelial ovarian cancer or peritoneal cancer treated with Bevacizumab (Avastin) Gynecologic Oncology Group phase II trial

Purpose

To compare two methods of determining therapeutic response and disease progression — modified Gynecologic Cancer Intergroup (GCIG) criteria based on CA-125 and Radiographic Evaluation Criteria in Solid Tumors (RECIST), in a phase II trial of bevacizumab for patients with recurrent or persistent epithelial ovarian and peritoneal carcinoma.

Results

Sixty-two patients were evaluable by RECIST, 59 for progression by CA-125, and 45 for response by CA-125..........

Conclusions

In this study, disease assessment by RECIST and CA-125 appears to correlate in general. However, approximately 10% of patients might demonstrate progression earlier by CA-125.

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Highlights

► CA125-defined response and progression were assessed for women with recurrent ovarian cancer.
► CA125 and RECIST-defined response and progression correlated in most cases, but CA125 progression significantly preceded RECIST in 8 cases.
► CA125-defined response to bevacizumab was associated with a statistically significant correlation with overall survival.

JCO Editorial: Moving Beyond Anti–Vascular Endothelial Growth Factor Therapy in Ovarian Cancer (Avastin,AMG-386)

the Oncologist: Characteristics of Oral Mucosal Events Related to Bevacizumab (Avastin) Treatment (study of 4 patients)

Background.
Bevacizumab, a monoclonal antibody targeting a vascular endothelial growth factor (VEGF) protein, has been reported to induce mucosal toxicities. However, the clinical characteristics of these particular toxicities have not been well characterized. We aimed at providing a detailed clinical description of signs and symptoms limited to the tongue mucosa in patients treated with bevacizumab.

Conclusion. These characteristic clinical findings are consistent with geographic tongue. However, large prospective evaluations are necessary to confirm this potential relationship. If bevacizumab is indeed associated with geographic tongue, increased awareness may result in improved reporting and characterization of this particular adverse event. 

"Asymptomatic geographic tongue does not necessitate
treatment or bevacizumab interruption, and patients should be
reassured about the benign nature and course of this condition.
Associated symptoms may be alleviated with topical anesthetic
agents, topical or systemic antihistamines, corticosteroids,
and anxiolytics [10, 11, 14]. Successful management
with topical tretinoin, systemic acitretin, vitamin A acid therapy,
and cyclosporin has also been reported in the non-oncologic
setting [11, 14]."

(NEJM)The New England Journal of Medicine: 3 artiicles - breast cancer/Avastin (Bevacizumab) Jan 2012

original article (abstract)

Bevacizumab and HER2-Negative Breast Cancer

original article (abstract)

Bevacizumab in Neoadjuvant Breast-Cancer Therapy

editorial (excerpt)

Fighting Fire with Fire: Rekindling the Bevacizumab Debate

Studies Reignite Debate over Avastin (Bevacizumab) in Breast Cancer - in Oncology/Hematology, Breast Cancer from MedPage Today

Action Points

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• These two studies found a benefit in the surrogate endpoint of complete pathologic response with the addition of bevacizumab in neoadjuvant treatment for HER2-negative breast cancer.



• Note that pathologic complete response was defined differently in the two studies -- in the breast and nodes in one and only in the breast in the other; applying the more stringent breast-plus-nodes criterion in the second study eliminated the statistical significance.

abstract: Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

Objective: The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy.

Methods: This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC.

Results: Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation.

Conclusions: Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

abstract: Intracranial hemorrhage in patients with cancer treated with bevacizumab (Avastin) : the Memorial Sloan-Kettering experience

Background: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor approved for recurrent glioblastoma (GBM), metastatic breast, colorectal and non-small-cell lung cancers (NSCLC). There has been a potentially increased risk of intracranial hemorrhage (ICH) in patients receiving bevacizumab.

Methods: We retrospectively identified patients with ICH who received bevacizumab between 1 January 2001 and 10 January 2009.

Results: We identified 1024 patients with ICH, 4191 patients who received bevacizumab and 12 (0.3%) who met both our criteria. There were eight women and four men with a median age of 66 years. Primary cancers were ovarian (n = 3), NSCLC (n = 3), colon (n = 1), angiosarcoma (n = 1) and GBM (n = 4). Intracranial tumors were present in 9 of the 12 patients; the remaining three (25%) had no evidence of intracranial pathology. Two hundred and fifty-seven patients with these same primary pathologies and brain tumors were treated with bevacizumab; ICH was seen in nine (3.7%), which was comparable to the 3.6% frequency seen in comparable patients not receiving bevacizumab.

Conclusions: ICH with bevacizumab treatment in this population is rare and does not appear to increase its frequency over the baseline rate of ICH in a comparable population. Most bevacizumab-related ICH occurs into central nervous system tumors but spontaneous hemorrhages were seen.

abstract: Extraperitoneal metastases from recurrent ovarian cancer. (study n=233 women) eg. lung, CNS, pulmonary, skin (cutaneous)

Blogger's note: requires subscription ($$$) for full text

OBJECTIVES:

To identify patterns of metastasis in patients with recurrent ovarian cancer. The influence of the route of chemotherapy administration and sequence of agents on those patterns is also examined.

RESULTS:

Thirty-five subjects developed extraperitoneal recurrent ovarian cancer, with 26 subjects (74%) after IP treatment, and 9 subjects (26%) after IV treatment. Of these extraperitoneal recurrences, 26 were in the thoracic/pulmonary cavity, 7 were within the central nervous system (CNS), and 2 were in the cutaneous (skin) tissues. The CNS and cutaneous lesions were secondary recurrences, and all occurred in subjects who had initially received IP cisplatin/paclitaxel followed by IV BEV for recurrent disease.

CONCLUSIONS:

Extraperitoneal recurrences were more common in women treated with IP chemotherapy for ovarian cancer. Specifically, women treated with IV BEV as secondary therapy after IP were at particularly high risk of extraperitoneal metastases, including in the CNS and cutaneous tissues. Physicians should be aware of the possibility of unusual metastases after the combination of IP chemotherapy and BEV, and future prospective studies of this population should carefully evaluate recurrence site patterns.

Avastin: New Ovarian Cancer Drug Approved By European Medicines Watchdog Gives New Hope To Sufferers | UK News + link to Cancer Drugs Fund in England/UK

"We are delighted that Avastin is now available to women across the country."
The National Institute for Health and Clinical Excellence has yet to consider the drugs for routine use by the NHS.
But it is available through the Cancer Drugs Fund in England. Doctors in other parts of the UK can make individual applications for funding.

New Articles -- EvidenceUpdates: A phase 3 trial of bevacizumab in ovarian cancer - abstract, reference + professional commentaries

also see linked reference:
Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011 Dec 29;365(26):2484-96. (Original) PMID: 22204725