Recurrent Platinum-Treated Ovarian Cancer: Avastin Dosing and Usage

The overall survival (OS) results in the GOG 213 study and the progression-free survival (PFS) results in the OCEANS study in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC) were achieved with Avastin® (bevacizumab) plus chemotherapy given at the approved dose until disease progression or unacceptable toxicity.

PFS results seen in the AURELIA study in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) were achieved with Avastin plus chemotherapy given at the approved dose until disease progression or unacceptable toxicity.

Avastin dosing in psOC and prOC

Avastin has approved dosing for use with chemotherapy in ovarian cancer patients, and is administered as a solution for intravenous (IV) infusion at the following dose and schedule [1]:

Tumor type Chemotherapy Avastin dose Avastin schedule
psOC Carboplatin and paclitaxel
15 mg/kg q3w
Carboplatin and gemcitabine
15 mg/kg q3w
prOC Paclitaxel (q1w) 10 mg/kg q2w
Pegylated liposomal doxorubicin (q4w) 10 mg/kg q2w
Topotecan (q1w) 10 mg/kg q2w
Topotecan (q3w) 15 mg/kg q3w

q1w=every week; q2w=every two weeks; q3w=every three weeks; q4w=every four weeks.

Important treatment considerations—Women of childbearing potential

  • Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Counsel patients about the possible risks, including hazard to the fetus and/or loss of pregnancy, of both continued treatment and prolonged exposure following discontinuation, keeping in mind the approximate half-life of Avastin (20 days; range 11–50 days). Patients should also be counseled to continue adequate contraception for 6 months following the last dose of Avastin 
  • Nursing mothers should be advised to discontinue nursing or Avastin, taking into account the half-life of the product and the importance of Avastin to the mother

Duration of Avastin in psOC and prOC

The FDA-approved Prescribing Information addresses the duration of Avastin treatment [1]:
Patients should continue treatment until disease progression or unacceptable toxicity. [1]

Important treatment considerations—Dose modifications

  • There are no recommended dose reductions 
  • Discontinue Avastin in patients with 
    • Gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess) 
    • Fistula formation involving an internal organ 
    • Wound dehiscence and wound healing complications requiring medical intervention
    • Serious hemorrhage (ie, requiring medical intervention)
    • Severe arterial thromboembolic event (ATE)
    • Life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism
    • Hypertensive crisis or hypertensive encephalopathy 
    • Posterior reversible encephalopathy syndrome (PRES)
    • Nephrotic syndrome
  • Temporarily suspend Avastin for: at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria, and severe infusion reactions 
  • The safety of resumption of Avastin therapy in patients that experienced PRES or ATE is unknown

Indications

Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (rOC)
Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

Avastin, either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% 
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) 
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin 
  • Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy 
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women that breastfeeding is not recommended during treatment with Avastin
  • Avastin may impair fertility

Most common adverse events

  • Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were

— Epistaxis
— Headache
— Hypertension
— Rhinitis

— Proteinuria
— Taste alteration
— Dry skin
— Rectal hemorrhage

— Lacrimation disorder
— Back pain
— Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Indication-specific adverse events

  • In psOC, grade 3 or 4 adverse events in the GOG 213 study occurring at a higher incidence (≥2%) in 325 patients receiving Avastin plus carboplatin and paclitaxel (chemotherapy) compared to 332 patients receiving chemotherapy alone were hypertension (11.1% vs 0.6%), fatigue (7.7% vs 2.7%), febrile neutropenia (6.2% vs 2.7%), proteinuria (8% vs 0%), abdominal pain (5.8% vs 0.9%), hyponatremia (3.7% vs 0.9%), headache (3.1% vs 0.9%), and pain in extremity (3.4% vs 0%). No grade 5 AE occurred with a ≥2% higher frequency in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm
  • In psOC, grade 3 or 4 adverse events in the OCEANS study occurring at a higher incidence (≥2%) in 247 patients receiving Avastin plus carboplatin and gemcitabine (chemotherapy) compared to 233 patients receiving chemotherapy alone were thrombocytopenia (40.1% vs 33.9%), nausea (4.5% vs 1.3%), fatigue (6.5% vs 4.3%), headache (3.6% vs 0.9%), proteinuria (9.7% vs 0.4%), dyspnea (4.5% vs 1.7%), epistaxis (4.9% vs 0.4%), and hypertension (17.0% vs 0.9%). Grade ≥3 anemia (16.2% vs 18.9%) and decreased white blood cell count (1.6% vs 4.3%) occurred with a ≥2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. No grade 5 AE occurred with a ≥2% higher frequency in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm
  • In prOC, grade 3–4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs 1.7%). There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

Please see full Prescribing Information, including Boxed WARNINGS, for additional important safety information.