Cervical Cancer: Avastin Safety Profile


The Avastin® (bevacizumab) side effect and toxicity profile in persistent, recurrent, or metastatic cervical cancer (CC) was evaluated in the large Gynecologic Oncology Group (GOG) 240 study. [1,45]

Safety profile of Avastin in CC was evaluated in the GOG 240 study: Avastin plus chemotherapy vs chemotherapy alone

Grade 1–4 and 3–4 adverse events observed in the GOG 240 study (with incidence difference of ≥5% between treatment arms) [1]

 

Grade 1–4 reactions

Grade 3–4 reactions

Avastin + chemotherapy (n=218)

Chemotherapy alone
(n=222)

Avastin + chemotherapy (n=218)

Chemotherapy alone
(n=222)

Metabolism and nutrition disorders

 

 

 

 

Decreased appetite

34%

26%

 

 

Hyperglycemia

26%

19%

 

 

Hypomagnesaemia

24%

15%

 

 

Hyponatraemia

19%

10%

 

 

Hypoalbuminaemia

16%

11%

 

 

General disorders and administration site conditions

 

 

 

 

Fatigue

80%

75%

 

 

Edema peripheral

15%

22%

 

 

Investigations

 

 

 

 

Weight decreased

21%

7%

 

 

Blood creatinine increased

16%

10%

 

 

Infections and infestations

 

 

 

 

Urinary tract infection

22%

14%

 

 

Infection

10%

5%

 

 

Vascular disorders

 

 

 

 

Hypertension

29%

6%

11.5%

0.5%

Thrombosis

10%

3%

8.3%

2.7%

Nervous system disorders

 

 

 

 

Headache

22%

13%

 

 

Dysarthria

8%

1%

 

 

Gastrointestinal disorders

 

 

 

 

Stomatitis

15%

10%

 

 

Proctalgia

6%

1%

 

 

Anal fistula

6%

 

 

Blood and lymphatic system disorders

 

 

 

 

Neutropenia

12%

6%

 

 

Lymphopenia

12%

5%

 

 

Psychiatric disorders

 

 

 

 

Anxiety

17%

10%

 

 

Reproductive system and breast disorders

 

 

 

 

Pelvic pain

14%

8%

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Epistaxis

17%

1%

 

 

Renal and urinary disorders

 

 

 

 

Proteinuria

10%

3%

 

 

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. 

Important safety information—GOG 240 study

  • Grade 3 or 4 adverse reactions in Study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone

Gastrointestinal and non-gastrointestinal fistulae reported in the GOG 240 study [1]

  • The incidence of gastrointestinal-vaginal fistulae was 8.3% in Avastin-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation
  • Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies

Indications

Persistent, recurrent, or metastatic cervical cancer (CC)
Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

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
    • Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin
    • 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

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 CC, grade 3 or 4 adverse reactions in Study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin 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.