Colorectal Cancer: Avastin Dosing and Usage

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous 5‑fluorouracil-based chemotherapy, is indicated for the first‑ or second‑line treatment of patients with metastatic colorectal cancer.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Avastin dosing in metastatic colorectal cancer

Avastin has approved dosing for use with various chemotherapy regimens used in patients with MCRC [1]

In MCRC, Avastin is administered as a solution for intravenous (IV) infusion at the following doses and schedules [1]

Tumor type Chemotherapy Avastin dose Avastin schedule
MCRC IFL* (First-line Study 2107) 5 mg/kg IV Every 2 weeks
FOLFOX4(Second-line Study E3200) 10 mg/kg IV Every 2 weeks
Fluoropyrimidine-based chemotherapy in patients who had progressed on a first-line Avastin-containing regimen (First- through second-line TML study§) 5 mg/kg IV Every 2 weeks
7.5 mg/kg IV Every 3 weeks

*5 mg/kg IV dose evaluated in first-line MCRC in combination with 5-FU/leucovorin (LV)/irinotecan (IFL).
10 mg/kg IV dose evaluated in second-line, Avastin-naive MCRC patients in combination with 5-FU/LV/oxaliplatin (FOLFOX4).
5 mg/kg IV every 2 weeks and 7.5 mg/kg IV every 3 weeks doses evaluated, in combination with fluoropyrimidine and either irinotecan- or oxaliplatin-containing chemotherapy, in MCRC patients who had progressed on a first-line Avastin-containing regimen.
§TML=Treatment through Multiple Lines (first and second line).
 

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

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 the first dose of Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Patients should also use effective contraception during treatment and for 6 months following the last dose of Avastin
  • Nursing mothers should be advised to discontinue nursing during treatment and for 6 months following their last dose of treatment

Duration of Avastin in metastatic colorectal cancer

For proven survival benefits in first and second line — start with Avastin, then continue beyond first progression [1,5]

Avastin® (bevacizumab) for Metastatic Colorectal Cancer Treatment Duration

* Oxaliplatinirinotecan or irinotecanoxaliplatin.

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

Indications

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous 5‑fluorouracil-based chemotherapy, is indicated for the first‑ or second‑line treatment of patients with metastatic colorectal cancer.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Important treatment considerations—Dose modifications

No dose reductions for Avastin are recommended.

Dose Modifications for Adverse Reactions

 

Adverse Reaction

Severity

Dose Modification

Gastrointestinal Perforation and Fistulae

  • Gastrointestinal perforation, any grade
  • Tracheoesophageal fistula, any grade
  • Fistula, Grade 4
  • Fistula formation involving any internal organ

Discontinue Avastin

Wound Healing Complications

  • Wound healing complications requiring medical intervention
  • Necrotizing fasciitis

Discontinue Avastin

Hemorrhage

  • Grade 3 or 4

Discontinue Avastin

  • Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more

Withhold Avastin

Thromboembolic Events

  • Arterial thromboembolism, severe

Discontinue Avastin

  • Venous thromboembolism, Grade 4

Discontinue Avastin

Hypertension

  • Hypertensive crisis
  • Hypertensive encephalopathy

Discontinue Avastin

  • Hypertension, severe

Withhold Avastin if not controlled with medical management; resume once controlled

Posterior Reversible Encephalopathy Syndrome (PRES)

Any

Discontinue Avastin

Renal Toxicity and Proteinuria

  • Nephrotic syndrome

Discontinue Avastin

  • Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome

Withhold Avastin until proteinuria less than 2 grams per 24 hours

Infusion Reaction

  • Severe infusion reaction

Discontinue Avastin

  • Clinically significant

Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve

 

  • Mild, clinically insignificant

Decrease infusion rate

Congestive Heart Failure

Any

Discontinue Avastin

Bevacizumab is the only FDA-approved biologic cancer therapy that is included as an option in National Comprehensive Cancer Network® (NCCN®) recommendations when continued through first- and second-line MCRC[36]

FIRST-LINE MCRC SECOND-LINE MCRC

Bevacizumab plus:

  • FOLFIRI
  • FOLFOX
  • IV 5-FU/LV
  • FOLFOXIRI

Bevacizumab plus:

  • FOLFIRI
  • FOLFOX
BEVACIZUMAB CONTINUED THROUGH FIRST- AND SECOND-LINE MCRC

Bevacizumab plus:

  • FOLFIRI
  • FOLFOX
  • CapeOX

FOLFIRI=5-FU/leucovorin (LV)/irinotecan; FOLFOX=5-FU/LV/oxaliplatin; IV=intravenous; FOLFOXIRI=5-FU/LV/oxaliplatin/irinotecan; CapeOX=capecitabine/oxaliplatin.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

Indications

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous 5‑fluorouracil-based chemotherapy, is indicated for the first‑ or second‑line treatment of patients with metastatic colorectal cancer.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% 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
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue 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. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (grade ≥3, 11% seen in GOG-0240)
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, 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 and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% 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% to 22% of patients because of adverse reactions

Indication-specific adverse events

  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
  • When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC5

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.