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Taal W et al. Lancet Oncol 2014;15:943–953

Wick W et al. N Engl J Med 2017;377:1954–1963

Protocol for: Wick W et al. N Engl J Med 2017;377:1954–1963 (https://www.nejm.org/doi/suppl/10.1056/NEJMoa1707358/suppl_file/nejmoa1707358_protocol.pdf)

 

Bevacizumab 10 mg/kg; administer intravenously in 100 mL 0.9% sodium chloride injection (0.9% NS) on days 1, 15, and 29, every 6 weeks until disease progression (total dosage/6-week cycle = 30 mg/kg), plus:

 

Note:

  • Bevacizumab administration duration for the initial dose is 90 minutes. If administration is well tolerated, the administration duration may be decreased stepwise during subsequent administrations to 60 minutes and, finally, to a minimum duration of 30 minutes

Lomustine 90 mg/m2 (maximum dose = 160 mg); administer orally as a single dose, without food, on day 1, every 6 weeks, until disease progression (total dosage/6-week cycle = 90 mg/m2; maximum dosage/6-week cycle = 160 mg)

Notes:

  • In the absence of ≥grade 2 hematologic toxicity, may increase the lomustine dose to 110 mg/m2 starting with cycle 2, thus:

    • Lomustine 110 mg/m2 (maximum dose = 200 mg); administer orally as a single dose, without food, on day 1, every 6 weeks, until disease progression (total dosage/6-week cycle = 110 mg/m2; maximum dosage/6-week cycle = 200 mg)

  • To reduce the likelihood of a medication error leading to severe myelosuppression, prescribe, dispense, and administer only enough capsules to supply 1 dose of lomustine. Educate patients that only 1 dose of lomustine is to be taken every 6 weeks and only after documentation of adequate hematologic recovery. (ISMP 2014; https://www.ismp.org/resources/oral-chemotherapy-we-simply-must-do-better. Accessed June 20, 2018)

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MODERATE–HIGH

Emetogenic potential on days 15 and 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

  • Antibacterial—not indicated

  • Antifungal—not indicated

  • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A multicenter, randomized, phase 3 trial (European Organisation for Research and Treatment of Cancer [EORTC] 26101) involved 437 patients with progressive glioblastoma after standard chemoradiation. Patients were randomly assigned in a 2:1 ratio to lomustine plus bevacizumab or lomustine alone. Patients in the combination therapy group received lomustine (90 mg/m2 with maximal dose of 160 mg, but increased to 110 mg/m2 with maximal dose of 200 mg if no grade >1 hematologic toxic effects were noted in the first cycle) every 6 weeks plus bevacizumab (10 mg/kg) every 2 weeks. Patients in the monotherapy group received lomustine (110 mg/m2; maximal dose of 200 mg) every 6 weeks.

Efficacy (N = 437)

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Efficacy (N = 437)
 

Lomustine plus Bevacizumab (N = 288)

Lomustine Alone (N = 149)

 

Median overall survival

9.1 months

8.6 months

HR 0.95, 95% CI 0.74–1.21; P = 0.65

Median progression-free survival

4.2 months

1.5 months

HR 0.49, 95% CI 0.39–0.61; P <0.001

Objective response rate

41.5%

13.9%

 

Therapy Monitoring

  1. Prior to each dose of lomustine: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes

  2. Baseline pulmonary function studies with frequent PFTs during treatment

  3. Prior to each dose of bevacizumab: Vital signs, urine dipstick for protein (perform 24-hour urine collection if ≥2+ protein)

  4. Weekly: CBC with differential, platelet count (monitor blood counts weekly for 6 weeks after a dose). Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1–2 weeks. Leukopenia occurs at 5–6 weeks after a dose and persists for 1–2 weeks

  5. Response assessment: Contrast-enhanced MRI of the brain every 6 weeks for 6 months, then every 12 weeks thereafter

Treatment Modification

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Treatment Modification

BEVACIZUMAB DOSE MODIFICATIONS

Adverse Event

Treatment Modification

Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ

Discontinue bevacizumab permanently

Serious bleeding

Wound dehiscence requiring medical intervention

Nephrotic syndrome

Hypertensive crisis or hypertensive encephalopathy or reversible posterior leukoencephalopathy syndrome (RPLS)

Congestive heart failure

Necrotizing fasciitis

Severe arterial or venous thromboembolic events

Discontinue bevacizumab permanently; the safety of reinitiating bevacizumab after a thromboembolic event is resolved is not known

Moderate to severe proteinuria

Patients with a ≥2+ urine dipstick reading should undergo further assessment, eg, a 24-hour urine collection. Suspend bevacizumab administration for ≥2 g of proteinuria/24 h and resume when proteinuria is <2 g/24 h

Severe hypertension not controlled with medical management

Hold bevacizumab pending further evaluation and treatment of hypertension

Mild, clinically insignificant infusion reaction

Decrease the rate of infusion

Clinically significant but not severe infusion reaction

Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. If decision is made to restart, the infusion may be continued at ≤50% of the rate prior to the reaction and increased in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle

Severe infusion reaction—hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, G3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis)

Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen). Discontinue bevacizumab

Planned elective surgery

Suspended bevacizumab at least 28 days before elective surgery and do not resume for at least 28 days after surgery or until surgical incision is fully healed

Recent hemoptysis

Do not administer bevacizumab

Evidence of rectosigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

 

LOMUSTINE DOSE MODIFICATIONS

Lomustine dose levels

Dose level +1

110 mg/m2 as a single dose; maximum 200 mg

Starting dose

90 mg/m2 as a single dose; maximum 160 mg

Dose level -1

75 mg/m2 as a single dose; maximum 130 mg

No >G1 neutropenia and no >G1 thrombocytopenia during cycle 1

Increase lomustine to dose level +1 beginning with cycle 2

Day 1 WBC <4000/mm3 or platelets <100,000/mm3

Delay therapy until WBC ≥4000/mm3 and platelets ≥100,000/mm3

WBC nadir during the prior cycle <2000/mm3, or ANC nadir during the prior cycle <1000/mm3, or platelet nadir during the prior cycle <50,000/mm3

Delay therapy until WBC ≥4000/mm3 and platelets ≥100,000/mm3 if necessary, then reduce lomustine to dose level -1 in subsequent cycle(s)

≥G3 liver toxicity (AST/ALT >5× ULN) and/or ≥G2 bilirubin (>1.5–3× ULN)

Delay therapy until resolution to ≤G1 (AST/ALT ≤3× ULN; bilirubin ≤1.5× ULN), then reduce lomustine 1 dose level in subsequent cycle(s)

Any G4 nonhematologic toxicity

Discontinue lomustine

≥G2 nonhematologic toxicity that does not recover to ≤G1 within 2 weeks

Any ≥G2 nonhematologic toxicity that recurs at the next cycle to ≥G2

Any pulmonary symptoms, but with PFT showing DLco ≥ predicted value

Continue with same lomustine dose

Any pulmonary symptoms, but with PFT showing <60% of predicted value

Discontinue lomustine

Decreased oxygen saturation at rest (eg, pulse oximeter <88% or Pao2 ≤55 mm Hg)

Shortness of breath at rest or shortness of breath that limits self-care or ADL

Severe cough limiting self-care or ADL

Cumulative lomustine dosage >1100 mg/m2

Discontinue lomustine due to concerns of developing pulmonary fibrosis

Creatinine clearance 10–50 mL/min

Reduce lomustine dose by 25%

Creatinine clearance <10 mL/min

Reduce lomustine dose by 50–75%

Notes:

• Usually no more than a total of 6–7 cycles (660–770 mg/m2) of lomustine is recommended. Patients receiving >1100 mg/m2 cumulative lomustine dosage have a higher risk of developing pulmonary toxicity. Patients with a baseline FVC or DLco <70% are particularly at risk (GLEOSTINE™ [lomustine] capsules; June 2018 product label. NextSource Biotechnology, LLC, Miami, FL)

• Patients who are pregnant or who become pregnant should be apprised of the potential hazard to the fetus from therapy with lomustine

Adverse Events (N = 430)

Grade 3–5 adverse events were recorded in 63.6% of patients assigned to lomustine plus bevacizumab and in 38.1% of patients assigned to lomustine alone. Grade 3–5 adverse events of special interest were pulmonary embolism (in 5% of the combination therapy group), arterial hypertension (in 24% of the combination therapy group and in <1% of the monotherapy group), and hematologic toxic effects (in 54% of the combination therapy group and in 50% of the monotherapy group). Deaths unrelated to the tumor were noted for 5 (2%) patients assigned to combination therapy (2 from myocardial infarctions, 1 from large-intestine perforation, 1 from sepsis, and 1 from intracranial hemorrhage) and 1 patient (<1%) assigned to monotherapy (as a result of lung infection). Treatment-related adverse events occurred in 85.2% and 53.1% of patients assigned to combination therapy and monotherapy, respectively, and treatment-related serious adverse events occurred in 38.5% and 9.5% of patients, respectively.

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

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