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PACLTOPO+BEVA

Cancer Type: Gynecologic, Cervix  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Bevacizumab (Biosimilar) - Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the Cervix
A - Regimen Name

PACLTOPO+BEVA Regimen
Paclitaxel-topotecan-bevacizumab


Disease Site
Gynecologic - Cervix

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of patients with metastatic, recurrent or persistent cervical cancer of all histologic subtypes (except small cell), who have ECOG performance status of 0 or 1 (see NDFP for detailed funding criteria) and cannot receive platinum-based chemotherapy.


Supplementary Public Funding

bevacizumab
New Drug Funding Program (Bevacizumab (Biosimilar) - Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the Cervix)

 
B - Drug Regimen

Different bevacizumab products are not interchangeable.
 

PACLitaxel
175 mg /m² IV over 3 hours Day 1
topotecan
0.75 mg /m² IV Days 1 to 3
(This drug is not currently publicly funded for this regimen and intent)
bevacizumab
15 mg /kg IV Day 1
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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

Paclitaxel: Patients should be pretreated with a corticosteroid as well as an antihistamine and a H2 blocker:

For example:

• dexamethasone 20mg PO 12 & 6 hours OR 20mg IV 30 minutes before paclitaxel

• diphenhydramine 50mg IV 30 minutes before paclitaxel

• ranitidine 50mg IV 30 minutes before paclitaxel

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. Bevacizumab should not be initiated in patients with recurrent hemoptysis, uncontrolled hypertension or wounds that require healing. Prior to treatment, a dental evaluation should be performed and major dental procedures completed. May consider hypersensitivity prophylaxis (see section D for examples) for patients who have had prior mild hypersensitivity reactions to bevacizumab and are continuing on bevacizumab-only treatment.

Dosage with toxicity

Hematologic toxicities

Do not start a new cycle until ANC ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L. Reduced doses should not be re-escalated.

Dose level  

Paclitaxel (mg/m2)    

Topotecan (mg/m2)   

Bevacizumab (mg/kg)  

0

175

0.75

15

-1

140

0.60

15

-2

105

0.45

15

 

Toxicity

Topotecan

Paclitaxel

Bevacizumab

Febrile neutropenia or Grade 4 neutropenia for > 7d

↓ 1 dose level, consider adding G-CSF for subsequent cycles if recurs*

↓ 1 dose level, consider adding G-CSF for subsequent cycles if recurs*

No change

Grade 4 thrombocytopenia or thrombocytopenic bleeding

↓ 1 dose level

↓ 1 dose level

Hold

*If recurs despite addition of G-CSF, reduce a second dose level

 

 

 

 

 

Hypersensitivity reaction

Reaction

Paclitaxel

Bevacizumab

Mild (e.g.

mild flushing, rash, pruritus)

 

Possible to complete the infusion under close supervision

 

May stop the infusion. Give diphenhydramine and corticosteroid if indicated. Resume infusion at slower rate under close supervision.

Moderate (e.g.

moderate rash, flushing, mild dyspnea, chest discomfort, mild hypotension)

 

Stop the infusion and give diphenhydramine 25-50 mg IV and methylprednisolone 125 mg IV.

 

Once symptoms have resolved, resume infusion at a rate of 10% of original rate for 15 minutes, then at 25% of original rate for 15 minutes, and if no further symptoms

develop, continue at original rate until infusion is complete.

 

 

Stop the infusion and hold for remainder of the day. Give diphenhydramine and corticosteroid, or other supportive measures if indicated. 

 

Consider discontinuing bevacizumab. If re-challenge on a different treatment day, use slower infusion rate.

Severe (e.g.

one or more of: respiratory distress requiring treatment, generalized urticaria, angioedema, hypotension requiring therapy)

 

Stop the paclitaxel infusion and give diphenhydramine and methylprednisolone as above. Use epinephrine or bronchodilators if indicated.

 

Discontinue. Do not re-challenge.

 

Stop the infusion and give diphenhydramine and corticosteroid. Use epinephrine or bronchodilators if indicated.

 

 

Discontinue. Do not re-challenge.

 

 

 

 

 

 

 

Non-hematologic toxicities

Any grade

Grade 3

Grade 4

Bevacizumab action

Paclitaxel/topotecan action

Uncontrollable hypertension*

 

 

 

Hold*

 

Consider hold or discontinue

Delayed wound healing; Surgery**

 

 

Proteinuria ≥2g/24 hours***

 

 

Wound dehiscence;

Necrotizing fasciitis

 

 

 

 

Discontinue

 

 

 

Consider hold or discontinue

 

Tracheo-esophageal fistula, other non-GI fistulae; GI perforation

 

Any internal fistula

Nephrotic syndrome; non recovery of proteinuria ≥2g/24 hours

Hypertension (not controlled with medical management)

Hypertension

Severe Hypersensitivity

 

 

PRES/RPLS

   

Arterial thromboembolism

 Pulmonary embolism

Venous thromboembolism (including pulmonary embolism)

Symptomatic cardiac failure

 

 

Recurrent hemoptysis > 2.5mL; Intracranial bleeding

 

 Bleeding (any)

Bleeding (any)

Any grade (continued) Grade 3 Grade 4 Bevacizumab action Paclitaxel/topotecan action

Grade 2 neuropathy

 

 

No change

↓ paclitaxel 2 dose levels

Hold topotecan until ≤ grade 1

 

Grade 3 neuropathy

Grade 4 neuropathy

No change

Hold paclitaxel and topotecan until ≤ grade 1, Resume paclitaxel at ↓ 2 dose levels.  If no recovery with a 2 week hold, consider discontinuing  

Grade 2 mucositis or diarrhea

Grade 3 mucositis,  diarrhea or other non-hematologic toxicity

 

No change

Hold topotecan until ≤ grade 1, then resume at ↓ 1 dose level.

 

 

Grade 4 mucositis,  diarrhea or other non-heme toxicity

No change

Discontinue

*If held for 3 weeks, discontinue bevacizumab and continue chemotherapy. If held 4 or more weeks, discontinue treatment
**Hold for 28 days PRIOR (if surgery elective) and AFTER major surgery, or until wound healed
***May restart when < 2 g/24hrs. If held more than 2 months, discontinue bevacizumab



Hepatic Impairment

Bilirubin Paclitaxel dose Topotecan dose Bevacizumab dose
1.5-2x ULN no change no change no change
>2-4 x ULN ↓ 1 dose level ↓ 1 dose level no change
> 4x ULN discontinue ↓ 1 dose level or omit no change
 

Renal Impairment

Creatinine Clearance (mL/min) 

Paclitaxel dose

Topotecan dose

Bevacizumab dose

40-60

no change

no change

no change

  20-39  

↓ 1 dose level

    <20     

discontinue


 
F - Adverse Effects

Refer to PACLitaxel, topotecan, bevacizumab drug monograph(s) for additional details of adverse effects

Increased rates of thromboembolism and fistulas were reported in cervical cancer patients in clinical trials.


Most Common Side Effects

Less Common Side Effects, but may be Severe or Life-Threatening

  • Alopecia
  • Nausea, vomiting
  • Peripheral neuropathy (may be severe)
  • Musculoskeletal pain
  • Hypertension (may be severe)
  • Hypersensitivity (may be severe)
  • Ovarian failure
  • Proteinuria (may be severe)
  • Diarrhea (may be severe)
  • Constipation
  • Fatigue
  • Increased LFTs (may be severe)
  • Abdominal pain
  • Cough, dyspnea
  • Edema
  • Insomnia
  • Mucositis
  • Anorexia
  • Headache
  • Rash (may be severe)
  • Dysguesia
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Hemorrhage (may be severe)
  • Eye disorders
  • Venous thromboembolism (may be severe)

 

 

  • Arterial thromboembolism
  • Cardiotoxicity, arrhthymia
  • Pulmonary hypertension
  • Thrombotic microangiopathy
  • Fistula (GI and non-GI)
  • GI obstruction, perforation
  • Secondary malignancy
  • Pancreatitis
  • Pneumonitis
  • Delayed wound healing
  • Necrotizing fasciitis
  • Osteonecrosis (jaw, others)
  • PRES, seizure
  • Cystoid macular edema
  • Renal failure
  • Secondary malignancy
  • Encephalopathy
 
 
G - Interactions

Refer to PACLitaxel, topotecan, bevacizumab drug monograph(s) for additional details


  • Use with caution with bisphosphonates and anti-angiogenic drugs given increased risk of ONJ
  • Use with caution with anthracyclines or thoracic radiation; this may increase the risk of cardiotoxicity
  • Concurrent use with radiation may increase the risk of radiation pneumonitis
  • Caution and monitor with CYP3A4 inducers (e.g. phenytoin, St. John's wort) and inhibitors (e.g. azole antifungals, macrolide antibiotics)
  • Caution and monitor with CYP2C8 inducers (e.g. phenobarbital) and inhibitors (e.g. gemfibrozil, monteleukast)
  • If G-CSF is used with topotecan, give after entire topotecan dose is given
  • Avoid phenytoin or monitor closely; avoid curcumin (tumeric) (these may reduce the effect of topotecan)
 
H - Drug Administration and Special Precautions

Refer to PACLitaxel, topotecan, bevacizumab drug monograph(s) for additional details.

Different bevacizumab products are not interchangeable.


Administration:

PACLitaxel

  • Use non-PVC equipment, including 0.22 micron in-line filter, in order to minimize patients’ exposure to DEHP leaching from PVC bags or sets; infuse over 3 hours.
  • Dilute in 500-1000 mL Normal Saline or 5% Dextrose, in a final concentration of 0.3-1.2 mg/mL.
  • Excessive shaking, agitation, or vibration may induce precipitation and should be avoided.
  • Precipitation may rarely occur with infusions longer than 3 hours.

Topotecan

  • Mix in 50mL-100mL minibag (NS or D5W); infuse over 30 minutes.
  • Final concentration should be between 0.02 mg/mL to 0.5 mg/mL.

Bevacizumab

  • Bevacizumab infusions should not be administered or mixed with Dextrose or Glucose solutions due to potential for drug degradation.
  • Mix in 100 mL bag NS. (Dilution should be 1.4 -16.5 mg/mL). 
  • Do not shake.  Should not be mixed or diluted with other drugs.
  • Compatible with PVC or polyolefin bags.
  • DO NOT ADMINISTER AS AN IV PUSH OR BOLUS
  • Infused over 90 minutes as loading dose, if tolerated next infusion can be given over 60 minutes; can thereafter be given over 30 minutes as maintenance dose
  • Refrigerate unopened vials and protect from light; do not freeze.

Contraindications:

  • Patients with known hypersensitivity to Chinese hamster ovary cell product, to other recombinant human or humanized antibodies, severe hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil)
  • Patients with untreated CNS metastases
  • Patients with recurrent hemoptysis (>2.5ml) or serious hemorrhage

Other Warnings/Precautions:

  • Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age
  • Patients with a history of arterial thromboembolism or significant cardiovascular disease or cardiac failure
  • Patients with coagulopathies (congenital, acquired or therapeutic)
  • Hypertension should be controlled prior to starting treatment
  • Bevacizumab should not be initiated for at least 28 days following major surgery or until wound healing has occurred; hold for 28 days prior to major elective surgery
  • The safety and efficacy of concurrent radiotherapy and bevacizumab has not been established.
  • Congestive heart failure (including LVEF decrease) has been reported in patients who have received other chemotherapy agents, especially anthracyclines.
  • Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC; baseline and before each cycle
  • Liver and renal function tests; baseline and before each cycle
  • Dental evaluation; baseline
  • Monitor blood pressure during paclitaxel infusion and every 2-3 weeks during bevacizumab therapy and more frequently in patients who develop hypertension.
  • EKG monitoring for patients who have arrhythmia during infusion
  • Baseline and regular dipstick urinalysis; 24 hour urine collection is recommended for patients with a 2+ or greater urine dipstick
  • Clinical toxicity assessment (including hypersensitivity, musculoskeletal, perforation, fistula, GI symptoms, hemorrhage, infection, ONJ, thromboembolism, wound healing, hypertension, neurologic and cardiac effects); at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Cardiac function tests (Echo, RNA and/or MUGA scans) especially in patients who are close to the lifetime cumulative dose of anthracyclines/anthracenediones; baseline and as clinically indicated
  • INR for patients receiving warfarin

 


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J - Administrative Information

Pharmacy Workload (average time per visit)
37.367 minutes
Nursing Workload (average time per visit)
69.833 minutes
 
K - References

Paclitaxel, topotecan and bevacizumab drug monographs, Cancer Care Ontario.

Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43.

August 2019 added bevacizumab (biosimilar) NDFP form and non-interchangeability description for bevacizumab


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.