LESSON 12

BCCA Protocol Summary for Adjuvant Therapy for Breast

Cancer using DOXOrubicin and Cyclophosphamide

Protocol Code BRAJAC

Tumour Group Breast

Contact Physician Dr. Karen

Gelmon
ELIGIBILITY:
Adjuvant treatment for high risk breast cancer without systemic
metastases.

TESTS:
Baseline: CBC & diff, platelets, bilirubin
Before each treatment: CBC & diff, platelets
If clinically indicated: bilirubin, creatinine

PREMEDICATIONS:
Antiemetic protocol for highly emetogenic chemotherapy (see protocol
SCNAUSEA)

TREATMENT:

Drug Dose BCCA Administration Guideline

DOXOrubicin 60 mg/m2 IV push
(ADRIAMYCIN
cyclophosphamide 600 mg/m2 IV in NS or D5W 100 to 250 mL over 20
min to 1 hour
Repeat every 21 days x 4 cycles.
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 If radiation therapy is required, it is given following completion of
chemotherapy (BCCA Cancer Management Manual).

DOSE MODIFICATIONS:

1. Hematological:

ANC (x 109/L) Platelets (x 109/L) Dose (both drugs)

Greater than or equal to Greater than or equal to 100%
1.5 1 to 1.49 90 70 to 89 75%
Less than 1 Less than 70 delay

2. Hepatic dysfunction: Dose modification required for DOXOrubicin

(see ).
3. Renal dysfunction: Dose modification may be required for
cyclophosphamide (see BCCA Cancer Drug Manual).

PRECAUTIONS:
1. Cardiac Toxicity: DOXOrubicin is cardiotoxic and must be used with
caution, if at all, in patients with severe hypertension or cardiac
dysfunction. Cardiac assessment recommended if lifelong dose of 400
mg/m2 to be exceeded (see BCCA Cancer Drug Manual).
2. Extravasation: DOXOrubicin causes pain and tissue necrosis if
extravasated. Refer to BCCA Extravasation Guidelines.
3. Neutropenia: Fever or other evidence of infection must be assessed
promptly and treated aggressively.

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 LESSION 13
BC Cancer Protocol Summary for Management of Immune-
Mediated Adverse Reactions to Checkpoint Inhibitors
Immunotherapy

Protocol Code SCIMMUNE

Tumour Group Supportive

Contact Physician Care

Dr. Kerry
Savage
Eligibility

Patients treated with immunotherapy agents with checkpoint inhibition,

including:

• CTLA-4 inhibitors (e.g., ipilimumab)

• PD-1 inhibitors (e.g., nivolumab, pembrolizumab)
• PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab)

These agents are associated with immune-mediated adverse reactions,

although the incidence may vary from agent to agent. Reactions can be
severe to fatal and usually occur during the treatment course. They may
include enterocolitis, intestinal perforation or hemorrhage, hepatitis,
dermatitis, neuropathy, endocrinopathy, as well as toxicities in other organ
systems. Early diagnosis and appropriate management are essential to
minimize life-threatening complications. For specific toxicities
management, see the following flow diagrams.

Serious immune-mediated reactions

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These can be severe to fatal and usually occur during the treatment
course. They may include enterocolitis, intestinal perforation or
hemorrhage, hepatitis, dermatitis, neuropathy, endocrinopathy, as
well as toxicities in other organ systems. Early diagnosis and
appropriate management are essential to minimize life-threatening
complications. For specific toxicities management, see the following flow
diagrams.

Infusion-related reactions

Isolated cases of severe reaction have been reported. In case of a

severe reaction, infusion of checkpoint inhibitors should be
discontinued and appropriate medical therapy administered.
Patients with mild or moderate infusion reaction may receive
checkpoint inhibitors with close monitoring. Premedications with
acetaminophen and anti-histamine may be considered

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Pneumonitis Monitoring
Radiographic changes, new or worsening cough,
chest pain, shortness of breath

Grade 2 Grade 3 or 4
Grade 1 Mild to moderate symptoms, worsens Severe symptoms, new or worsening hypoxia,
Radiographic changes only from baseline life- threatening

• Physician notified and collaborative • Hospitalize

symptom management initiated • Discontinue checkpoint inhibitors
• Withhold checkpoint inhibitors • Monitor daily
• Consider high resolution CT scan • predniSONE 2 to 4 mg/kg/day PO
• Monitor daily • Patient education of steroid use
• predniSONE 1 mg/kg/day PO • Pulmonary and infectious disease
• Patient education of steroid use consultation
• Pulmonary and infectious disease • Consider bronchoscopy, lung biopsy
consultation • Upon discharge, book nursing follow
• Consider bronchoscopy, lung biopsy up call as needed
• Book nursing follow up call as needed

Reassess every 1 to 3 days

If improved to baseline
If improved to baseline • Taper steroid over at least 1 month
• Taper steroid over at least 1 month If persists or worsens after 2 days
BEFORE resuming checkpoint inhibitors • Consider non-steroid immunosuppressive
If persists or worsens after 2 weeks agents
• Treat as Grades 3 or 4

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Enterocolitis Monitoring
Diarrhea, abdominal pain, mucus or blood in
stools- with or without fever, ileus, peritoneal signs
Grade 3 or 4
Grade 3: diarrhea of 7 or more stools per day
Grade 1 Grade 2 over baseline, incontinence, IV fluids for 24 h or
Diarrhea of 4 to 6 stools per day over more, impaired daily activities; colitis with
Diarrhea of less than 4 baseline, IV fluids less than 24 h , severe abdominal pain, requiring medical
normal daily activities, abdominal pain,
stools per day over mucus or blood in stool.
interventions, peritoneal signs of bowel
perforation
baseline; asymptomatic Grade 4: life-threatening colitis, perforation
colitis • Physician notified and collaborative symptom
management initiated
• Physician notified and collaborative • Withhold (if Grade 3) or discontinue (if
symptom management initiated Grade 4 or persistent Grade 3)
• Withhold checkpoint inhibitors checkpoint inhibitors
• Antidiarrheal treatment • Gastroenterology consultation
• If persists beyond 3-5 days* or recur, • Rule out bowel perforation; if bowel
start predniSONE 0.5 to 1 mg/kg/day perforation is present, DO NOT
• Physician notified of assessment• PO
Patient education of steroid use
administer corticosteroids
• Nursing management per • Nursing management per
•
•
Consider endoscopic evaluation
predniSONE 1 to 2 mg/kg/day PO
• Prophylactic antibiotics for opportunistic
infections
• Book nursing follow up call as needed • Patient education of steroid use
• Nursing management per
• Antidiarrheal treatment * 1-2 days if combination check-
point inhibitors
• Book nursing follow up
• Book nursing follow up call as needed
call for next business
day and/or create care
plan if BC Cancer nurse
unable to follow up
Improvement to Grade 1 or less
• Taper predniSONE over at least 1 month
before resuming checkpoint inhibitors
• Patient education of steroid tapering per
physician order
If no response within 5 days or recur
• Consider treatment with inFLIXimab;
if refractory to inFLIXimab, consider
mycophenolate
• Continually evaluate for evidence of
gastrointestinal perforation or peritonitis
• Consider repeat endoscopy

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 Monitoring
Abnormal liver function test, jaundice, tiredness

Grades 3 or 4
ALT (or AST) more than 5 X ULN
or
Total bilirubin more than 3 X ULN
or
Improvement to Grade 1 or less ALT (or AST) increases ≥50% baseline and lasts ≥1 week in
patients with liver metastasis who begin treatment with Grade
• Resume checkpoint inhibitors2 elevation of ALT (or AST)
• If steroid used, taper over
at least 1 month BEFORE
resuming checkpoint
• Physician notified and collaborative symptom management
inhibitors initiated
• Discontinue checkpoint inhibitors
• Consider prophylactic
• Rule out infectious or malignant causes or obstruction
antibiotics for •• Gastroenterology
Increase LFTs monitoring to every 1 to 2 days until resolution
consultation
opportunistic infections
• predniSONE 1 to 2 mg/kg/day PO
• Prophylactic antibiotics for opportunistic infections
• Patient education of education on steroid use
• Patient
steroid tapering • per
Book future nursing follow up call as needed
physician order

If LFTs return to Grade 2 or less

• Taper predniSONE over at least 1 month

For persistent Grades 3 or 4 for more than 3 to 5 days,

worsens, or recurs:
• Consider non-steroid immunosuppressive agents (e.g.,
mycophenolate)

Liver

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 Grade 2
ALT (or AST) 3 to less
than 5 X ULN

• Physician notified and

collaborative symptom
management initiated
• Withhold checkpoint inhibitors
• Rule out infectious or malignant causes
or obstruction
• Increase LFTs monitoring to
every 3 days until resolution
• Book future nursing follow up call as

If AST/ALT 3 × ULN or lower and bilirubin

1.5 × ULN or lower, or return to baseline
• Resume checkpoint inhibitors
Ifelevation persists more than 5-7 days or worsen
• predniSONE 0.5 to 1 mg/kg/day PO
• consider prophylactic antibiotics for opportunistic infections
• taper predniSONE over at least 1
month before resuming checkpoint
inhibitors
• Patient education of steroid tapering per physician order

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 Renal

Monitoring
Grade 2 Grade 3
Grade 1 Creatinine >1.5
- 3.0 x ULN
Creatinine >3.0 - 6.0 x
ULN Grade 4 >6.0 x
Creatinine >1 - 1.5 x ULN
ULN
• Physician notified and collaborative symptom • Physician notified and collaborative symptom
management initiated management initiated
Increase
•
• in serum
Withhold
Nephrology creatinine,
checkpoint decreased
inhibitors
consultation urine
•
• output,
Discontinue hematuria, edema
checkpoint inhibitors
Nephrology consultation
• Creatinine every 2 to 3 days • Creatinine daily
• predniSONE 0.5 to 1 mg/kg/day PO • predniSONE 1 to 2 mg/kg/day PO
• Patient education on steroid use • Patient education on steroid use
• Consider renal biopsy • Consider renal biopsy
• Book future nursing follow up call as needed • Book future nursing follow up call as needed

• Creatinine weekly

If improved to Grade 1
• Taper steroid over at least 1 month

When return to baseline

• Resume routine creatinine

If improved to Grade 1
• Taper steroid over at
least 1 month
BEFORE resuming
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 ipilimumab and
nivolumab and
routine creatinine
If persists for more than 7 days or worsens
• Treat as Grade 4
• Physician notified and collaborative symptom management initiated
• Continue checkpoint inhibitors
• If TSH less than 0.5 x LLN, or TSH greater than 2 x ULN, or consistently out of range in 2 subsequent
measurements: include free T4 at subsequent cycles as clinically indicated
• Consider endocrinology consultation
Endocrine

• Physician notified and collaborative symptom If improved with or without

management initiated hormone replacement:
• Evaluate endocrine function
• Consider pituitary scan • Taper steroid over at least 1 month
• Withhold checkpoint inhibitors if abnormal lab or BEFORE resuming checkpoint inhibitors
pituitary scan • Consider prophylactic antibiotics for
• Endocrinology consultation opportunistic infections
• predniSONE 1 to 2 mg/kg/day PO Continue standard monitoring
• Repeat labs in 1 to 3 weeks; MRI in 1 month if symptoms • Patients with adrenal insufficiency may
persist but normal lab or pituitary scan need to continue steroids with
• Appropriate hormone replacement if symptomatic with mineralocorticoid component
abnormal lab or pituitary scan

• Physician notified and collaborative symptom

management initiated
• Rule out sepsis
• Withhold checkpoint inhibitors
• Evaluate endocrine function
• Endocrinology consultation
• Consider pituitary scan When adrenal crisis ruled out:
• Repeat labs in 1 to 3 weeks; MRI in 1 month if symptoms
persist but normal lab or pituitary scan • Treat as symptomatic endocrinopathy
• Endocrinology consult
• Stress dose of IV steroids with mineralocorticoid activity
• IV fluids

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Monitoring
Persistent or unusual headaches, extreme tiredness, weight gain or loss, mood or behaviour
changes (e.g., decreased libido, irritability, forgetfulness) dizziness or fainting, hair loss,
feeling cold, constipation, voice gets deeper

Asymptomati
c TSH

Symptom
atic
endocrino

Suspicion of
adrenal crisis
(e.g., severe
dehydration,
hypotension,
shock out of

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Skin Monitoring
Rash, pruritus (unless an alternate etiology has been identified)

Grade 3-4
Grade 1 to 2 More than 30% of skin surface, life-
30% of skin surface or less threatening

• Physician notified and collaborative symptom

management initiated
• Physician notified of assessment • Withhold or discontinue checkpoint inhibitors
• Nursing management per • Consider skin biopsy
• Dermatology consult
• Sun safety (see • predniSONE 1 to 2 mg/kg/day PO
(ormethylPREDNISolone1 to 2 mg/kg/day IV)
• Skin care; moisturizers, soaps • Patient education on steroid use
• Book nursing follow up call for next business day
• Topical corticosteroids and/or create care plan if BC Cancer nurse unable to
• diphenhydrAMINE PO follow up
• Book nursing follow up call for next
business day and/or create care plan if
BC Cancer nurse unable to follow up
If improves to Grade 1
• taper predniSONE over at least 1 month, add
prophylactic antibiotics for opportunistic infections, and
resume checkpoint inhibitors
If persists more than 1-2 weeks or recurs
• Consider skin biopsy
• Withhold checkpoint inhibitors
• predniSONE 0.5 to 1 mg/kg/day PO
• Patient education on steroid use
• Once improving, taper predniSONE over
at least 1 month, consider
prophylactic antibiotics for opportunistic
infections, and resume checkpoint
inhibitors

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