Toxicities of TKI

Dose Modification and Management – Non-Hematologic Toxicities ( CDK4/6)

      Grade 1 or 2                     No dose adjustment is required.
      Grade ≥3                          Withhold until symptoms resolve to: 

                                                    • Grade ≤1; 

                                                    • Grade ≤2  if not considered a safety risk for the patient. Resume at the       

                                                                  next lower dose

NHS UK Immunotherapy guidelines 

	Grade 1	Grade 2	Grade 3	Grade 4
Neutrophil count	< 1500	1000-1500	<1000	<500
Anemia	Less than 10 gm	8-10 gm	Hgb <8.0 g/dL; transfusion indicated	Life-threatening consequences; urgent intervention indicated
Thrombocytopenia	>75K	50-75K	25-50K	<25K

Skin toxicities

1. Hand-foot syndrome- ASCO resource
2. Mucositis
3. Skin rash- refer to ESMO EGFR toxicity and NHS IO toxicity guides

ESMO EGFR skin toxicities

GI toxicities

1. Diarrhea
2. Nausea/Vomiting
3. Elevated lipase/amylase
4. Mucositis: see above

GI system	Grade 1-mild or radiologic	Grade 2-limiting IADL	Grade 3-limiting self care ADL	Grade 4-Life threatening
Constipation	Occasional use of stool softeners	Regular use of stool softeners	manual evacuation	Admission, ICU etc
Diarrhea	Increased BM 1-3 above baseline	4-6 BM more than baseline	More than 7 above baseline
Dry mouth	Mild, thick saliva, flow of saliva > 0.2ml/mt, no change to diet	Moderate symptoms, diet modified, copious water, lubricants	Inability to adequately aliment orally; tube feeding or TPN indicated; unstimulated saliva <0.1 ml/min
Esophagitis
Mucositis/Stomatitis	Mild symptoms	Moderate pain, modified diet, able to maintain caloric intake	Severe pain, interfering with PO intake
Nausea	Mild, no change to oral intake	Reduced oral intake without wt loss	Poor fluid and caloric intake,wt loss, supplemental nutrition
Vomiting	Mild	Oupatient IV hydration	TPN, admission
General	Grade 1-mild or radiologic	Grade 2-limiting IADL	Grade 3-limiting self care ADL
Fatigue	Relieved by rest	Not relieved by rest affecting IADL	Not relieved by rest; affecting Self care ADL

CV toxicities

1. Hypertension
2. LV dysfunction
3. QTc prolongation
4. Arterial thromboembolism

Lung toxicities

1. Pneumonitis

2. Dysphonia

Other known toxicities

1. Proteinuria

2. Cytopenias

3. Fatigue

4. Hypothyroidism

5. Wound healing

6. Hyperglycemia

TKI toxicity

General approach to toxicities

Step 1- grade the toxicity;  affecting self care or IADL?

Step 2- decide if the patient needs to be evaluated right away ( i.e ER) or within 24 hr or within a week. 

Step 3- holding the drug, supportive care, guidelines for restarting the drug

Skin Toxicities

Grade 1- no impact on ADL, localized, no superinfection

Grade 2- generalized, some impact on IADL, no superinfection--> within 24 hr--> cultures, pain control, antibiotic, hold the drug

Grade 3- Generalized, superinfection, impact on self-care ADL-->urgent evaluation esp if fever.

Management of grade 3:

- requires hospital admission. 

- focused exam, CBC, blood cultures, cultures of the affected area, viral culture,

-antibiotic, antiviral or antifungal

1. Hand-foot syndrome: Differentiate from PATEO syndrome, allergic eczema, bleomycin acral toxicity

2. Oral mucositis

3. Skin rash

GI toxicities:

Diarrhea- abemaciclib

Grade 1 no dose change needed

Grade 2- maximal supportive measures, hold for 24 hr or longer until less than grade 1. If needing to hold for > 24 hr, dose reduce when resuming

Grade 3/4- Suspend until Grade 1 or less. resume at next lower dose

Cytopenias

Neutropenia with CDK4/6 inhibitor: 

-Monitor CBC beginning of each cycle, day 15 of cycles 1 and 2

-patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated.

Grade 1 no dose change needed

Grade 2- no dose change

Grade 3 with fever or grade 4 without fever: hold until grade 2 or less. Reduce the dose to next lower level; 2 level reduction if recurrent or recovery > 7 days

Grade 3/4- Hold until Grade 2 or less. Resume at next lower dose if ANC recovery takes 7 days or more. Recheck ANC weekly.

Thrombocytopenia with CDK4/6 inhibitor:

Hold for grade 3/4, resume at one lower dose. Resume at 2 doses lower if recurrent grade 3. Plt count has to recover to grade2  or less.

Anemia in cancer

Role of ESA

Other known toxicities

1. Proteinuria

2. Cytopenias

3. Fatigue

4. Hypothyroidism

5. Wound healing

6. Hyperglycemia

Hyperglycemia

Abnormal glucose above baseline with no medical intervention

Change in daily management from baseline for a diabetic; oral antiglycemic agent initiated; workup for diabetes

Insulin therapy initiated; hospitalization indicated

Life-threatening consequences; urgent intervention indicated

Hyperglycemia with PIK3 kinase inhibitor

Anticipatory /preventative monitoring for toxicities

1. BP controlled for 1 week prior to starting VEGF Ab or TKI

2. EGFR skin toxicity prevention: Before initiating EGFR inhibitor therapy, several preventive measures can reduce the risk of skin rash. Areas of dry skin should be moisturized twice daily, because good hydration can prevent TKI-associated rash. Patients should minimize sun exposure and use sunscreen with a protection factor of at least 15 to prevent photosensitivity rash. Patients should also avoid products that dry out or irritate the skin, such as soaps or alcohol-based perfume products.

3. Hyperglycemia

4. Cardiac monitoring- echo, EKG