3.2 Treatment criteria for initiation of TKI

3.2 Treatment criteria for initiation of TKI¹

Tyrosine kinase inhibitors (TKIs) are palliative treatments aimed at symptom relief and life extension.

It is a tablet treatment that should be taken either once or twice daily. For some medicinal products, a pause is included (Sunitinib is taken either for 4 weeks followed by a 2-week pause or 2 weeks of treatment followed by a 1-week pause, which is repeated. Tivozanib is taken for 3 weeks followed by a 1-week pause, which will be repeated).
For some medicinal products, food should not be consumed immediately before or after administration (Pazopanib and Cabozantinib should be taken at least 1 hour before or at least 2 hours after food).
A course of treatment lasts 4 or 6 weeks. The patient will be evaluated by a CT scan of the chest and abdomen (and an MRI of the cerebrum for cerebral metastases) every 3 months (after 2 or 3 courses of treatment).

For 1st line TKI:

The median progression-free survival (mPFS) is approximately 9 months. Median overall survival (mOS) depends on the IMDC risk group (see section on prognostic stratification tools for patients with mRCC)
According to the RECIST criteria, 60–80% of patients respond to the treatment with either:
- Regression (complete response (CR)) – rarely seen
- Partial response (PR) – seen in 30–40%
- Stabilisation of the disease (stable disease (SD)) – in 30–40% for a shorter or longer period of time

First visit to the Oncology Department

At the first visit to the Oncology Department, a full medical record must be recorded, focusing on:

Medical history:

Dispositions (family history of cancer with particular emphasis on cases of kidney cancer)
Symptoms (fatigue, weight loss, impaired appetite, sweating/hot flushes, pain, etc.)
Comorbidity (hypertension, ischaemic heart disease, impaired cardiac pump function (EF) and its cause, arrhythmias, cerebral apoplexy, diabetes mellitus, renal insufficiency, autoimmune and other chronic disorders)
Full medication status. It should state whether the patient is undergoing:
1. Anticoagulant therapy, which medicinal product and cause (arrhythmias, deep vein thrombosis (DVT), pulmonary embolism (LE) or other coagulopathy)
2. Cholesterol-lowering medicine and which medicinal product

Social information:
1. Civil status
2. Network
3. Employment (working, sick leave, early retirement, pensioner or other)
4. Functional level (self-reliant, need help with self-care or other)

Clinical assessment:

General condition (good, acute or chronic condition) incl. performance status (PS).
Vital signs incl. BP, pulse, temperature, saturation and weight
Objective examination incl. evaluation of enlarged lymph nodes, stethoscopy of heart and lungs, examination of abdomen, extremities and skin

Paraclinical:

At the first outpatient visit, the following must be examined:

Urine dipstick: obs for protein (if +3 for protein, do 24-hour urine for protein elimination)
Blood tests: haematology (Hb, thrombocytes, leukocytes + differential count), fluid counts (creatinine, urea, sodium, potassium, ionised calcium and magnesium), liver function tests (ALT, AST, LDH, alkaline phosphatase, INR and coagulation counts (2.7 + 10), CRP and TSH
ECG: rhythm, acute changes and QTc interval assessment
MRI scan: cerebrum (performed or ordered)
CT scan: thorax and abdomen (baseline must be <1 month old)
MUGA: assessment of the heart’s pumping function (performed or ordered)
IMDC: risk stratification

Treatment criteria

The following criteria must be met in connection with initiation of TKI. Deviations must be discussed with a specialist, and this must be documented in the medical record.

*If no (explain in medical record)

TREATMENT CRITERIA	YES	NO*	ACTIONS IF ANSWER IS NO
Bioptic verified mRCC
Performance status (PS) < 2			Consider lower starting dose (50%)
Renal function eGFR > 30 ml/min			TKI is primarily excreted via the liver, but a smaller proportion is excreted via the kidneys. Consider lower starting dose (50%). If the dose is tolerated, dose escalation may be attempted at Cycle 2
Liver function Bilirubin < 1.5 x upper limit of normal AST/ALT < 3 x upper limit of normal or < 5 in liver metastases			TKI is primarily excreted via the liver 1) Use TKI other than Pazopanib, as there is an increased risk of deteriorating liver function during concomitant treatment with Pazopanib 2) Consider lower starting dose (50%) with weekly check of liver lab results
ECG QTcF <450 ms for men and <470 ms for women			Review the patient’s medication list for medications that may cause prolonged QTc. Consult with a cardiologist
Blood pressure < 140/90 mmHg			Consider white-coat hypertension and ask the patient to take blood pressure at home or at their GP . If continued high blood pressure, initiate anti-hypertensive medications or intensify anti-hypertensives already used via GP (see section 5.2.2)
Ejection fraction (EF) > 40% (measured by MUGA)			Refer the patient for cardiological assessment for ECHO and initiation of anticongestive therapy if EF < 40% is confirmed. The TKI may only be started once the cardiologist has drawn up a plan. Consider reduced dose of TKI due to presumed reduced risk of cardiotoxicity
Protein excretion in urine < 3+			24-hour urine collection if: 1) 24-hour urine protein is 1–3,4 g/day: begin TKI at a reduced dose (50%) with 24-hour urine protein measurement at each visit at the outpatient clinic (day 28 or day 42) 2) 24-hour urine protein > 3.5 g/day: refer to nephrologist before starting TKI
No Marevan as AC therapy			If Marevan, consider switching to low-dose heparin (Innohep), as there may be large fluctuations in INR during TKI therapy
No cholesterol-lowering medication			There is an increased risk of hepatic effects during concomitant treatment with pazopanib and simvastatin, or tivozanib and rosuvastatin (and probably the other cholesterol-lowering drugs). Therefore, simvastatin/Rosuvastatin/cholesterol-lowering medication should be temporarily discontinued when starting pazopanib
No strong CYP3A4 inducers or inhibitors (see Section 5.4)			Consider the importance of other medication or whether it can be replaced with other medication
Cerebral TCI/cerebral apoplexy or myocardial infarction more than 1 month ago			TKI can exacerbate these conditions. Patient/relatives must be informed if this treatment criterion is compromised
No major surgery within 4 weeks			TKI reduces wound healing. The wound must therefore be nicely healed before starting TKI
MRI scan of cerebrum without cerebral metastases			In cerebral metastases: 1) If the patient is asymptomatic and has 1–3 cerebral metastases, consider radiation therapy. TKI can be started, but must be temporarily discontinued in connection with radiation therapy 2) If the patient is symptomatic and has 1–3 cerebral metastases, begin steroid treatment according to guidelines and consider radiation. TKI can be started 3) If the patient has multiple cerebral metastases but asymptomatic. Initiate TKI 4) If the patient has multiple metastases and has symptoms, begin steroid treatment and consider whole-brain radiation before starting TKI
CT scan of chest and abdomen < 1 month			If baseline CT scan > 1 month, consider ordering a subacute CT scan as new baseline

Links to summary of product characteristics from table:

Instructions for patient/relative

BP measurement
Dispense supportive medication (Domperidone, Imolope, cream for hands and feet, oral care products)
Blood tests between cycles (Pazopanib: midway through cycle 2 and 3; Cabozantinib: midway through cycle 1 and 2; Sunitinib: day 28 of cycle 1; Tivozanib: midway through cycle 1, 2, and 3)
Management of adverse reactions and provision of diary + CTC form
Contact with the department in the event of unacceptable adverse reactions

Assessment during TKI

The patient is assessed at the outpatient clinic by a doctor or nurse every 4 or 6 weeks, where the following is carried out:

Clinical assessment and checking of BP, pulse, weight, temperature and saturation, if applicable
Toxicity registration according to CTC AE version 5.0 (see section on grading )
Control of blood tests (haematology, fluid count incl. ionised calcium + magnesium, liver count, CRP+TSH)
Medication status
Assessment of new symptoms
Decision on dose modification and/or other measures (see section on management of adverse reactions )
Urine dipstick for Proteinuria (every 3 months)

Evaluation of response

The efficacy of TKI is assessed every 3 months. (12 weeks) with CT scan of the chest and abdomen and MRI of the cerebrum if the patient is known to have cerebral metastases.

Assessment of response depends on: