the cua comorbidities booklet

Managing Comorbidities in Castration Resistant Prostate Cancer 1

Introduction Baseline exam in patients with CRPC 2 Patient history, physical exam, and baseline laboratory tests 2 CUA-CUOG 2015 Guidelines: Management of CRPC 3 Summary of monitoring requirements for CRPC therapies 4

Electrolyte assessments and drug interaction considerations Prior to starting therapy 6 Hypocalcemia 6 Hypomagnesemia 7 Hypophosphatemia 8 Hypokalemia 8 Drug-drug interaction considerations 10

Metabolic abnormalities Managing diabetes in patients with CRPC 11 Musculoskeletal issues 14 Glaucoma 14

Cardiovascular abnormalities Androgen deprivation therapy and cardiovascular risk 15 Prevention of cardiovascular disease 15 Managing hypertension 16 Heart failure 20

Renal dysfunction 21

Hepatic dysfunction 22

References 23

Table of Contents

Managing Comorbidities in Castration Resistant Prostate Cancer2

Baseline exam in patients with CRPCIn addition to the cancer-related history, physical exam, laboratory tests, and imaging exams, before starting any therapy beyond androgen deprivation therapy in castration-resistant prostate cancer (CRPC) patients, one should include the following:

Patient history• Medication history; review pharmacy-generated current medication list• Determine history of the following: Neurological disorder Stroke Alcoholism Smoking Myocardial infarction Congestive heart failure Hypertension Diabetes Glaucoma Osteoporotic fractures Dental health

Physical exam • Include weight and blood pressure

Baseline laboratory and other tests 3 Complete blood count (CBC)

3 Electrolytes (sodium, potassium, calcium, magnesium, and phosphorus) at baseline and during follow-up

3 Random blood glucose

3 Creatinine and creatinine clearance

3 Alkaline phosphatase

3 Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and bilirubin)

3 Lactate dehydrogenase (LDH)

3 Electrocardiogram (ECG)

Introduction


CUA-CUOG 2015 Guidelines: Management of CRPC

In the presence of bone metastases:1

• Denosumab or zoledronic acid are recommended to reduce the risk of skeletal complications

• Palliative radiation therapy or Radium-223 should be considered in patients with pain

CRPC without

metastases

mCRPC with minimal

or no symptoms

mCRPC with

symptoms

Post docetaxel

Adapted from 2015 CUA-CUOG Guidelines1

Secondary hormonal therapy

AbirateroneAbiraterone

Enzalutamide

Docetaxel

Enzalutamide

Cabazitaxel

Radium-223

Docetaxel

Screen for metastases based on PSADT

Radium-223

PSADT = prostate-specific antigen doubling time


Drug name

Cabazitaxel25 mg/m2 IVq 3 weeks

Docetaxel75 mg/m2 IVq 3 weeks

Denosumab120 mg SCq 4 weeks

Zoledronic acid4 mg IVq 3-4 weeks

Jevtana(Sanofi Canada)

Taxotere(Sanofi Canada)

Xgeva (Amgen)

Zometa (Novartis)

Monitoring

Monitor CBC weekly during cycle 1, before each treatment cycle, and as required thereafter so that the dose can be adjusted if needed

Measure serum creatinine at baseline and with each blood count

Prior to each infusion:

Neutrophil count (do not administer until neutrophil count is ≥1,500 cells/mm3)

Hepatic function: ALT, AST, alkaline phosphatase, serum bilirubin

Correct pre-existing hypocalcemia

Supplement with calcium and vitamin D (minimum 1,000 mg elemental calcium and 800 IU vitamin D daily)

Monitor calcium: - Given some reports of early and severe hypocalcemia after the first dose, it is suggested that calcium be checked 1 to 2 weeks after the first injection and then every 4 weeks prior to each injection

Conduct an oral exam prior to initiation of treatment

Consider dental exam with appropriate preventive dentistry

Correct pre-existing hypocalcemia

Supplement with calcium and vitamin D (minimum 1,000 mg elemental calcium and 800 IU vitamin D daily)

Monitor serum calcium, electrolytes, phosphate, and magnesium every 4 weeks prior to each injection

Monitor renal function (creatinine clearance) every 4 weeks prior to each injection so that dose can be adjusted if needed

Conduct an oral exam prior to initiation of treatment

Consider dental exam with appropriate preventive dentistry

Continued on page 5

Summary of monitoring requirements for CRPC therapies

Chemotherapy

Bone-targeted agents

Brand name(company)


Adapted from the Canadian Urological Association2

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; ECG = electrocardiogram; LFT = liver function test; QTc = corrected QT interval

Drug name

Abirateroneacetate 1,000 mg/day PO QD plus prednisone 5 mg PO BID

Enzalutamide 160 mg (four 40-mg capsules) PO QD

Brand name(company)

Zytiga (Janssen)

Xtandi (Astellas)

Monitoring

LFTs (serum transaminases and bilirubin) prior to starting treatment, every 2 weeks for the first 3 months of treatment and monthly thereafter

Monitor blood pressure, serum potassium, and fluid retention monthly

General monitoring for laboratory or clinical parameters should be as per routine practice

Monitor blood pressure at baseline and monthly during treatment

For patients at risk of electrolyte abnormalities and/or QTc prolongation, measure ECG and serum electrolytes at baseline and monitor throughout treatment

Summary of monitoring requirements for CRPC therapies (cont’d.)

Hormonal therapy


Pearls in the management of electrolyte abnormalities • All bone-targeted therapies should be discontinued and next dose withheld until electrolytes and calcium are corrected

Prior to starting therapy• Assess calcium, phosphorus, and magnesium• Normalize levels prior to therapy initiation• All patients require calcium and vitamin D supplementation3

Men with prostate cancer ≤50 years of age are recommended to consume 1,000 mg of calcium daily and men >50 years of age need 1,200 mg

Calcium intake from all sources should not exceed 2,000 mg per day for men >51 years of age and not exceed 2,500 mg per day for men 19-50 years of age

A daily supplement of vitamin D containing 400-1,000 IU is recommended

HypocalcemiaLevels: • Mild to moderate 1.8-2.2 mmol/L • Severe <1.75 mmol/L

Electrolyte assessments and drug interaction considerations

Mild to moderate1.8-2.2 mmol/L

Severe<1.75 mmol/L

Increased oral calcium supplementation (1 gram/day)Double or triple calcium supplementationIncrease vitamin D supplementationMagnesium levels may also affect calcium levels, so ensure there is no concomitant hypomagnesemia

Consider hospital admission for intravenous infusion of calcium

Symptoms: • paresthesia • laryngospasm • prolonged QT intervals • muscle spasms • neuromuscular • electrocardiographic • cramps irritability changes that mimic • tetany • cognitive impairment myocardial infarction, • circumoral numbness • personality or heart failure • seizures disturbances

Treatment:


HypomagnesemiaLevels: • Mild-to-moderate 0.5-0.7 mmol/L • Severe <0.5 mmol/L

Symptoms: • weakness • muscle cramps • cardiac arrhythmia • increased irritability of the nervous system with tremors • athetosis • jerking • nystagmus • extensor plantar reflex

Treatment: Mild to moderate0.5-0.7 mmol/L

Moderate/severe and symptomatic<0.5 mmol/L

Diet Green vegetables (eg, spinach) Some legumes (eg, beans and peas), nuts, seeds, and whole, unrefined grains

Magnesium can be administered either orally in an oxide or gluconate form or parenterally as a sulfate salt

Oral supplementation Magnesium oxide (Mag-Ox, MagGel 600, Uro-Mag): used for the treatment of magnesium deficiencies or magnesium depletion from malnutrition, restricted diet, alcoholism, or magnesium-depleting drugs

Magnesium gluconate (Magtrate, Mag-G, Magonate): 500 mg contains 27 mg of elemental magnesium

Parenteral supplementation Magnesium sulfate: 1 g contains 8.12 mEq of magnesium (98 mg of elemental magnesium)


HypophosphatemiaLevels: • Mild to moderate 0.35-0.80 mmol/L • Severe <0.32 mmol/L

Symptoms: • muscle weakness, including cardiac and respiratory dysfunction • mental status changes

Treatment: • Dietary: intake from diet alone may be adequate, including dairy items, meats, and beans • Oral phosphate supplementation: oral phosphate supplements are well tolerated except in high doses, which can produce diarrhea Phosphate-Sandoz (Novartis) at 500 mg BID (each 500 mg effervescent tablet dissolved in water provides the equivalent of 16 mmoL of phosphate, 3 mmoL of potassium and 20 mmoL of sodium)

HypokalemiaLevels: • Mild to moderate: 3-3.5 mEq/L • Severe: <3 mEq/L

Symptoms: • muscle weakness • cramping • fasciculations • paralytic ileus • hypoventilation • hypotension


Treatment:Mild to moderate3-3.5 mEq/L

Severe<3 mEq/L

Increase dietary sources of potassium Dried fruits such as figs, nuts, leafy green vegetables, tomatoes, coconut water, citrus fruits, oranges, or bananas

Ensure that coinciding hypomagnesemia and hypophosphatemia are ruled out or managed

Oral potassium chloride supplements (Klor-Con, Sando-K, Slow-K, K-Dur) Klor-Con: each wax matrix tablet contains 600 mg or 750 mg of potassium chloride equivalent to 8 mEq or 10 mEq of potassium Sando-K: each effervescent tablet contains 600 mg potassium chloride, or 8 mEq of potassium Slow-K: each tablet contains potassium chloride 600 mg (approximately 8 mEq) in a slow-release wax core K-Dur: immediately dispersing extended release tablet of potassium chloride containing 1500 mg (20 mEq) of microencapsulated potassium (Kdur-10 has 10 mEq)

Consider hospital admission


Drug-drug interaction considerations

Drugs that reduce abiraterone levels

Agents that can increase the serum levels of enzalutamide

Agents that are reduced due to enzalutamide (ie, reduced efficacy)

• Interactions are due to induction or inhibition of liver enzymes

Drugs whose concentration may increase with abiraterone

Drugs whose concentration may decrease with abiraterone

PhenytoinCarbamazepineRifampinPhenobarbital

Gemfibrozil

Clinically significant: Warfarin (check INR closely and dose increase may be required)

Unknown clinical significance: Esomeprazole, omeprazole Midazolam Fentanyl/tramadol Phenobarbital and phenytoin Colchicine Haloperidol Beta-blockers Calcium-channel blockers Anti-cancer medications (cabazitaxel, sunitinib) Macrolide antibiotics (clarithromycin, azithromycin, erythromycin) Statins metabolized by CYP3A4 (atorvastatin, simvastatin) Levothyroxine Prednisone

TamsulosinBeta-blockers, including metoprololNortriptylineTramadol

Codeine

Abiraterone:

Enzalutamide:


Prednisone is an integral part of some life-prolonging treatments for castration-resistant prostate cancer (CRPC). Specifically, clinical trials demonstrating survival benefit for abiraterone and docetaxel, were conducted with concomitant oral prednisone at 10 mg/day. Prednisone may have various side effects, as described below. However, in several CRPC clinical trials, prednisone at the dose of 10 mg/day was very well tolerated and severe side effects were rare. In addition, in the case of abiraterone therapy, the use of prednisone at 10 mg/day is slightly above physiological replacement therapy as abiraterone alone results in adrenal insufficiency. Moreover, the potential side effects are uncommon even with long-term exposure.

Managing diabetes in patients with CRPCA diagnosis of diabetes can be made according to the following criteria:

Metabolic abnormalities

Fasting plasma glucose (FPG) ≥7.0 mmol/LFasting = no caloric intake for at least 8 hours

ORA1C ≥6.5% (in adults)

Using a standardized, validated assay in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes

OR2hPG (plasma glucose) in a 75 g oral glucose tolerance test

(OGTT) ≥11.1 mmol/LOR

Random PG ≥11.1 mmol/LRandom = any time of day, without regard to the interval since the last meal

Adapted from the Canadian Diabetes Association 2013 Guidelines4

Continued on page 12


• New onset diabetes occurs in less than 1% of CRPC patients taking low-dose prednisone

• Abiraterone and enzalutamide alone do not disturb glucose metabolism or cause hyperglycemia

• In patients with diabetes, the addition of low-dose prednisone will rarely cause significant changes in glycemic control

If glycemic disturbance occurs, glycemic medication should be adjusted accordingly by the physician managing the patient’s diabetes

• Monitor fasting blood glucose levels every 3 months (more often in patients with significant blood glucose changes and/or symptoms [eg, increased thirst, increased urination, weight loss]) and the patient’s family physician can maintain them on their diabetes therapies

• If blood glucose rises into the diabetic range, the patient’s family physician should be notified for management

• In rare cases of difficulty in managing glycemia, the patient should be referred to an endocrinologist and consideration be given to altering CRPC treatment with prednisone

Continued from page 11


The Canadian Diabetes Association 2013 Guidelines treatment algorithm for the management of type 2 diabetes

At diagnosis of type 2 diabetesStart lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5%

If not at target (2-3 months)

Start/increase metformin

Patient characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obese Comorbidities (renal, cardiac, hepatic) Preferences and access to treatment Other

Agent characteristics Blood glucose lowering and durability Risk of inducing hypoglycemia Effect on weight Contraindications and side effects Cost and coverage Other

If not at glycemic target

Initiate insulin +/- metformin

If not at glycemic target

Make timely adjustments to attain target A1C within 3 to 6 months

Start metformin immediatelyConsider initial combination

with another antihyperglycemic agent

A1C ≥8.5% Symptomatic hyperglycemia with metabolic decompensation

L

I

F

E

S

T

Y

L

E

• Add another agent from a different class • Add/intensify insulin regimen

Add an agent best suited to the individual:

Adapted from the Canadian Diabetes Association 2013 Guidelines4

CHF = congestive heart failure; GI = gastrointestinal

Alpha-glucosidase inhibitor (acarbose)

Insulin

Insulin secretagogue:Meglitinide

Thiazolidinedione

Weight loss agent (orlistat)

Sulfonylurea

Incretin agents:DPP-4 inhibitors

GLP-1 receptor agonists

Rare

Yes

Yes

Rare

None

Yes

Rare

Rareto

$$

$-$$$$

$$

$$

$

$$

$$$$

Neutral to

Neutral to

Improved postprandial control, GI side effects

No dose ceiling, flexible regimens

Less hypoglycemia in context of missed meals, but usually requires TID to QID dosing

Gliclazide and glimepiride associated with less hypoglycemia than glyburide

CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

$$$

GI side effects

GI side effects

Class Relative A1C lowering

Hypo-glycemia

Weight CostOther therapeutic considerations

Add an agent best suited to the individual (agents listed in alphabetical order):


Musculoskeletal issues• Musculoskeletal issues are caused by: Long-term androgen deprivation therapy Bone metastases Long-term corticosteroid use

Patient history• Patients on prolonged prednisone therapy may develop corticosteroid myopathy, manifested by proximal muscle weakness and wasting However, this is uncommon at the doses used in prostate cancer and is generally reversible upon discontinuation of prednisone

• Patients with a significant history of osteoporosis, prior fractures, or poor bone mineral density (BMD), should already be on a bone-targeted therapy, such as denosumab, which would protect against the consequences of bone loss and metastases

• Patients should be counselled to perform regular exercise (30-minute daily walks at a minimum) which can mitigate muscle weakness, osteoporosis, and weight gain that can be associated with CRPC as well as therapies used to treat the disease

Glaucoma • Patients with a known history of glaucoma should be counselled to have their glaucoma monitored more frequently by their ophthalmologist while on prednisone therapy


Androgen deprivation therapy (ADT) and cardiovascular risk• Almost all observational/retrospective studies have demonstrated an association between ADT and an increased risk of myocardial infarction, cerebrovascular accident and sudden cardiac death

• ADT is also associated with an increased risk of: diabetes QTc prolongation

• The risk of death from cardiovascular disease (CVD) is increased with the following risk factors: History of myocardial infarction History of cerebrovascular events Congestive heart failure Peripheral arterial disease Hypertension Chronic obstructive pulmonary disease (COPD) Renal disease

• Close monitoring of patients with the following CVD risk factors is recommended: Metabolic syndrome Diabetes Obesity Chronic renal impairment

Prevention of cardiovascular disease• Daily physical exercise is considered the key lifestyle modification to avoid these consequences of ADT

Other preventative strategies:

• Lifestyle modifications: smoking cessation weight loss (when required)

Cardiovascular abnormalities



• Annual lipid profile

• Statin therapy

• Glucose-lowering therapy Metformin (850 mg/day for 2 weeks and 850 mg twice a day afterwards) coupled with lifestyle modifications such as dietary advice and regular aerobic exercise for 6 months is a well-tolerated treatment option that causes significant reduction in abdominal girth, weight, and systolic blood pressure

• Antihypertensive therapy

• Aspirin (unless contraindicated) Recommended for men with existing CVD or in men who recently developed CVD from ADT

Managing hypertension• Hypertension, like diabetes, should be normalized before starting therapy

• Hypertension is not a contraindication for any of the therapies for CRPC

• If previously unknown hypertension is discovered, initiate therapy, or consider consultation with the patient’s family physician or an internist

• Caution in patients with poorly controlled hypertension and/or history of CVD

• Optimal treatment of blood pressure is necessary, since hormonally-based therapies can cause a rapid onset of high blood pressure

• Blood pressure should be monitored regularly (at least monthly)

• Temporary suspension of CRPC therapy is recommended for patients with severe hypertension (SBP >200 mmHg or DBP >110 mmHg)

• Treatment-emergent hypertension should be treated appropriately

• Treatment may be resumed once hypertension is controlled


Canadian Hypertension Education Program 2014 recommendations for the treatment of hypertension: considerations in the individualization of pharmacologic therapy

Initial therapy Second-line therapy Notes and/or cautions


Hypertension without other compelling indications for a specific agent

Diabetes mellitus – target blood pressure <130/80 mmHg

Diastolic hypertension with or without systolic hypertension (target BP <140/90 mmHg)

Isolated systolic hypertension without other compelling indications (target BP for age <80 is <140/90 mmHg; for age ≥80 the target SBP is <150 mmHg

Diabetes mellitus with microalbuminuria*, renal disease, cardiovascular disease or additional cardiovascular risk factors

Diabetes mellitus not included in the above category

Thiazide/thiazide-like diuretics, beta-blockers, ACE inhibitors, ARBs, or long-acting calcium channel blockers (consider ASA and statins in selected patients).

Consider initiating therapy with a combination of first-line drugs if the blood pressure is ≥20 mmHg systolic or ≥10 mmHg diastolic above target.

Thiazide/thiazide-like diuretics, ARBs or long-acting dihydropyridine calcium channel blockers.

ACE inhibitors or ARBs.

ACE inhibitors, ARBs, dihydropyridine CCBs or thiazide/thiazide-like diuretics.

Combinations of first-line drugs.

Combinations of first-line drugs.

Addition of a dihydropyridine CCB is preferred over a thiazide/thiazide-like diuretic.

Combination of first-line drugs. If combination with ACE inhibitor is being considered, a dihydropyridine CCB is preferable to thiazide/thiazide-like diuretic.

Not recommended for monotherapy: alpha blockers, beta-blockers in those ≥60 years of age, ACE inhibitors in black people.

Hypokalemia should be avoided in those prescribed diuretic monotherapy. ACE inhibitors and direct renin inhibitors are potential teratogens, and caution is required if prescribing to women of child bearing potential.

Combination of an ACE inhibitor with an ARB is not recommended.

Same as diastolic hypertension with or without systolic hypertension.

A loop diuretic could be considered in hypertensive chronic kidney disease patients with extracellular fluid overload.

Normal albumin to creatinine ratio [ACR] < 2.0 mg/mmol in men and women.


Canadian Hypertension Education Program 2014 recommendations - continued



Cardiovascular disease – target blood pressure <140/90 mmHg

Coronary artery disease

Recent myocardial infarction

Heart failure

Left ventricular hypertrophy

Past stroke or transient ischemic attack

ACE inhibitors or ARBs (except in low-risk patients); beta-blockers for patients with stable angina.

Beta-blockers and ACE inhibitors (ARBs if ACE inhibitor intolerant).

ACE inhibitors (ARBs if ACE inhibitor intolerant) and beta-blockers.Aldosterone antagonists (mineral corticoid receptor antagonists) may be added for patients with a recent cardiovascular hospitalization, acute myocardial infarction, elevated BNP or NT- proBNP level or NYHA Class II to IV symptoms.

ACE inhibitor, ARB, long-acting CCB or thiazide/thiazide-like diuretics.

ACE inhibitor and a thiazide/thiazide-like diuretic combination.

Long-acting CCBs. When combination therapy is being used for high-risk patients, an ACE inhibitor/ dihydropyridine CCB is preferred.

Long-acting CCBs if beta-blocker contraindicated or not effective.

ACE inhibitor and ARB combined. Hydralazine/ isosorbide dinitrate combination if ACE inhibitor and ARB contraindicated or not tolerated. Thiazide/ thiazide-like or loop diuretics are recommended as additive therapy.

Thiazide/thiazide-like or loop diuretics are recommended as additive therapy. Dihydropyridine CCB can also be used.

Combination of additional agents.

Combination of additional agents.

Avoid short-acting nifedipine. Combination of an ACE inhibitor with an ARB is specifically not recommended. Exercise caution when lowering SBP to target if DBP is ≤60 mmHg.

Non-dihydropyridine CCBs should not be used with concomitant heart failure.

Titrate doses of ACE inhibitors and ARBs to those used in clinical trials. Carefully monitor potassium and renal function if combining any of ACE inhibitor, ARB and/or aldosterone antagonist.

Hydralazine and minoxidil can increase left ventricular hypertrophy.

Treatment of hypertension should not be routinely undertaken in acute stroke unless extreme BP elevation. Combination of an ACE inhibitor with an ARB is not recommended.


Canadian Hypertension Education Program 2014 recommendations - continued


Non-diabetic chronic kidney disease – target blood pressure <140/90 mmHg

Other conditions – target blood pressure <140/90 mmHg

Non-diabetic chronic kidney disease with proteinuria†

Renovascular disease

Peripheral arterial disease

Does not affect initial treatment recommendations.

Dyslipidemia Does not affect initial treatment recommendations.

Overall vascular protection

ACE inhibitors (ARBs if ACE inhibitor intolerant) if there is proteinuria. Diuretics as additive therapy.

Does not affect initial treatment recommendations.

Statin therapy for patients with ≥3 cardiovascular risk factors or atherosclerotic disease.

Low dose ASA in patients >50 years.

Combinations of additional agents.




Carefully monitor renal function and potassium for those on an ACE inhibitor or ARB. Combinations of an ACE inhibitor and ARB are not recommended in patients without proteinuria.

Avoid ACE inhibitors or ARBs if bilateral renal artery stenosis or unilateral disease with solitary kidney.

Avoid beta-blockers with severe disease.

Caution should be exercised with the ASA recommendation if blood pressure is not controlled.

* Albuminuria is defined as persistent albumin to creatinine ratio [ACR] >2.0 mg/mmol in men and women.

† Proteinuria is defined as urinary protein >500 mg/24 hr or albumin to creatinine ratio [ACR] >30 mg/mmol.

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ASA = acetylsalicylic acid; BNP = brain natriuretic peptide; CCB = calcium channel blocker; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association

Adapted from the 2014 Canadian Hypertension Education Program Recommendations5


Heart failurePrior to initiation of any therapy for CRPC, patients should have stable cardiac function. Any signs or symptoms of heart failure should be evaluated prior to instituting any form of therapy. If a doubt exists, a cardiac ultrasound or MUGA scan may be performed to evaluate cardiac function, or the patient can be referred to an internist/cardiologist.

New York Heart Association (NYHA) heart failure classifications

Scoring system for the diagnosis of acute heart failure

Class

Predictor

I

II

III

IV

Functional capacity: how a patient with cardiac disease feels during physical activity

Possible score Patient’s score

Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.

Age >75 years 1Orthopnea present 2Lack of cough 1Current loop diuretic use (before presentation) 1Rales on lung exam 1Lack of fever 2Elevated NT-proBNP* 4Interstitial edema on chest x-ray 2

14 Total =

Likelihood of heart failure Low 0-5 Intermediate 6-8 High 9-14

Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.

Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.

Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort increases.

Adapted from the American Heart Association6

Adapted from the Canadian Cardiovascular Society Heart Failure Management Guidelines7

* Elevated NT-proBNP (N-terminal prohormone of brain natriuretic peptide) was defined as >450 pg/mL if age <50 years and >900 pg/mL if age >50 years.


Renal dysfunctionRenal dysfunction is common with prostate cancer due to obstruction of the lower or upper urinary tract. Imaging should always be repeated to identify reversible etiologies.

Managing renal dysfunction• Creatinine is a good indicator of renal function, but clearance needs to be calculated using the Cockroft-Gault equation

Cockcroft-Gault equation

CrCl (ml/min) = (140-age [years]) x actual weight (kg) x 1.2 (if male)

• Lab tests calculate creatinine clearance automatically when blood tests are done, but these may sometimes be unreliable, especially in elderly patients

Notes: This figure is designed to reflect the risk of progression by intensity of colouring, with blue boxes as lowest risk stage and bright red boxes as highest risk stage. Monitoring and referral is dependent on clinical situation. Individual circumstances will dictate referral or monitor decision.

*Referring clinicians may wish to discuss with their nephrology service depending on local arrangements for monitoring or referring.

**The instance of monitoring in red box (A2 and G3b) is not an error. While an admittedly high risk box may not warrant specialist intervention. If in doubt, telephone consultation with nephrologist or internist recommended.

A2

Moderately increased

3-30 mg/mmol

A1

Normal to mildly increased

<3 mg/mmol

Urine ACR categoriesDescription and range

A3

Severely increased

>30 mg/mmol

eGFR categories (mL/min/1.73 m2) Description and range

G1 Normal or high ≥90 Monitor Refer*

G2 Mildly decreased 60-89 Monitor Refer*

G3a Mildly to moderately decreased 45-59 Monitor Monitor Refer

G3b Moderately to severely decreased 30-44 Monitor Monitor** Refer

G4 Severely decreased 15-29 Refer* Refer* Refer

G5 Kidney failure <15 Refer Refer Refer

Adapted from the BC Ministry of Health8

Referral decision-making by estimated glomerular filtration rate (eGFR) and albuminuria

SCreat (µmol/L)


Adapted from NPS Medicinewise9

Hepatic dysfunctionManaging hepatic dysfunction• Since most life-prolonging agents are metabolized through the liver, hepatic dysfunction may be a limitation with CRPC therapies

Parameter Assign 1 point

Ascites Absent Slight Moderate

Bilirubin (µmol/L) < 11 11–45 > 45

Albumin (g/L) > 35 28–35 < 28

Prothrombin time < 4 4–6 > 6 (seconds over control), or INR < 1.7 1.8–2.3 > 2.3

Encephalopathy None Grade 1–2 Grade 3–4

Total score of 5–6 Grade A (well compensated disease)Total score of 7–9 Grade B (disease with significant functional compromise)Total score of 10–15 Grade C (decompensated liver disease)

Assign 2 points Assign 3 points

Treatment limitations with hepatic dysfunctionGrade A

Moderate hepatic impairment (Child-Pugh Class B)

Severe hepatic impairment (Child-Pugh Class C)

Treatment-induced hepatic dysfunction

No dose adjustment for either abiraterone or enzalutamide

No dose adjustment for enzalutamide

Abiraterone and enzalutamide are contraindicated

The majority of cases of hepatotoxicity occur within the first 3 months of treatment and are more likely in patients with pre-existing liver impairment

Abiraterone is contraindicated

Treatment limitations with renal dysfunction• None of the hormonal or chemotherapeutic agents for CRPC are excreted by the kidneys. Therefore, patients with creatinine clearance of greater than 30 can be treated with any of the agents.


References1. Saad F, Chi K, Finelli A et al. The 2015-CUA-CUOG guidelines for the management of castration resistant prostate cancer (CRPC). Available at: http://www.cua.org/en/guidelines.

2. Canadian Urological Association. Beyond PSA monitoring in the management of advanced prostate cancer. April 2014.

3. BC Cancer Agency. Nutrition guide for men with prostate cancer. Available at: http://www.bccancer.bc.ca/PPI/copingwithcancer/pamphlets/nutrition.htm.

4. Canadian Diabetes Association. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2013;37 (Suppl 1):S1-212.

5. Canadian Hypertension Education Program. The 2013 Canadian Hypertension Education Program Recommendations. Available at: www.hypertension.ca.

6. American Heart Association. Classes of heart failure. Available at: http://www.heart. org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_ UCM_306328_Article.jsp.

7. McKelvie RS, Moe GW, Ezekowitz JA et al. The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. Can J Cardiol 2013;29(2):168-81.

8. British Columbia Ministry of Health. Chronic kidney disease: identification, evaluation and management of adult patients. Available at: http://www.bcguidelines.ca/guideline_ckd.html

9. NPS Medicinewise. Child-Pugh classification of liver disease. Available at: http://www.nps.org.au/publications/health-professional/nps-radar/2009/december-2009/ prasugrel/prasugrel-webextra-1.

10. Rhee H, Gunter JH, Heathcote P et al. Adverse effects of androgen deprivation therapy in prostate cancer and their management. BJU Int 2014;Oct 18. doi: 10.1111/bju.12964.

11. Galvão DA, Taaffe DR, Spry N et al. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol 2010;28(2):340-7.

12. Galvão DA, Taaffe DR, Spry N et al. Acute versus chronic exposure to androgen suppression for prostate cancer: impact on the exercise response. J Urol 2011;186(4):1291-7.

13. Sountoulides P, Rountos T. Adverse effects of androgen deprivation therapy for prostate cancer: prevention and management. ISRN Urol 2013 Jul 25;2013:240108. http://dx.doi. org/10.1155/2013/240108.

14. Ahmadi H, Daneshmand S. Androgen deprivation therapy for prostate cancer: long-term safety and patient outcomes. Patient Relat Outcome Meas 2014 Jul 5;5:63-70. doi: 10.2147/PROM.S52788. eCollection 2014.

15. Association of androgen-deprivation therapy with excess cardiac-specific mortality in men with prostate cancer. BJU Int 2014 Aug 15: doi: 10.1111/bju.12905.

16. Nobes JP, Langley SE, Klopper T et al. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int 2011;109(10):1495-502.


Notes

the cua comorbidities booklet

Documents