Hypercalcemia of malignancy. Apirom Laocharoenkeat

Transcription

1 Hypercalcemia of malignancy Apirom Laocharoenkeat

2 ผ ป วยหญ งอาย 51ป เป นมะเร งเต านมชน ดแพร กระจาย CC : ม อาการ nausea /vomiting และ mental changes HPI:ได ร บ docetaxel cycle 4 เม อ 18 ว นก อน ญาต ผ ป วยให ข อม ลว าผ ป วยด มน ามาก แต เม อส ปดาห ท แล วผ ป วยไม ร บประทานอาหาร และเม อ 2 ว นก อน ม อาการม นงง และส บสน PMH : metastatic breast cancer FH/SH : บ ดาเส ยช ว ตจาก lung cancer,มารดาย งม ช ว ตอย ไม ม พ น องท องเด ยวก น Review of systems Physical Exam : BP 99/62 P 109 T 37 General confused female HEEN normal Neck Supple, slight axillary lymphadenopathy Lung Decreased breath sounds,bilateral wheezes Heart RR tachycardia Abdomen BS Extremities WNL, prior lymph node dissection on left - arm. Neuro Oriented to persons, but no time or location

3 Laboratory tests Na 143 WBC 6.8 AST 32 K 3.9 Hgb 12.7 ALT 33 Cl 110 Hct 37.7 LDH 160 CO2 24 Plts 164 Alk phos 210 BUN 47 T.prot 5.4 GGT 40 Cr 1.6 Alb 2.4 T.Bili Ca 14mg/dl PT/PTT 14/23 TREATMENT?

4 Introduction Incidence: 10-20% of all cancer patients( advanced st) Incidence: 0.5-1% of pediatric patients Prognosis: Hypercalcemia in patient with cancer signifies a very poor prognosis. Less than 6 months. App. 50% die within 30 days.

5 Survival curves for patients with cancer and hypercalcemia

6 Incidence by tumor type Squamous cell carcinoma of Lung Breast Multiple Myeloma Lymphomas HL NHL (high grade) T-cell lymphoma Others:Ovary,liver,pancrease, esophagus,cervix Unknown primary % 30-40% 20-40% % 14-33% 50% 7% 7% Adapted from Kaplan

7 Normal Calcium homeostasis Oral intake 1000mg/day 150mg is absorbed 850mg is excreted Distribution in the body Soft tissue 1000mg Extracellular fluid 900mg Bone 1kg

8 Distribution of Calcium in The Body

9 Normal calcium homeostasis Excretion through the kidney 150mg/day Hormonal control Parathyroid hormone Calcitriol Calcitonin

10 Parathyroid hormone Serum calcium Phosphate PTH PTH Bone resorption Renal reabsorption Formation of Calcitriol Renal phosphate loss Serumcalcium Phosphate

11 Calcitriol (1,25(OH 2 )Vit D 3 ) Parathyroid hormone Phosphate Calcitriol(1,25(OH2)Vit D3) Calcitriol (1,25(OH2)Vit D3) Gut absorption Renal reabsorption Bone turn over Serum calcium Phosphate

12 Calcitonin Serum calcium Calcitonin Bone reabsorption Serum calcium Phosphate Act as an antagonist to PTH,Short-term control of serum calcium SC/IM

13 Normal calcium Normal calcium level = mg/dl Non-ionized, inactive protein bound form 45-50% Non-ionized, inactive complex diffusible form 5-15% Active, free ionized form 40-50%

14 The constituents of total calcium within the serum

15 Correct for albumin Corrected calcium = Measure Calcium ( normal albumin patient s albumin) OR =Measure Calcium patient s albumin+4 normal albumin = 4

16 Etiology of Hypercalcemia of Malignancy 1. Bone resorption The most important cause of hypercalcemia of malignancy. Classified into four types. Caused by osteoclasts, but may be due to direct tumor invasion of bone Primarily mediated through tumor production of PTH related protein Other mediators or costimulatory factors IL-6, IL-1, TGF-, and TNF-,RANK

17 Type of Hypercalcemia Associated with Cancer Type Frequency (%) Bone metastases Causal agent Typical Tumors Local osteolytic Hypercalcemia (result from bone Destruction) 20 Common, extensive Cytokines, chemokines, PTHrP Breast CA,MM,lymphoma Humoral hypercalcemia Of malignancy 80 Minimal or absent PTHrP Squamous cell carcinoma(head and neck,esophagus, cervix,lung),renal cancer,ovarian cancer, endometrial cancer, HTLV associated cancer,breast cancer 1,25 (OH) 2 D- secreting lymphomas <1 Variable 1,25 (OH) 2 D Lymphoma (all types) Ectopic hyperparathyroidism <1 Variable PTH Variable HTLV= human T-cell lymphotropic virus, MM=multiple myeloma, PTHrP=PTH related protein

18 Etiology (cont ) 2. Inadequate renal compensation(clearance) Often due to PTH rp Other factors often involved with Breast cancer and Myeloma 3. intestinal calcium absorption Uncommon mechanism Seen in some lymphoma patients Due to production of calcitonin by tumor tissue

19 Sequence homology between PTHrP and PTH PTHrP mimics some, but not all,of the effect of PTH. Binding with the same receptors on skeletal and renal target tissue. Increased blood level of PTHrP have been found in solid tumor,but not In hematologic malignancy.

20 Clinical Presentation Signs and symptoms related to degree of elevation and rate of rise of serum calcium

21 Renal manifestation Polyuria Polydipsia (กระหายน ามากผ ดปกต ) Dehydration Decrease in GFR nephrocalcinosis PTHrH Calcium resorption ( renal tubular) hypercalcemia High concentration of Calcium in urine Polyuria Calcium resorption Renal blood flow dehydration

22 GI manifestation Constipation Anorexia Nausea/vomiting Acute pancreatitis (rare) Anorexia,Nausea/vomiting associated with loss of circulating fluid volume exacerbate dehydration

23 Neurologic manifestation Lethargy, fatigue Confusion, irritability Depression, sleep disorders, Muscle weakness, hypotonia, loss of deep tendon reflexes audiotory acuity Seizures, stupor, coma

24 Cardiac manifestation Shortened QT interval Widened T wave Heart block, asystole Atrial or Ventricular arrythmias Synergize digoxin toxicity

25 Confounding factors Demographic variables Age, performance status Co-morbid disease Renal dysfunction, hepatic dysfunction Tumor sites Brain mets, adrenal mets, liver mets

26 Treatment 1. Treat underlying cancer 2. Management based on degree of hypercalcemia Mild hypercalcemia (corrected calcium <12) Morerate hypercalcemia (corrected calcium 12-14) Severe hypercalcemia (corrected calcium >14)

27 Mild hypercalcemia: Asymtomatic (corrected calcium <12) Encourage fluid intake Discontinue drugs that calcium renal blood flow

28 Effect of rehydration on hypercalcemic patients

29 Mild hypercalcemia: Symtomatic Rule out other causes of symptoms Hydration: Normal Saline ml/hr Correct dehydration (after corrected, manage fluid overload with furosemide) Lower calcium by mg/dl Onset is hours Promotes renal calcium excretion Hypocalcemic agent:bisphosphonate.

30 Bisphosphonates Clodronate Disodium tab. Pamidronate injection Zoledronic acid injection Ibandronate injection

31 Bisphosphonates: Pamidronate (30mg IV over 2-24hrs) Zoledronic acid (4mg IV over 15 mins) MODE of ACTION: Inhibit osteoclast-mediated bone resorption Lower calcium by 2-4mg/dl Onset: 48 hrs Peak effect at 5-7 days Should not repeat if given < 7 days

32 Moderate hypercalcemia (corrected calcium 12-14) No severe neurologic or cardiac effects(life threatening) 1. Hydration as in symptomatic mild hypercalcemia 2. Palmidronate 60mg IV (over 4-24 hrs) or 3. Zoledronic acid 4mg IV ( over 15 mins)

33 Moderate hypercalcemia Life threatening 1. Hydration as in symptomatic mild hypercalcemia 2. Palmidronate 90mg IV (over 4-24 hrs) or 3. Zoledronic acid 4mg IV ( over 15 mins) 4. Calcitonin 4 IU/kg SQ or IM q 6 hrs for 2-4 days (with 1unit test dose) Lower calcium by 2-3mg/dl, onset 1-4 hrs Tolerance occurs with continuous use 3-5 days Salmon calcitonin is preferred More potent and less expensive

34 Effect of calcitonin (100 U daily) in hypercalcemic patients

35 Severe hypercalcemia Same as moderate hypercalcemia with life threatening

36 Laboratory tests Na 143 WBC 6.8 AST 32 K 3.9 Hgb 12.7 ALT 33 Cl 110 Hct 37.7 LDH 160 CO2 24 Plts 164 Alk phos 210 BUN 47 T.prot 5.4 GGT 40 Cr 1.6 Alb 2.4 T.Bili Ca 14mg/dl PT/PTT 14/23 Ca 14mg/dl, Alb 2.4 (14+0.8(4-2.4)) (corrected calcium = 15.28mg/dl) cancer associated severe hypercalcemia TREATMENT?

37 Severe hypercalcemia 1. Hydration as in symptomatic mild hypercalcemia 2. Palmidronate 90mg IV (over 4-24 hrs) or 3. Zoledronic acid 4mg IV ( over 15 mins) 4. Calcitonin 4 IU/kg SQ or IM q 6 hrs for 2-4 days (with 1unit test dose) Lower calcium by 2-3mg/dl, onset 1-4 hrs Tolerance occurs with continuous use 3-5 days Salmon calcitonin is preferred More potent and less expensive

38 Administration of Bisphosphonate 1. Palmidronate Dose should not exceed 90mg diluted in ml of NSS or 5%Dextrose IV over 2-24hr given monthly Stable at room temperature 24 hr.

39 Administration of Bisphosphonate 2. Zoledronic acid Dose 4mg Diluted in 100ml of NSS or 5%Dextrose in water IV over mins( Do not infuse over < 15mins) given monthly Stable at room temperature 24 hr.

40 Administration of Bisphosphonate 3. Ibandronate Dose 2-4mg (metastatic bone disease 6 mg) Diluted in 500ml of NSS or 5%Dextrose in water IV over 2 hr(in case of metastatic bone disease 1 hr.) Stable at temperature 2 oc -8 o C 24 hr.

41 Warning Osteonecrosis of jaw. Invasive dental procedure should be avoided during treatment. May cause deterioration in renal function.

42 Follow-up Evaluation after 48 hours 1. If Ca ++ within normal limits (WNL) Discharge patient home 2. If Ca ++ Still high and symptomatic Maintain hydration Repeat at Ca ++ day 5

43 Follow-up Evaluation on day If Ca ++ within normal limits (WNL) Discharge patient home 2. If Ca ++ Still high Repeat pamidronate or zoledronic acid Repeat evaluation at 48 hrs and 5 days

44 Follow-up If Ca ++ remain high after 2 nd dose of pamidronate or zoledronic acid, consider 2 nd agent

45 Other Agents Corticosteroids : Prednisolone mg. Plicamycin 25 mcg/kg IV over 4-6 hr. (discon. since 2000) Phosphates 1-3g/day Gallium nitrate 200 mg/m2/day CIV for 5 days (inhibit osteoclast activity)

46 Chronic Hypercalcemia of Malignancy Management. 1. Palmidronate 90mg IV over 2-24 hrs monthly or 2. Zoledronic acid 4mg IV over 15 mins monthly.

47 Thanks for your attention.