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Treatment to relieve symptoms and side effects, such as hypercalcemia, is an important part of cancer care. The parathyroid gland, which releases parathyroid hormone, and the kidneys help control blood calcium levels. Vitamin D and parathyroid hormone work to adjust calcium levels.
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Anti-RANKL therapy denosumab and antibodies against PTHrP are promising therapies, but their clinical use should be further explored to more clearly document the effects.

In Albright first proposed the term humoral hypercalcemia in patients with cancer and hypothesized that mechanisms different from direct bone resorption by tumor cells may cause such a complication 1. CIH represents the most common paraneoplastic syndrome, with an incidence of 15 cases per , people per year 3 , 4. Except in patients with multiple myeloma and breast cancer, the prognosis of the cancer patients with CIH is usually poor, with a mean survival rate of months 5.

Enhanced bone resorption is the primary cause of hypercalcemia of malignancy and the release of tumor-derived mediators induces this increase in osteoclast-mediated resorption 4 , 5. The mechanisms of osteoclast-mediated resorption are humoral effects of systemically elevated tumor-derived factors and local autocrine or paracrine effects of factors produced by the tumor cells metastasized to bone i. Both normal and malignant bone and hemopoietic marrow cells interact together with a complex network of agents i. PTHrP is a distinct gene product with sequence homology to PTH only in a limited domain at the amino-terminal end of the molecule 5.

Management of hypercalcemia of malignancy

Both produce humoral hypercalcemia by increasing the resorption of bone throughout the skeleton and the renal resorption of calcium 7. However, PTH stimulates bone resorption and formation, while PTHrP stimulates only osteoclasts, showing a very low osteoblastic activity 7 , 8. The best established role of PTHrP is to stimulate the proliferation of chondrocytes in the growth plate and to delay the mineralization of hypertrophic cartilage 5 , 8. During fetal life PTHrP is secreted from perichondrial cells and chondrocytes at the end of long bones 9.

Hypercalcemia of Malignancy (HM)

It stimulates the proliferation of chondrocytes and suppresses their terminal differentiation Figure 1. Signalling through this pathway promotes both cancer cell proliferation and PTHrP production, with subsequent increased calcium reabsorption Figure 2. Actions of the parathyroid hormone-related protein PTHrP during fetal life at the end of long bones. PTHrP stimulates the proliferation of chondrocytes and suppresses their terminal differentiation. Interactions between osteoclasts and cancer-cells. Very high serum calcium levels are observed in patients with parathyroid cancer, but also the PTH levels are usually elevated Unfortunately, the preoperative diagnosis of parathyroid cancer is difficult, because no sensitive tumor markers are available, although its localization is easy 13 , The first step of management of hypercalcemia should be to assess the hydration state and saline infusion is currently the standard of treatment, depending upon the severity of dehydration.

However, if employed alone, volume expansion is ineffective in restoring normocalcemia because rehydration does not interfere with osteoclastic function. Loop diuretics i. They inhibit osteoclasts, induce apoptosis in these cells and bind to bone, blocking osteoclastic resorption and osteolysis 19 , Once inside osteoclasts, BPs hamper adhesion to the mineralized matrix, reduce lysosomial enzymes and activate a pro-apoptotic pathway 20 , Patients treated with BP have a delayed time to skeletal fracture, and a reduced need for radiation therapy and orthopedic surgery to treat bone metastases 20 - Osteonecrosis of the jaw is a severe complication described in patients treated with BPs, especially in those with myeloma treated for a long time with pamidronate or zoledronate or in patients who have undergone teeth extractions or other invasive interventions on the jaw or maxilla bone The first BPs etidronate and clodronate are now rarely used to treat CIH due to the availability of more potent compounds 25 , Randomized trials have proved that pamidronate is superior to clodronate, etidronate and mithramycin 26 , Zoledronate is a third-generation BP and can be administered in a dose 10 times lower than pamidronate 28 , It has been shown to be superior to pamidronate in the rate of normocalcemia, duration of control of CIH and time to relapse, therefore 4 mg zoledronate is the reference treatment for initial management of CIH, while higher doses can be used in relapsing or refractory patients Ibandronate is especially useful in patients with breast or hematological cancer A randomized trial comparing ibandronate and pamidronate showed a comparable activity of the two drugs in reducing calcium levels, while the median duration of response appeared to be longer for ibandronate This drug has an extremely low rate of nephrotoxicity and represents the compound of choice for patients with moderate renal impairment or those treated with concomitant nephrotoxic therapies and no dose reductions are needed 28 , Other drugs are now considered of second choice, although some of them may still be used for salvage treatment of refractory patients.

Mithramycin is a cytotoxic antibiotic that has tropism for the osteoclasts and inhibits bone resorption through the blocking of RNA synthesis, but it is less effective and convenient for patients compared to pamidronate 4 , Gallium nitrate may reduce solubilization of hydroxyapatite and tubular renal resorption, but does not inhibit the development or recruitment of osteoclasts and thus can be considered for the management of patients with CIH refractory to BP 34 - Calcitonin may inhibit osteoclastic bone resorption and enhance renal excretion of calcium Unfortunately, tachyphylaxis of receptors occurs frequently and it should be used only in selected cases, in combination with corticosteroids for patients with kidney failure 4 , The RANKL system is the central pathway leading to osteoclast differentiation and activation, and currently represents the most promising target for the treatment of CIH 4 , 38 , Osteoprotegerin OPG , a protein of the TNF family, specifically binds to RANKL and therefore prevents differentiation of osteoclasts and promotes their apoptosis, blocking bone resorption by depletion of mature osteoclasts 21 , 41 , This agent, when administered to postmenopausal osteoporotic women, showed a rapid and sustained dose-dependent decrease of bone turnover 41 - It was able to induce an early and sustained decrease of bone resorption in patients with bone localizations of multiple myeloma or breast cancer, but unfortunately the role of denosumab in the management of CIH has not yet been confirmed Another attractive strategy consists in the development of antibodies directed against human PTHrP.

A humanized anti-PTHrP antibody was tested in animal models of CIH and was found to be able to improve bone metabolism and calcium renal excretion, achieving a complete normalization of calcium levels 44 , In conclusion, in patients with CIH the first step of therapy is usually to restore renal function which is often impaired due to dehydration. Enhanced bone resorption represents the main cause of hypercalcemia and thus the second step is BP administration. Pamidronate, zoledronate and ibandronate are at present the main-stay of treatment. Non-BP drugs have limited activity and several side-effects.

Features include large-volume diarrhoea and hypokalaemia.

Enhanced osteoclast activity and diminished osteoblast activity results in overall increased bone resorption. In some cases, hypercalcaemia of another cause is worsened by immobility. A community-based survey in Sweden found a prevalence of hypercalcaemia between 0. Complications include: Nephrolithiasis and nephrocalcinosis. Nephrolithiasis is rare when hypercalcaemia is due to cancer, but is seen in some people with primary hyperparathyroidism [ Ralston, ; Bushinsky and Monk, ; Ziegler, ; Carroll and Schade, ].

Pancreatitis may be a presentation of either acute or chronic hypercalcaemia [ Chan et al, ; Carroll and Schade, ; Clines, ]. When symptoms are present, they are often non-specific and relate to both the severity and rate of onset. Clinical features of hypercalcaemia include: Skeletal Bone pain. Fractures associated with underlying bone disorders fragility fractures in hyperparathyroidism or pathological fractures in malignancy.

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Neuromuscular and neuropsychiatric Drowsiness, delirium, coma. Fatigue, muscle weakness. Impaired concentration and memory. Neurological signs for example upper motor neurone deficits and ataxia. Gastrointestinal Nausea, vomiting, anorexia, weight loss. Constipation, abdominal pain. Peptic ulcer, pancreatitis both rare. Renal Renal colic due to renal stones.

Polyuria, polydipsia, and dehydration due to nephrogenic diabetes insipidus. Renal impairment due to nephrocalcinosis. Cardiovascular Hypertension. Cardiac arrhythmias rare. Other Itching, keratitis, conjunctivitis, and corneal calcification Many people are asymptomatic The information that many people with hypercalcaemia are asymptomatic, particularly when hypercalcaemia is mild, is derived from a narrative review [ Bushinsky and Monk, ]. Symptoms are often non-specific and relate to severity and rate of onset This information is derived from narrative reviews [ Bushinsky and Monk, ; Weiss-Guillet et al, ; Pallan et al, ].

Take blood to measure serum calcium and albumin concentrations. Ensure that the calcium concentration is adjusted 'corrected' for the serum albumin concentration. The calculation of a corrected calcium value is usually completed by local laboratories but may be inaccurate at extreme albumin concentrations, in paraproteinaemia, or in acidosis. Take blood to measure serum calcium and albumin concentrations This recommendation is based on a narrative review [ Smellie et al, ]. Avoid prolonged application of a tourniquet Historically, it was thought that applying a tourniquet for venepuncture increased the apparent serum calcium concentration [ McMullan et al, ].

Tumor induced hypercalcemia

Two narrative reviews recommend avoiding prolonged application of a tourniquet presumably due to uncertainty regarding the issue [ Smellie et al, ; Waters, ], and a narrative case review advises to repeat the sample in case there has been excessive tourniquet use [ Joshi et al, ]. Alb is serum albumin concentration. This formula is based on narrative reviews [ Murphy et al, ; Waters, ]. Other versions of the correction formulae exist [ Bilezikian et al, ].

The information that the calculation may be inaccurate at extreme albumin concentrations, in the presence of paraproteinaemia or acidosis is reported in narrative reviews [ Bushinsky and Monk, ; Smellie et al, ; Pallan et al, ]. Three-quarters of samples were from hospital inpatients. The higher the initial plasma calcium concentration, the more likely the repeat test confirmed hypercalcaemia [ Harrop et al, ].

High Calcium Levels or Hypercalcemia

The recommendation to admit people with severe or symptomatic hypercalcaemia is based on narrative reviews [ Selby, ; Smellie et al, ; Waters, ]. When to diagnose mild, moderate, and severe hypercalcaemia These recommendations are derived from narrative reviews [ Smellie et al, ; Waters, ]. Check for any previous calcium concentrations to assess the chronicity of hypercalcaemia. In primary hyperparathyroidism, the increase in serum calcium is usually mild and stable, or slowly progressive over a period of years.

Take a blood sample to test parathyroid hormone PTH levels if available in primary care. Check with the local biochemistry laboratory regarding PTH testing collection requirements such as recording the sample collection time, and sample transport arrangements. Renal function and serum electrolytes to assess for chronic kidney disease.

Full blood count to diagnose or exclude anaemia of chronic disease. Erythrocyte sedimentation rate or C-reactive protein may be increased in cancer or other inflammatory or granulomatous conditions. Serum and urine protein electrophoresis, including testing for urine Bence—Jones protein to exclude myeloma. Liver function tests to exclude liver metastases or chronic liver failure, and also alkaline phosphatase may be increased in primary hyperparathyroidism, Paget's disease with immobilization, myeloma, or bone metastases.

Thyroid function tests to exclude thyrotoxicosis. Urinalysis for urine protein if chronic kidney disease is suspected. This includes the management of people with suspected cancer, but does not include people with suspected hyperparathyroidism. Admission to hospital or urgent referral may be required for example if Addison's disease or thyrotoxicosis is suspected. If mobilization is not possible, or the serum calcium concentration remains increased, refer to an endocrinologist, rheumatologist, or specialist in bone disease, depending on local service provision.

Admit the person if they have severe hypercalcaemia or severe symptoms. This is due to the increased risk of severe complications based on expert opinion from narrative reviews [ Selby, ; Smellie et al, ; Waters, ]. Refer to an endocrinologist if familial hypocalciuric hypercalcaemia is suspected This is based on expert opinion in a clinical review that this diagnosis needs to be confirmed or excluded by secondary care [ Pallan et al, ]. Stop any relevant drugs if appropriate and recheck the serum calcium This recommendation is based on expert opinion from narrative reviews [ Bushinsky and Monk, ; Waters, ; Pallan et al, ].

The recommendation to look for another underlying cause or refer the person to an endocrinologist or other appropriate specialist if the adjusted serum calcium level remains high after discontinuation of the drug, is based on what CKS considers to be good clinical practice. It is also based on evidence from narrative reviews that primary hyperparathyroidism is the most common cause of hypercalcaemia in the community [ Chan et al, ; Bushinsky and Monk, ], particularly when hypercalcaemia is mild [ Bilezikian, ].

The recommendation to consider admitting people with suspected calcium—alkali syndrome is based on expert opinion from narrative reviews, that correction of fluid and electrolyte abnormalities may be needed [ Chan et al, ; Yoshizawa, ]. The recommendation to contact the person's mental health specialist if they are taking lithium is based on expert opinion from a narrative review [ Jones and Twomey, ]. Referral to a respiratory or other relevant specialist if sarcoidosis is suspected This recommendation is based on what CKS considers to be appropriate referral pathways, and is also based on expert opinion from narrative reviews [ Wu and Schiff, ; Dempsey et al, ].

Action for people with previously undiagnosed chronic kidney disease This recommendation is based on what CKS considers to be good clinical practice, opinion from a CKS expert reviewer, and expert opinion in the NICE guidelines, Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care [ National Clinical Guidelines Centre, ]. Referral to an endocrinologist if non-parathyroid endocrine disease is suspected The recommendation to refer non-parathyroid endocrine disease is based on the opinion of CKS that the investigation and management of these conditions thyrotoxicosis, Addison's disease is beyond the scope of primary care.

Immobilization in Paget's disease The recommendation to address a person's immobilization, if possible, and monitor the person's serum calcium concentration is based on what CKS considers to be good clinical practice, and expert opinion in a narrative review [ Inzucchi, ].

Hypercalcemia of malignancy and new treatment options - Video abstract 83681

The recommendation to refer the person to a specialist if mobilization is not possible or the person's serum calcium concentration remains high, is based on evidence that oral or intravenous bisphosphonates are effective in such cases.