general oncology from devita presentation

1. TUMOR LYSIS SYNDROME
Dr. ANUJ GUPTA

2. INTRODUCTION
• oncologic emergency
• caused by massive tumor cell lysis
• release of large amounts of potassium, phosphate, and nucleic
acids into the systemic circulation.
• Often on initiation of cytotoxic therapy in patients with high-grade
lymphomas (particularly the Burkitt subtype) and ALL
• Spontaneously with other tumor types that have a high proliferative
rate, large tumor burden, or high sensitivity to cytotoxic therapy.

3. PATHOGENESIS
• In malignancy with a
– high proliferative rate,
– large tumor burden, and/or a
– high sensitivity to treatment, initiation of cytotoxic chemotherapy, cytolytic
antibody therapy, radiation therapy, or sometimes glucocorticoid therapy
alone
can result in the rapid lysis of tumor cells.
• Releases massive quantities of intracellular contents (K+, phosphate, and
nucleic acids ) into the systemic circulation l/t
– hyperkalemia
– hyperphosphatemia
– secondary hypocalcemia
– hyperuricemia and
– acute kidney injury

4. • Hyperuricemia - consequence of catabolism of purine
nucleic acids to hypoxanthine and xanthine, and then to
uric acid via the enzyme xanthine oxidase
• marked increase in uric acid excretion can result in
– the precipitation of uric acid in the renal tubules
– can induce renal vasoconstriction,
– impaired autoregulation,
– decreased renal blood flow, and inflammation,
resulting in acute kidney injury
• Uric acid is poorly soluble in water, particularly in usually acidic
environment in distal tubules and collecting system of kidney
• Overproduction & overexcretion of uric acid in TLS can l/t crystal precipitation &
deposition in the renal tubules, & acute uric acid nephropathy with AKI
PATHOGENESIS conti…

5. Hyperphosphatemia
• The phosphorus concentration in malignant cells is up to 4 times higher than in normal
cells.
• rapid tumor breakdown often l/t hyperphosphatemia
• which can cause secondary hypocalcemia
• Hyperphosphatemia with calcium phosphate deposition in renal tubules can also cause
acute kidney injury
• In addition, precipitation in the heart may lead to cardiac arrhythmias.
• Since with the widespread use of hypouricemic agents, calcium phosphate deposition
(nephrocalcinosis), rather than hyperuricemia, has become the major mechanism of
acute kidney injury in TLS
PATHOGENESIS conti…

6. Xanthinuria
• Allopurinol blocks the catabolism of hypoxanthine and xanthine
• Thus, pts with massive TLS receiving allopurinol are at risk for xanthine
precipitation in the tubules, resulting in xanthine nephropathy or xanthine
stone formation
• Xanthine concentration is not increased by rasburicase (recombinant urate
oxidase), which is now preferred
PATHOGENESIS conti…

9. CLINICAL MANIFESTATIONS
• largely reflect the associated metabolic abnormalities
Include-
• nausea, vomiting, diarrhea, anorexia, lethargy
• Hematuria
• heart failure, cardiac dysrhythmias
• seizures, muscle cramps, tetany
• syncope, and
• possible sudden death
• flank pain can occur if there is renal pelvic or ureteral
stone formation

10. DEFINITION AND CLASSIFICATION
• Cairo-Bishop definition, proposed in 2004, provided specific
laboratory criteria for the diagnosis of TLS both at
presentation and within seven days of treatment

12. • A grading system for severity of TLS (on a scale from 0 to 5) in pts with
laboratory TLS
• The Cairo-Bishop classification has been adopted by the COG for use in t/t
protocols for advanced stage lymphoma and by an international panel of
experts assembled to establish evidence-based guidelines for prevention
and treatment of pediatric and adult TLS
• This scheme for grading severity is far more useful than the most recent
modification of the widely used National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI-CTCAE v4.03), which only
grades TLS as
– grade 3 (present),
– grade 4 (life-threatening consequences; urgent intervention
indicated), or
– grade 5 (death).

14. ETIOLOGY AND RISK FACTORS
• The risk of TLS is greatest in patients treated for hematologic malignancies
• Certain intrinsic tumor-related factors are a/w a higher risk. These include
– High tumor cell proliferation rate
– Chemosensitivity of the malignancy
– Large tumor burden, as manifested by
• bulky disease >10 cm in diameter and/or
• WBC >50,000 per microL,
• a pretreatment serum LDH >2 times UNL,
• bone marrow involvement
conditions that predispose to development of TLS
– Pretreatment hyperuricemia (serum uric acid >7.5 mg/dL [446 micromol/L]) or
hyperphosphatemia
– A preexisting nephropathy or exposure to nephrotoxins
– Oliguria and/or acidic urine
– Dehydration, volume depletion, or inadequate hydration during treatment

17. Prevention and treatment
• preventive measures include foremost hydration, allopurinol, and oral
phosphate binders
• beginning preferably 24 hours before chemotherapy administration
• Aggressive hydration, the most important intervention, should begin
immediately, administering at least 3,000 mL/m2 per day, when
possible delaying tumor therapy so hydration can be administered.
• Urine alkalinization -controversial as it favors precipitation of
calcium/phosphate complexes in renal tubules— calcium phosphate,
unlike uric acid, becomes less soluble at an alkaline pH.
• Furthermore, metabolic alkalemia can worsen neurologic manifestations
of hypocalcemia.

19. • Hyperkalemia -should be treated aggressively
• Cation exchange resins should be used, recognizing their value will be delayed.
• Calcium giuconate antagonizes cardiac effects of hyperkalemia and can be
especially helpful if there is concomitant hypocalcemia.
• Sodium bicarbonate corrects acidemia and shifts potassium back into cells
• administering hypertonic dextrose and insulin can augment this.
• Loop diuretics can eliminate excess potassium in patients without renal failure
• hemodialysis is indicated in renal impairment.

20. • Symptomatic hypocalcemia should be treated with calcium at the lowest
doses required to relieve symptoms
• To avoid calcium-phosphate precipitation, most symptomatic acutely
hypocalcemic patients with hyperphosphatemia due to TLS (particularly if
the calcium phosphate product is >60 mg2 per dL2 should not be treated
with calcium until hyperphosphatemia is corrected
• In most situations, clinicians should use other oral phosphate binders
• patients with severe symptoms of hypocalcemia (eg, tetany or cardiac
arrhythmia) should be considered for calcium replacement regardless of
the phosphate level
• Asymptomatic patients with hypocalcemia do not require treatment.

21. • Hyperphosphatemia and its resultant hypocalcemia require oral
phosphate binders
• except to manage hyperkalemia avoid calcium administration,
because it can promote metastatic calcifications
• Given its central role in ARF, hyperuricemia should be managed
aggressively
• Allopurinol, an analog of the purine base hypoxanthine, lowers uric
acid by inhibiting xanthine oxidase, the enzyme converting
hypoxanthine to xanthine and xanthine to uric acid

22. • Its active metabolite, oxypurinol, also inhibits xanthine oxidase
• Because both allopurinol and oxypurinol inhibit uric acid synthesis, but have no
effect on preexisting uric acid, uric acid levels usually do not fall until after 48 to 72
hours of treatment
• inhibition of XO l/t increase in plasma hypoxanthine and xanthine levels, with
increased renal excretion of both metabolic products
• Like uric acid, xanthine (pKa = 7.4) but not hypoxanthine (pKa = 1.98) may
precipitate contributing to AKI
• Oral allopurinol – bioavailability 50%; alternately, intravenous allopurinol may be
administered
• Allopurinol should be discontinued if allergic reactions such as skin rashes and
urticaria occur (incidence increased in patients receiving amoxicillin, ampicillin, or
thiazides)

23. Dose in adults is 100 mg/m2 every 8 hours (maximum 800 mg/
day)
In children, the dose is 50 -100 mg/m2 every 8 hrs (maximum
300 mg/m2 per day) or 10 mg/kg per day in divided doses every
8 hours
doses of allopurinol should be adjusted for creatinine clearance

24. • Febuxostat
• alternative to allopurinol to prevent TLS in pts at intermediate to high risk for TLS.
• Used in pts who cannot tolerate allopurinol in a setting in which rasburicase is
either not available or contraindicated.
• orally administered, potent, selective inhibitor of XO
• Dose adjustment is not needed in pts with mild to moderate renal impairment
• There are fewer drug-drug interactions with febuxostat than with allopurinol
• It is quite a bit more expensive than allopurinol

25. • An alternate approach use of rasburicase
• a recombinant urate oxidase developed to replace uricozyme, a
non-recombinant urate oxidase.
• promotes the degradation of uric acid to the much more water-
soluble compound allantoin.
• Because urate oxidase degrades uric acid rather than prevent its
synthesis rapid (fall to 0.5 to 1 mg/dL within 4 hours of rasburicase
injection) reduction in uric acid
• Despite normalization of uric acid levels with rasburicase, a small %
may required dialysis

26. • Patients with G6PD deficiency, hydrogen peroxide, a breakdown product
of uric acid, can cause methemoglobinemia and, in severe cases,
hemolytic anemia
• For this reason, rasburicase is contraindicated in pts with G6PD deficiency
• dose of 0.2 mg/kg for up to 5 days
• However, except in rare patients with very high serum levels of uric acid,
much less is sufficient
• A 5-day course of rasburicase is about 15,000 times more expensive than a
5-day course of allopurinol and 15 to 30 times more than intravenous
allopurinol,

28. • Among the indications for renal replacement
therapy in patients with TLS are :
– Severe oliguria or anuria
– Intractable fluid overload
– Persistent hyperkalemia
– Hyperphosphatemia-induced symptomatic hypocalcemia
– A calcium-phosphate product ≥70 mg2/dL2

29. THANKS

30. HYPERCALCEMIA OF
MALIGNANCY
DR.ANUJ GUPTA

31. INTRODUCTION
• most common paraneoplastic syndrome
• occurring in 10% to 30% of pts with advanced cancer
• Estimated yearly prevalence for all cancers is 1.46% to 2.74%
• 4 times more common in stage IV cancer & is a/w a poor
prognosis

32. • Most common cancers are
– lung cancer, MM, and RCC.
– f/b breast and CRCs
– the lowest rates were reported in prostate cancer
• Thirty-day mortality was previously reported at 50%
• However, a recent analysis showed a median length of stay of
4 days, and an in-hospital mortality rate of 6.8%.
INTRODUCTION conti..

33. PATHOGENESIS
• Results from increased bone resorption and release of calcium from
bone secondary to 4 different mechanisms present in underlying
malignant processes
1. Local osteolytic hypercalcemia results from boney metastasis
2. Tumor secretion of parathyroid hormone-related protein (PTHrP)
also known as "humoral hypercalcemia of malignancy"
3. Tumor production of calcitriol
or 1,25-hydroxy vitamin D
4. Finally, in rare instances
"ectopic hyperparathyroidism"

34. • Tumor secretion of parathyroid hormone-related protein (PTHrP) also
known as "humoral hypercalcemia of malignancy“
• PTHrP has some homology with PTH and binds to same receptors as PTH
– increasing bone resorption
– reabsorption of calcium in DCTs
– inhibition of phosphate transport in the PCTs
• This results in hypercalcemia and hypophosphatemia similar to
hyperparathyroidism
• It is the most common cause of hypercalcemia in patients with non-
metastatic solid tumors and in some patients with NHL
PATHOGENESIS conti…

35. • Local osteolytic hypercalcemia results from bony metastasis.
• local release of cytokines, such as TNF and IL-1, which then
– stimulate the differentiation of osteoclast precursors into mature
osteoclasts and
– increase bone resorption
• it is mostly seen in breast cancer and NSCLC
• Other osteoclast activating factors such as IL-1 beta, lymphotoxin,
TNF and IL-6 stimulate osteoclastogenesis in MM & some cases of
lymphoma.
PATHOGENESIS conti…

36. • Tumor production of calcitriol or 1,25-hydroxy vitamin D
• present in almost all cases of hypercalcemia a/w HL
• about 1/3 cases of NHL
• increased calcitriol production is also responsible for hypercalcemia
related to granulomatous diseases such as sarcoidosis and
tuberculosis where the liver enzyme 25-hydroxylase responsible for
activating Vitamin D is upregulated.
• In rare instances, tumors such as ovarian carcinoma, lung
carcinoma, or PNETs can secrete ectopic PTH and cause
hypercalcemia also known as "ectopic hyperparathyroidism"
PATHOGENESIS conti…

37. • Hypercalcemia is categorized according to
serum total calcium level:
– mild hypercalcemia -10.5 to 11.9 mg/dL
– moderate hypercalcemia- 12 to 13.9 mg/dL and
– severe hypercalcemia >14 mg/dL

38. CLINICAL MANIFESTATIONS
• Dictated by both the
– level of serum calcium
– rate of the serum calcium
• Mild or indolent hypercalcemia can be asymptomatic, or it can
be a/w mild nonspecific symptoms such as lethargy and
musculoskeletal pain
• In contrast, severe, rapidly progressive hypercalcemia can be
a/w significant volume depletion and acute renal insufficiency,
as well as dramatic neurocognitive symptoms ranging from
altered mental status to coma

39. The mnemonic "moans, groans, stones, and bones with psychic overtones"
describes the clinical manifestations

40. Physical Examination
• Physical findings are few and depend on
– the underlying disease process,
– the acuity of disease progression, and
– patient's other comorbidities
• Mild elevations in calcium levels are usually asymptomatic.
• With moderate to severe hypercalcemia, esp if the calcium level rises rapidly,
patients can present with altered mental status, confusion or even coma.
• Nonspecific abdominal pain or flank pain with radiation to groins concerning for
kidney stones may be present.
• Proximal muscle weakness and pain on palpation or joint pain are other physical
exam findings.
• Hyperreflexia and tongue fasciculation

44. Management

45. Mild hypercalcemia with calcium 10.5-11.9 mg/dL
• usually asymptomatic
• does not require any specific treatment
• addressing the underlying malignant process
• general measures including removal of excess calcium intake from enteral
feeds and supplements
• Medications a/w hypercalcemia such as lithium, thiazide diuretics, vitamin
D and calcitriol if present should also be withheld

46. moderate hypercalcemia -Calcium levels 12.0-13.9 mg/dL
• largely depends on patient's symptoms and renal function
• intravascular volume repletion is sufficient -
– to increase calciuresis and
– decrease calcium levels by increasing GFR and the filtered
load of calcium as well as
– inhibiting reabsorption of calcium in the proximal tubules.

47. Severe hypercalcemia - calcium levels > 14.0 mg/dL
• can be a/w kidney injury and other symptoms including mental status
changes
• If more severe symptoms are present, calcitonin can be used along with
intravascular volume repletion to decrease calcium levels more rapidly
• Loop-diuretics can be used in certain instances
– after complete intravascular volume repletion in order to increase
calciuresis or
– when saline infusion is limited by renal failure or heart failure
• Loop diuretics use has fallen out of favor given potential for intravascular
volume depletion and worsening of renal dysfunction and hypercalcemia

48. • Bisphosphonate therapy which blocks osteoclastic bone
resorption is the main and most effective long-term treatment
usually initiated in patients with mild to severe hypercalcemia
on presentation
• Glucocorticoids can be used in cases of hypercalcemia a/w
calcitriol production.

49. Immediate management
• In severe and symptomatic hypercalcemia also known as
"hypercalcemic crisis", immediate intravascular volume repletion
with NS at a rate of 200-500 ml per hour should be initiated and
continued until pt is adequately volume resuscitated and has good
urine output of 100-150 ml/hr
• Furosemide therapy can be used thereafter to increase calciuresis
but is generally discouraged if patient can tolerate volume repletion
• Immediate but short-acting Calcitonin 4 units/kg SC or IM every 12
hrs can be used for a short period of time while awaiting the
response to bisphosphonate therapy which can take 2-4 days
• Often tachyphylaxis to the effects of calcitonin develops within 48
hours of initiation of therapy.

51. THANKS