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Proleukin® (aldesleukin for injection)
for High-Dose I.V. Bolus Administration
Clinical Practice Guide
Rusti Portillas, MS...
Disclaimer
This presentation contains specific guidelines relating to administering
Proleukin, and criteria for delaying o...
Objectives
• To review the FDA-approved indications for the
administration of high-dose bolus Proleukin
therapy*
• To revi...
What Is Proleukin?
• IL-2 is one of a group of cytokines that mediate
signals between cells during an immune response
• Ca...
Indications for Proleukin
• The FDA-approved indications for IV bolus Proleukin
therapy in adult patients are:
– Metastati...
Why Proleukin?
•

Proleukin may induce a durable, complete response 1,2

•

Overall response rates (complete responses + p...
Pharmacokinetics of Proleukin
• Distribution half-life is 13 minutes, and the
elimination half-life is 85 minutes after a
...
Treatment Regimen
•

Administer Proleukin at a dose of 600,000 IU/kg every 8
hours by a 15-minute IV infusion for a maximu...
Treatment Regimen (cont)
1 Course of Treatment
rIL-2
600,000 IU/kg
q8h by
15-min infusion
for a maximum
of 14 doses

5 day...
Drug Interactions
•

Proleukin may affect the CNS, so interactions could occur following
concomitant administration of psy...
Proleukin Side Effects:
Physiologic Categories
• Flu-like
(constitutional symptoms)

• Hepatic

• Capillary leak syndrome
...
Suggested Pretherapy Interventions
• Discontinue antihypertensive medications
• Start acetaminophen, indomethacin, and H2
...
Flu-Like Effects
• Chills/rigors may occur within 1 to 2 hours of each
dose. If they persist, consider increasing
premedic...
Capillary Leak Syndrome (CLS)
•

IL-2 therapy is associated with CLS

•

CLS is an escape of protein and fluid from the va...
Cardiovascular Effects
• Fully assess patient’s cardiac status and risk
factors prior to therapy
• Monitor blood pressure,...
Cardiovascular Effects
The target blood pressure (BP) during HD IL-2 therapy
Normal BP for Patient

Target BP for Patient
...
Relative and Absolute Criteria for
Corrective Measures
Any relative criterion
Initiate corrective measure and/or delay IL-...
Cardiovascular Effects: Criteria for
Corrective Measures
Relative criteria
Sinus tachycardia (120-130 BPM)

Absolute crite...
Hemodynamic Effects: Criteria for
Corrective Measures
Relative criteria
Maximum neosynephrine 1-1.5 microgram/kg/min
Minim...
Pulmonary Effects
• Fully assess patient’s pulmonary status and
risk factors prior to therapy
• Monitor respiratory rate a...
Pulmonary Effects: Criteria for
Corrective Measures
Relative criteria
Resting shortness of breath
Requiring 3-4 L O2 for s...
Renal Effects
• Oliguria (low urine output)
• Monitor patients with nephrectomies or renal
dysfunction frequently to asses...
Renal Effects: Criteria for
Corrective Measures
Relative criteria
Urine 80-160 mL/8-hour shift
Urine 10-20 mL/hr
Creatinin...
Neurological Effects
• Mental status changes, drowsiness and trouble
sleeping
• Most symptoms are dose dependent and occur...
Neurological Effects: Criteria for
Corrective Measures
Relative criteria
Vivid dreams
Emotional lability
Absolute criteria...
Dermatologic Effects
• Generalized erythematous rash with or without
pruritus is common
• Dry desquamation of palms and so...
Hematologic Effects
•
•

Monitor complete blood cell (CBC), differential,
platelet count

•

Upon treatment discontinuatio...
Hematologic Effects: Criteria for
Corrective Measures
Relative criteria
Guaiac+ sputum, emesis, and/or stool
Platelets 30,...
Gastrointestinal Effects
• Nausea, vomiting, and anorexia are usually mild to
moderate in severity and generally dose depe...
Hepatic Effects
• Transient changes in liver function tests are most
common
• Monitor patient’s bilirubin, alkaline phosph...
Gastrointestinal Effects: Criteria for
Corrective Measures
Relative criteria
Diarrhea >1,000 mL/8-hour shift
Ileus and/or ...
Endocrine and Metabolic Effects
• Thyroid dysfunction is manifested most commonly
by subclinical hypothyroidism, but hyper...
Infection: Criteria for Corrective
Measures
Relative criteria
Absolute criteria
Strong clinical suspicion or documented

S...
Proleukin Side Effects
Remember that Proleukin adverse events are typically
• Predictable, manageable, and generally rever...
Conditions That Require
Holding a Dose
Body system

Hold dose for:

Cardiovascular

Atrial fibrillation, supraventricular ...
Conditions That Require
Holding a Dose (cont)
Body system

Hold dose for:

Subsequent doses
may be given if:

Respiratory
...
Conditions That Require
Holding a Dose (cont)
Body system

Hold dose for:

Subsequent doses
may be given if:

Body as a wh...
Conditions That Require Holding
a Dose (cont)
Body system

Hold dose for:

Subsequent doses
may be given if:

Digestive

S...
Conditions That Require Holding
a Dose (cont)
Body system

Hold dose for:

Subsequent doses
may be given if:

Urogenital

...
Retreatment
• Additional courses should be considered
for those with tumor shrinkage following last course
of therapy, unl...
Treatment Plan
• Telemetry VS ICU
• Developing highly specialized RN group
• PICC insertion
•

Lab Values prior to treatme...
Discharge Interventions
• Standard discharge instructions
• Usually RX are written eg: Lasix & Potassium,
Zyrtec, Sarna Lo...
THANK-YOU
QUESTIONS?

43
Bibliography
Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with
meta...
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Proleukin rnmt zion last revision

  1. 1. Proleukin® (aldesleukin for injection) for High-Dose I.V. Bolus Administration Clinical Practice Guide Rusti Portillas, MSN, RN, Duke University- Doctor of Nursing Practice PLK-900136 1
  2. 2. Disclaimer This presentation contains specific guidelines relating to administering Proleukin, and criteria for delaying or discontinuing Proleukin, which may or may not be included in or differ from the Proleukin prescribing information. The Proleukin prescribing information is included with this presentation and also provided to you at the time of this presentation. This presentation is not all-encompassing of medical practice and should not replace medical care or clinical judgment for individual patient care. 2
  3. 3. Objectives • To review the FDA-approved indications for the administration of high-dose bolus Proleukin therapy* • To review Proleukin prescribing information with health professionals • To review physiologic side effects – Tolerability – Safety • To discuss practice guidelines for managing highdose (HD) interleukin-2 (IL-2) patients *For questions regarding Proleukin, please call the NOVARTIS Pharmaceuticals Proleukin Hotline at 1-866-9PROLEUKIN (977-6538). 3
  4. 4. What Is Proleukin? • IL-2 is one of a group of cytokines that mediate signals between cells during an immune response • Can invoke an anti-tumor response in some patients • Proleukin is a recombinant form of IL-2 • Proleukin (i.e., recombinant IL-2, or rIL-2) helps the immune system fight cancer cells by causing widespread immune activation 4
  5. 5. Indications for Proleukin • The FDA-approved indications for IV bolus Proleukin therapy in adult patients are: – Metastatic renal cell carcinoma (mRCC) (approved in 1992) – Metastatic melanoma (mM) (approved in 1998) 5
  6. 6. Why Proleukin? • Proleukin may induce a durable, complete response 1,2 • Overall response rates (complete responses + partial responses; CR+PR) of 15% to 16% have been obtained with Proleukin therapy3 • Proleukin is the ONLY approved therapy that has shown a complete and durable response in mRCC or mM • mRCC and mM patients may be candidates for front-line bolus Proleukin if they have normal organ function and are otherwise healthy (Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0 or 1) 1. Fisher et al. Cancer J Sci Am. 2000;6(suppl 1):S55-S57. 2. Atkins et al. Cancer J Sci Am. 2000;6(suppl 1):S11-S14. 3. Proleukin prescribing information. Novartis Pharmaceuticals Corporation. Please see important safety information on slide 13 and full prescribing information, including boxed warning, on slides 55-56 6
  7. 7. Pharmacokinetics of Proleukin • Distribution half-life is 13 minutes, and the elimination half-life is 85 minutes after a 5-minute IV infusion • Biological effects resulting from a series of cellular responses and cytokine release do not peak until several hours after initial exposure to IL-2 Proleukin prescribing information. Novartis Pharmaceuticals Corporation 7
  8. 8. Treatment Regimen • Administer Proleukin at a dose of 600,000 IU/kg every 8 hours by a 15-minute IV infusion for a maximum of 14 doses (1 cycle) • Following 9 days of rest, repeat the treatment cycle for another 14 doses for a maximum of 28 doses per course • Administer Proleukin as tolerated. Dosage modifications should be made by holding a dose or discontinuing treatment for that cycle • Decision to discontinue, hold, or restart Proleukin therapy must be made after a global patient assessment • Each vial contains 22 million IU (1.3 mg) of Proleukin and should be reconstituted aseptically with 1.2 mL of sterile water for injection, USP. When reconstituted as directed, each mL contains 18 million IU (1.1 mg) of Proleukin Proleukin prescribing information. Novartis Pharmaceuticals Corporation 8
  9. 9. Treatment Regimen (cont) 1 Course of Treatment rIL-2 600,000 IU/kg q8h by 15-min infusion for a maximum of 14 doses 5 days Cycle 1 REST 9 days rIL-2 600,000 IU/kg q8h by 15-min infusion for a maximum of 14 doses 5 days Cycle 2 Maximum number of doses per course: 28 Proleukin prescribing information. Novartis Pharmaceuticals Corporation 9
  10. 10. Drug Interactions • Proleukin may affect the CNS, so interactions could occur following concomitant administration of psychotropic drugs • Concomitant administration of drugs with nephrotoxic, cardiotoxic, myelotoxic or hepatotoxic effects with Proleukin may increase toxicity in these organ systems • Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high-dose Proleukin and antineoplastic agents • Reduced kidney and liver function secondary to Proleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs • Myocardial injury appears to be increased in patients receiving Proleukin and IFN-alpha concurrently • Exacerbation or initial presentation of several autoimmune and inflammatory disorders has been observed following concurrent use of IFN-alpha and Proleukin • Concomitant administration of glucocorticoids with Proleukin should be avoided (may reduce antitumor effectiveness) • Beta-blockers and other antihypertensives may potentiate hypotension seen with Proleukin Abridged from Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 10
  11. 11. Proleukin Side Effects: Physiologic Categories • Flu-like (constitutional symptoms) • Hepatic • Capillary leak syndrome (CLS) • Neurologic • Cardiovascular • Dermatologic • Pulmonary • Hematologic • Renal • Metabolic • Gastrointestinal Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 11
  12. 12. Suggested Pretherapy Interventions • Discontinue antihypertensive medications • Start acetaminophen, indomethacin, and H2 blocker before administering IL-2 • Start maintenance IV fluids (ie, lactated Ringer’s solutions) as 50-100 mL/h immediately before administering IL-2 • Premedicate the patient for nausea before administering IL-2 Schwartzentruber. J Immunother. 2001;24:287-293. 12
  13. 13. Flu-Like Effects • Chills/rigors may occur within 1 to 2 hours of each dose. If they persist, consider increasing premedication before the next dose • Fever occurs 1 to 2 hours after the onset of chills/rigors. If fever occurs at times other than after the first or second dose of IL-2, an infectious source should be investigated • Nursing interventions for rigors (Dilaudid, Ativan) • Fatigue is typically dose-dependent Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50. 13
  14. 14. Capillary Leak Syndrome (CLS) • IL-2 therapy is associated with CLS • CLS is an escape of protein and fluid from the vascular system into the extravascular space • Assess cardiopulmonary status and risk factors prior to each dose of therapy • Monitor blood pressure, heart/lung sounds, pulse, and organ function, including mental status and urine output prior to each dose of therapy • CLS and other adverse events often resolve with interruption of therapy • If adverse events persist, the treatment cycle may be discontinued Gale et al. Biotherapy: A Comprehensive Overview. 2nd ed. 2001:195-244. 14
  15. 15. Cardiovascular Effects • Fully assess patient’s cardiac status and risk factors prior to therapy • Monitor blood pressure, heart sounds, and pulse regularly • Fluid replacement should be performed judiciously, as this may potentially worsen CLS • Symptoms often resolve with interruption or discontinuation of therapy Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50. 15
  16. 16. Cardiovascular Effects The target blood pressure (BP) during HD IL-2 therapy Normal BP for Patient Target BP for Patient <100 mm Hg >80 mm Hg 100-120 mm Hg >85 mm Hg >120 mm Hg >90 mm Hg Schwartzentruber. J Immunother. 2001;24:287-293. 16
  17. 17. Relative and Absolute Criteria for Corrective Measures Any relative criterion Initiate corrective measure and/or delay IL-2 ≥3 relative criteria Initiate corrective measures and delay IL-2 Stop IL-2 if adverse events are not easily reversed Any absolute criterion Initiate corrective measures and delay IL-2 Stop IL-2 if adverse events are not easily reversed Schwartzentruber. J Immunother. 2001;24:287-293. 17
  18. 18. Cardiovascular Effects: Criteria for Corrective Measures Relative criteria Sinus tachycardia (120-130 BPM) Absolute criteria Sustained sinus tachycardia Atrial fibrillation Supraventricular tachycardia Ventricular arrhythmias Elevated cardiac isoenzymes or troponin Electrocardiogram changes indicative of ischemia Schwartzentruber. J Immunother. 2001;24:287-293. 18
  19. 19. Hemodynamic Effects: Criteria for Corrective Measures Relative criteria Maximum neosynephrine 1-1.5 microgram/kg/min Minimum neosynephrine >0.5 microgram/kg/min Absolute criteria Maximum neosynephrine 1.5-2 microgram/kg/min Minimum neosynephrine >0.8 microgram/kg/min Schwartzentruber. J Immunother. 2001;24:287-293. 19
  20. 20. Pulmonary Effects • Fully assess patient’s pulmonary status and risk factors prior to therapy • Monitor respiratory rate and lung sounds frequently • Assess for cough or increased sputum production • Minimize anxiety during respiratory distress • Elevating the head, limiting activity, and administering low-dose oxygen may help • Symptoms often resolve with interruption or discontinuation of therapy 20 Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50.
  21. 21. Pulmonary Effects: Criteria for Corrective Measures Relative criteria Resting shortness of breath Requiring 3-4 L O2 for saturation >95% Rales 1/3 way up the chest Absolute criteria >4 L O2 per nasal cannula (40% mask) to achieve O2 saturation >95% Endotracheal intubation Moist rales ½ way up the chest Effusion requiring thoracentesis or chest tube while on therapy Schwartzentruber. J Immunother. 2001;24:287-293. 21
  22. 22. Renal Effects • Oliguria (low urine output) • Monitor patients with nephrectomies or renal dysfunction frequently to assess renal perfusion status • Measure fluid intake/output and blood urea nitrogen (BUN) and creatinine often • Weigh patients daily Gale et al. Biotherapy: A Comprehensive Overview. 2nd ed. 2001:195-244. 22
  23. 23. Renal Effects: Criteria for Corrective Measures Relative criteria Urine 80-160 mL/8-hour shift Urine 10-20 mL/hr Creatinine 2.5-2.9 mg/dL Absolute criteria Urine output <80mL/8-hour shift Urine output rate <10 mL/hr Creatinine level >3 mg/dL Schwartzentruber. J Immunother. 2001;24:287-293. 23
  24. 24. Neurological Effects • Mental status changes, drowsiness and trouble sleeping • Most symptoms are dose dependent and occur later in treatment cycle • Concomitant psychotropic agents may increase the potential risk for CNS toxicity • Neurologic effects can worsen before getting better • Monitor patients often for any changes in mental status Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50. 24
  25. 25. Neurological Effects: Criteria for Corrective Measures Relative criteria Vivid dreams Emotional lability Absolute criteria Hallucinations Persistent crying Mental status changes not reversible within 2 hours Inability to subtract serial 7s or spell “world” backwards Disorientation Schwartzentruber. J Immunother. 2001;24:287-293. 25
  26. 26. Dermatologic Effects • Generalized erythematous rash with or without pruritus is common • Dry desquamation of palms and soles may occur • Apply nonsteroidal and nonalcoholic emollients/lotions • Rarely require interruption of treatment • Consider judicious use of topical steroids • Discontinue IL-2 if there is moist desquamation of skin 26 Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50.
  27. 27. Hematologic Effects • • Monitor complete blood cell (CBC), differential, platelet count • Upon treatment discontinuation, a rapid rebound of white cells may be anticipated prior to stabilization of blood counts • Proleukin can increase patients’ risk of sepsis. Patients with indwelling catheters have higher risk of infections with grampositive (staph) organisms. • 27 Leukopenia, thrombocytopenia, anemia, lymphocytosis, and/or eosinophilia can occur Prophylactic antibiotics have been shown to decrease the incidence of staphylococcal infections Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50.
  28. 28. Hematologic Effects: Criteria for Corrective Measures Relative criteria Guaiac+ sputum, emesis, and/or stool Platelets 30,000-50,000/mm3 Absolute criteria Frank blood in sputum, emesis, and/or stool Platelet count <30,000/mm3 Schwartzentruber. J Immunother. 2001;24:287-293. 28
  29. 29. Gastrointestinal Effects • Nausea, vomiting, and anorexia are usually mild to moderate in severity and generally dose dependent • Small, frequent meals may mitigate GI distress • Observe for and report any GI bleeding • Premedication for nausea, emesis, and/or diarrhea may be required Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50. 29
  30. 30. Hepatic Effects • Transient changes in liver function tests are most common • Monitor patient’s bilirubin, alkaline phosphatase, and liver enzymes (SGOT/AST, SGPT/ALT) • Use caution when concomitantly administering medications that are metabolized by the liver 30 Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50.
  31. 31. Gastrointestinal Effects: Criteria for Corrective Measures Relative criteria Diarrhea >1,000 mL/8-hour shift Ileus and/or abdominal distension Bilirubin >7 mg/dL Absolute criteria Diarrhea >1000 mL for 2 consecutive shifts Vomiting unresponsive to medication Severe abdominal distension affecting breathing Severe abdominal pain, unrelenting Schwartzentruber. J Immunother. 2001;24:287-293. 31
  32. 32. Endocrine and Metabolic Effects • Thyroid dysfunction is manifested most commonly by subclinical hypothyroidism, but hyperthyroidism has occurred • Thyroid function tests before and routinely during therapy is recommended, with replacement therapy as indicated • Electrolyte imbalance, including low serum levels of potassium and magnesium • Electrolyte and mineral serum levels should be monitored routinely, with replacement therapy for low levels Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 32
  33. 33. Infection: Criteria for Corrective Measures Relative criteria Absolute criteria Strong clinical suspicion or documented Schwartzentruber. J Immunother. 2001;24:287-293. 33
  34. 34. Proleukin Side Effects Remember that Proleukin adverse events are typically • Predictable, manageable, and generally reversible • Dose- and schedule-dependent • Usually resolve within 2 to 3 days after discontinuation of therapy – Fatigue, skin toxicity, anorexia, and neurologic toxicity may persist longer • Long-term sequelae associated with Proleukin are extremely rare Schwartzentruber. J Immunother. 2001;24:287-293. 34
  35. 35. Conditions That Require Holding a Dose Body system Hold dose for: Cardiovascular Atrial fibrillation, supraventricular tachycardia, bradycardia that requires therapy or is recurrent or persistent Systolic BP <90 mm Hg with increasing requirements for pressors Any ECG change consistent with MI, ischemia, or myocarditis with or without chest pain; suspicion of cardiac ischemia Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 35 Subsequent doses may be given if: Asymptomatic with full recovery to normal sinus rhythm Systolic BP ≥90 mm Hg and stable or improving requirements for pressors Asymptomatic, MI and myocarditis ruled out; clinical suspicion of angina is low; there is no evidence of ventricular hypokinesia
  36. 36. Conditions That Require Holding a Dose (cont) Body system Hold dose for: Subsequent doses may be given if: Respiratory O2 saturation <90% O2 saturation >90% Neurologic Mental status changes, including moderate confusion or agitation Mental status changes completely resolved Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 36
  37. 37. Conditions That Require Holding a Dose (cont) Body system Hold dose for: Subsequent doses may be given if: Body as a whole Sepsis syndrome, patient is clinically unstable Sepsis syndrome has resolved, patient is clinically stable, infection is under treatment Skin Bullous dermatitis or marked worsening of preexisting skin condition; avoid topical steroid therapy Resolution of all signs of bullous dermatitis Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 37
  38. 38. Conditions That Require Holding a Dose (cont) Body system Hold dose for: Subsequent doses may be given if: Digestive Signs of hepatic failure, including encephalopathy, increasing ascites, liver pain, hypoglycemia Discontinue all further doses of current course. A new course of treatment, if warranted, may be initiated in no sooner than 7 weeks if all signs of hepatic failure have resolved Stool guaiac repeatedly >3-4+ Stool guaiac negative Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 38
  39. 39. Conditions That Require Holding a Dose (cont) Body system Hold dose for: Subsequent doses may be given if: Urogenital Serum creatinine (Cr) >4.5 mg/dL or of ≥4 mg/dL in the presence of severe volume overload, acidosis, or hyperkalemia Cr <4 mg/dL and fluid and electrolyte status is stable Persistent oliguria, urine output of <10 mL/hr for 16-24 hrs with rising Cr Urine output >10 mL/hr with a decrease in Cr >1.5 mg/dL or normalization of Cr Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 39
  40. 40. Retreatment • Additional courses should be considered for those with tumor shrinkage following last course of therapy, unless contraindicated • Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge Proleukin prescribing information. Novartis Pharmaceuticals Corporation. 40
  41. 41. Treatment Plan • Telemetry VS ICU • Developing highly specialized RN group • PICC insertion • Lab Values prior to treatment (see order set) • IVF 8-10 liters possibly/increasing IVF when bolusing, encouraging oral intake • Aggressive phosphorous replacement • Skipping doses vs discontinuing 41
  42. 42. Discharge Interventions • Standard discharge instructions • Usually RX are written eg: Lasix & Potassium, Zyrtec, Sarna Lotion • Discharge instructions IL-2 sheet 42
  43. 43. THANK-YOU QUESTIONS? 43
  44. 44. Bibliography Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14. Balch CM, Buzaid AC, Soong SG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(suppl 1):S55-S57. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688-696 Flaherty LE. Rationale for intergroup trial E-3695 comparing concurrent biochemotherapy with cisplatin, vinblastine, and DTIC alone in patients with metastatic melanoma. Cancer J Sci Am. 2000;6(suppl 1):S15-S20. Gale DM, Sorokin P. In: Rieger PT, ed. Biotherapy: A Comprehensive Overview. 2nd ed. Sudbury, MA: Jones and Bartlett; 2001:195-244. Griffin-Brown J. In: Yarbro C, Frogge M, Goodman M, et al, eds. Cancer Nursing: Principles and Practice. 5th ed. Sudbury, MA: Jones and Bartlett; 2000:214-240. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106-130. Lindsey KR, Rosenberg SA, Sherry RM. Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2. J Clin Oncol. 2000;18:1954-1959. Proleukin prescribing information. Novartis Pharmaceuticals Corporation. Rini BI, Vogelzang NJ. Prognostic factors in renal carcinoma. Semin Oncol. 2000;27:213-220. Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother. 2001;24:287-293. Schwartzentruber DJ. In: Rosenberg SA, ed. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins. 2000:32-50. 44

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