Transcript Chemo_toxicity_Residents

Management of Chemoimmunotherapy toxicities
Characteristics of Cancer Cells –the problem to us all
• Cell cycle acceleration with rapid division
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• Immortality cell due to diminished apoptosis
• Altered cell-cell communication and disordered proliferation
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Invasiveness and metastasis threaten healthy organs and
ultimately compromises the host
Cancer Cells versus the best of men –
left unchecked -- who is likely to win?
Goal of Cancer Treatments
• Curative
• Palliative
• Minimize toxicity
• Improve quality of life
• Scientifically garner lessons learned to improve future
care
Established Treatment Modalities
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Surgery
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Radiotherapy
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Chemotherapy including stem cell transplant
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Endocrine therapy
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Immunotherapy
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Biological therapy
Chemo-immunotherapy Classes
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Targeted therapies target moleculary defined target: Gleevec, gefitinib, sunitinib and
bortezomib
Differentiating agents : retinoids, ATRA and bexarotene, arsenic trioxide
Hormone therapy in hormone driven cancers such as breast, prostate, and endometrial
cancers
Immunotherapy can be active or passive or non-specific: rituximab, campath, IL-2,
BCG, interferon
Immunomodulating drugs include thalidomide, lenalidomide, Provenge
Anti-cancer drugs
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Alkylating agents directly damage DNA and not
phase-specific
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Antimetabolites –interrupt DNA and RNA and are Sphase cell cycle specific.
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Anti-tumor antibiotics such as anthracyclines
interfere with DNA replication enzymes
– Not phase specific
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Topoisomerase inhibitors -- interfere with
topoisomerases & copying of DNA strands
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Mitotic inhibitors -- plant alkaloids and interfere with
mitosis
– Mostly M- phase of the cell cycle
CommonToxicities to many of these agents
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Myelosuppression
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Dermatology – Alopecia, hand-foot syndrome
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Neurologic toxicity
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Tumor lysis syndrome
Gastrointestinal – nausea/vomitting
Case
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Staff Seargent Jones is a 25 y/o female with metastatic colorectal cancer in the setting of
family history of HNPCC
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She started cycle 2 chemoimmunotherapy with 5-FU and cetuximab 2 days ago
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She now presents to you as ER admitting resident with c/o nausea/vomitting and
inability to keep food down
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Exam:
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VS: Bp 95/50 HR 110 Temp 98.5
ill-appearing but no focal findings except mild cachexia and hyperpigmented palms, feet and lips
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Hgb 8, wbc 3.6, plt 40, ALT 100, AST 79, Tbili 1.3 Bun 35 sCR 1.8
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You will now do what?
Gastrointestinal Complication
• TOXIC INJURY OF ORAL AND GASTROINTESTINAL MUCOSA
• CLINICAL SYMPTOMS
- stomatitis with ulceration and pain
- abdominal pain, watery stools not related to
infection, hemorrhagic stools
• CONSEQUENCES
- infections  mainly with opportunistic endogenous
GI microflora
- bleeding
- perforation
- worsening of general status due to poor nutrition
NAUSEA AND VOMITING
• PATOGENESIS
– Not well understood
– One hypthesis = chemotherapy causes 5HT release from enterochromafin cells of
stomach and gut, activating its receptors and initiating depolarization of vagus
nerve
• Uncontrolled chemotherapy induced naseau/vomitting results
in
- difficulties with oral drugs administration and oral feeding
- exacerbation of oral cavity, pharynx and esophagus mucosal injury
- Suboptimal chemo treatment due to drug discontinuation
Scope of the problem -- Chemotherapy Induced Nausea
Vomitting (CINV)
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Incidence of acute and delayed N&V prospectively studied in 298 adult patients
receiving HEC or MEC for the first time from 14 oncology practices in six countries
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Patients completed a 6-day diary including emetic episodes, nausea assessment, and
antiemetic medication use
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Result:
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Overall incidence of acute nausea > 35% and acute emesis = 13%
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Delayed nausea with HEC pt = 60% and emesis = 50%
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Delayed nausea with MEC pt = 52% and emesis = 28%
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Delayed symptoms appeared without acute symptoms after HEC (emesis, 38%; nausea, 33%) and MEC
(emesis, 19%; nausea, 21%)
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** >75% of physicians and nurses underestimated the incidence of delayed CINV after both HEC and MEC
Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced
nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004
Classification schema
• Acute
– Begins 1-2 hrs after initiation, peaks at 4 hrs
• Delayed
– >24 hours after chemo
• Anticipatory/hyperacute
– Prior to chemotherapy as a conditioned reaction to prior
episodes of emesis with treatment
Patient-specific risk factors
• Higher-risk groups
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Young
Female
High pretreatment expectation of nausea
Poor n/v control with prior chemotherapy
• High ETOH consumption = ? negative risk
factor
#1 risk factor is drug dependent
• The type of chemotherapy delivered
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Dose
schedule of administration
route
individual patient variables
Chemo Emetogenic Potential
• High (level 4)
– >90% risk of emesis without treatment
Cisplatin , Mechlorethamine, .Streptozotocin,
Cyclophosphamide(> 1,500 mg/m2), Carmustine,
Dacarbazine,Dactinomycin
• Moderate (level 3)
– 31-90% risk of emesis without treatment
Carboplatin.Cyclophosphamide <1,500
mg/m2,,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,
Oxaliplatin , Cytarabine >1 g/m2, Ifosfamide Irinotecan
• Low (level 2)
– 10-30% risk of emesis without treatment
• Minimal (level 1)
Mitoxantrone, Paclitaxel, Docetaxel, Mitomycin,
Topotecan,Gemcitabine, Etoposide, Pemetrexed,
Methotrexate, Cytarabine < 1,000 mg/m2,Fluorouracil
Bortezomib, Cetuximab, Trastuzumab
– <10% risk of emesis without treatment
Vinorelbine,Bevacizumab, Rituximab, Bleomycin
Vinblastine, Vincristine, Busulphan, Fludarabine,
2-Chlorodeoxyadenosine
Classes & examples of Anti-emetics
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5-HT3 Receptor Antagonists: Ondansetron, Granisetron ,Dolasetron, Palonosetron
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Substance P Antagonists (NK-1 Receptor Antagonists
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Corticosteroids
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Benzodiazepines: Lorazepam, Olanzapine
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Phenothiazines: Prochlorperazine
Butyrophenones: Droperidol and haloperidol
Dopamine 2 Antagonists: Metoclopramide
Cannabis – don’t medically recommend to patients as a military physician
5-HT3 antagonists
• Cornerstone of controlling acute nause/vomitting
– Equally effective across older formulations
– Few adverse effects – HA, constipation
– Relatively convenient dosing
• Lower efficacy for delayed type of nause/vomitting
• Even the generic remain expensive
• Palonosetron (Aloxi)
– Longer half life -- 40 hours
– Better against delayed n/v
– Studies ongoing to determine whether or not it should be the 5-HT3 antagonist of
choice
Neurokinin-1 (NK-1) antagonists
• Aprepitant (Emend)
– Oral drug only  125 mg po day 1, 80 mg po day 2-3
– Resulted in significant n/v improvement compared to
dexamethasone alone or dexamethasone with 5-HT3 antagonist
– Adverse events: Hiccups, dyspepsia
– Very expensive --three tabs = $322
– CYP 450 3A4 inducer
Corticosteroids
• Old drugs with unclear mechanism for controlling CINV
• Best when used with other anti-emetics
• Effective for acute and delayed CINV
• Dexamethasone
– 20 mg IV for highly emetogenic
– 8-20 mg for less emetogenic
– Continue PO daily or BID for 4 days
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• Methylprednisolone IV also used
Other adjunctive antiemetic
• Benzodiazepine  helpful in anticipatory n/v
– Lorazepam used first line
• Metoclopramide (Reglan)
• Prochlorperazine (Compazine)
• Dronabinol (Marinol)
• Olanzapine (Zyprexa)
– Has ODT formulation and may be helpful in sundowning
inpatients with n/v
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Breakthrough & Refractory Emesis
• Challenging to reverse when preventive agents fails
– Ensure adequate hydration and consider admission
– Check and correct electrolyte imbalances
– Use IV route and scheduled doses
• May lead to anticipatory nausea/vomiting with next cycle if
uncontrolled
• For refractory emesis
– Supportive care, hydration, nutritional supplementation
– Strongly consider cessation/alteration of chemotherapy regimen
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Think Outside the Box (TOB)
• Could it be disease related
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Brain mets
Bowel obstruction
Paraneoplastic effects (hypercalcemia, hyponatremia)
Radiation enteritis
• Could it be new infection
• Could other emetogenic meds like opioids be
contributing?
Case – Hospital day 2
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Staff Sergeant Jones is feeling better with schedule anti-emetics, rehydration and
correction electrolytes discovered on additional labs
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She reports 5 episodes of diarrhea overnight with increasing dysphagia
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Exam show normal vital signs and oral lesions with new sores on bilateral lips
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Labs: LFT 2.5 x ULN, wbc 2.2, ANC 800, hgb 7.8, plt 30, Bun 35 sCR 1.5
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What the clinical issues now and how would you proceed?
Diarrhea
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Major toxicity of several drugs used to treat gastrointestinal cancers such as 5-FU
and irinotecan
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Rule out infection before giving anti-motility agent – c-diff if at risk
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Anti-Motility Drugs
– Loperamide (Imodium)
– Diphenoxylate (Lomotil)
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Octreotide (Sandostatin)
– Somatostatin analogue
– Works to prolong GI transit time
– Subcutaneous administration
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Acute diarrheal reaction to irinotecan  Atropine at time of treatment
Mucositis (Mouth Sores)
• More common with
certain drugs
– 5-fluorouracil (5-FU)
– Methotrexate
– Doxorubicin (Adriamycin)
– Cyclophosphamide
(Cytoxan)
Mucositis
• Prevention
– Icing of the mouth during treatment
• Treatment Options
– Gel Clear
– Magic Mouthwash
– Viscous lidocaine
– Narcotics
• Maintain vigilance for both local viral and systemic infection
HEPATOTOXICITY
• Etiology – many drugs and infection
• CONSEQUENCES are many including suboptimal drug delivery,
bleeding due to poor synthetic funciton and long term liver
compromise
• SURVEILLANCE
- serum bilirubin, AlAt, AspAt, GGTP, NH3, PT/PTT
- Liver u/s and biopsy as needed
• PREVENTION
- Dose adjustment to current liver function
- Monitor infection with hepatotropic viruses (HBV, HCV)
RENAL TOXICITY
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Classic nephrotoxic chemotherapy = platinum drugs (cisplatin,
carboplatin, less so oxaliplatin) and methotrexate
• PREVENTION
- cisplatin – administration of magnesium sulphate, mannitol
for diuresis induction and hyperhydratation
- metotrexate – hyperhydratation, diuretics,urine alkalization
- Avoid and discontinue concomittant nephrotoxin
NSAIDS,
IV contrast etc
Case – Hospital day 4
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Nurse reports to you that Staff Sergeant Jones has fever of 100.5 with chills
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You give verbal stat orders for labs and xray
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Nurse raises concern that you should come to ward and evaluate patient as the team just left
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Your exam demonstrates an ill appearing pt shivering in bed. She reports to you that she is fatigued
& her feet and hand “feels funny”. Temp is reported with BP 95/50 and HR 120. Severe mucositis is
present. Lung and heart otherwise nl. Left upper arm picc line site is erythematous without exudate.
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She has no other vascular access
STAT labs show LFT 3 x ULN, wbc 1.1, ANC 400, hgb 5.8, plt 18, Bun 35 sCR 1.3
• How would you proceed?
Case – Hospital day 4
• Clinical problems
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Fatigue
Diarrhea
Neutropenic fever with unstable VS
Possible Catheter related line infection
Grade 3 Anemia and thrombocytopenia
Worsening mucositis – you’re dealing with this !!
Hepatic and renal dysfunction – you know this already !!
And what’s with the hyperpigmented feet and hand feeling funny?
Fatigue: Multifactorial
• Anemia
– Erythropoietin (Procrit)/darbepoetin (Aranesp)
• Depression
– Selective serotonin reuptake inhibitor (SSRI)
• Sleep Disturbance
-- Sleep aid: zolpidem tartrate (Ambien),
eszopiclone (Lunesta)
• Psychostimulants
-- Methylphenidate (Ritalin)
Bone marrow suppression
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Very common complication of chemotherapy
• Has potential to cause mortality than any other complication
• Leads to
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Thromocytopenia – bleeding and more bleeding
– Anemia – fatigue, cardiovascular and cerebrovascular events
– Neutropenia – bacterial infection
– Lymphopenia and hypogammaglobulinemia => risk of viral,
fungal and protozoal infection
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Neutropenic Fever
• Neutropenic fever is a medical emergency
• Infectious mortality in chemotherapy patients was 75% before
empiric antibiotic therapy became the standard of care
– Similar mortality (70% ) seen with a delay in administration of empiric
antibiotics in patients with neutropenic fever
• The Infectious Disease Society of America (IDSA) guideline provides
best of expert advice -- last updated 2010
NEUTROPENIA FEVER
Duration and extent of bone marrow depression
depends on drug
NEUTROPENIA
CHANGING PARADIGMS
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Shift from Gram-positive to Gram-negative pathogens
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New Gram-positive and Gram-negative
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Increasing importance of fungi, especially Candida sp in neutropenic patients
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Increasing incidence of resistant pathogens (MRSA, VRE, Candida)
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Availability of G-CSF and GM-CSF
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Development of broad spectrum antimicrobials
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Early use of empiric antimicrobial therapy
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Improved infection control
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Use of prophylactic antimicrobial therapy remain controversial and not adviced
IDSA INITIAL ANTIBIOTIC CONSIDERATION
• Only 23% of febrile neutropenic episodes are assocaited
with bacteremia
– Gram positive organism – 57% with 5% mortality
– Gram negative organisms – 34% with 18% mortality
– Polymicrobial –9%
• The goal of initial empiric abx is to prevent serious
mortality and morbidiy
• Coverage of pseudomonas aeruginosa continues to drive
initial antibiotic choices
IDSA 2010 update accessed 1/3/12
IDSA INITIAL ANTIBIOTIC THERAPY
CONSIDERATION
• Negative blood cultures does not preclude empiric antibiotics in febrile
neutropenic patients
– May have occult infection
• No clinical trial have shown superiority of one single empiric regimen
• Ultimate selection should be based on
– Whether patient’s risk is low vs high
– Localizing infectious signs or symptoms – pulmonary infiltrates or cellulitis
– Epidemiologic trends of pathogens causing infections in neutropenic patients
• Special attention to local and individual patient patterns of bacterial
colonization and resistance
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IDSA 2010 update accessed 1/3/12
IDSA INITIAL ANTIBIOTIC THERAPY
CONSIDERATION
• Drug allergies
• Drug interactions
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• Organ dysfunction -- renal and liver
IDSA 2010 update accessed 1/3/12
Initial management of fever and
neutropenia—IDSA 2010 update
Initial management of fever and
neutropenia—IDSA 2010 update
IDSA INITIAL ANTIBIOTIC
THERAPY CONSIDERATION
IDSA 2010 update accessed 1/3/12
IDSA INITIAL ANTIBIOTIC THERAPY:
CR-BSI
• Follow IDSA guidelines
• Indications for catheter removal
– Tunnel infection or periport infection
– S. Aureus, Bacillus spp., P. aeruginosa, S. maltophilia, VRE, Candida
spp. Corynebacterium spp, Stenotrophomona
– ?Established infection with Acinetobacter spp
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• If other types of bacteria, may consider treating through
the line
• Consult ID to help you !!
DERMATOLOGIC COMPLICATIONS
HYPERPIGMENTATION
• Usually resolves with drug
discontinuation
 gingival margin pigmentation seen
with cyclophosphamide usually
permanent
• Patterns of pigmentation
– Diffuse
– Local at site of infusion
◦ Sites of pressure /trauma
– Hydrea and cisplatin
HAND-FOOT SYNDROME
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AKA palmar–plantar erythrodysesthesia
– Originally described in high-dose
cytarabine treated patients but now capecitabine,
Liposomal doxorubicin , infusional 5FU, taxanes
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Skin lesions begin as erythema and edema of
the palms or soles and is associated with
sensitivity to touch or paresthesia
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Can progress to desquamation of the affected
areas and significant pain
g
Treatment
• No proven preventive therapy
– Management largely symptomatic with dose reduction or
discontinuation of drug
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– Pyridoxine (vitamin B6) may help reduce the incidence and
severity
– Celebrex reported to reduce incidence
• Emollients (eucerin) commonly used
Hypersensitivity reactions
You may be called !!
• Can occur either from
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Drug itself –> monoclonal antibodies
Solubility vehicle  Cremophor for paclitaxel
• Prevented with premedication
– Steroids and benadryl
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• Management of hypersensitivity reactions
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Epinephrine
Hydrocortisone
histamine blockers
monitoring and treat unstable vital signs
Extravasation injury
• The accidental extravasation of intravenous drugs
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• Sequelae depend on the agent and amount
– Can see erythema, pain, tissue necrosis and sloughing of the skin
• Vesicants = most toxic drugs
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anthracycline
– vinca alkaloids
– nitrogen mustards
– paclitaxel
– cisplatin
Treatment of extravasation
• D/C chemo immediately
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• Cool site with ice packs but warm soaks for vinca
alkaloids
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• Consult surgery for persistent/progressive local
symptoms
– early local debridement reduces extent of injury
Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review.
Skin Toxicity from targeted therapy
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Epidermal growth factor
receptors (EGFR)
expressed by cancer
cells as well as basal
keratinocytes, sebocytes,
the outer root sheath,
and some endothelial
cells
Monoclonal antibodies to
EGFR
Cetuximab, panitumumab
EGFR pathway inhibitors
Acneiform eruption;
paronychial inflammation;
photosensitivity
Erlotinib
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Infusion reactions; acneiform
eruption; paronychial
inflammation; photosensitivity
EGFR inhibitors are thus
associated with
dermatologic side
Gefitinib
effects
Multitargeted tyrosine
kinase inhibitors
Lapatinib
Imatinib
Dasatinib
Sorafenib
Sunitinib
Skin exanthem; SJS; acute
generalized exanthematous
pustulosis; Sweets syndrome;
hand-foot syndrome;
photosensitivity; pigmentary
changes, hair depigmentation;
alopecia
Erlotinib eruption on the arms
Alopecia
•Innocent by-stander as rapid proliferating cel
•Terminal hair follicles with rapid matrix formation more affected
-scalp > body hair, eyebrows, eyelashes
-Rapidity of loss depends on intensity & schedule of chemo
- Lost quickly after transplant and gradually over weeks with cyclic chemo
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Often
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Bleomycin
Etoposide
Methotrexate
Mitoxantrone
Paclitaxel
– Ifosphamide
– Paclitaxel
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Common
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Cyclophosphamide
Daunorubicin
Doxorubicin
Docetaxel
Idarubicin
Infrequent
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5-FU
Hydroxyurea
Thiotepa
Vinblastine
Vincristine
Vinorelbine
Rare
–
procarbazine
Pharmacologic interventions for
alopecia
• No successful preventive strategy
• Topical minoxidil  shorten time to maximum regrowth
• Alpha tocopherol  ? less alopecia reported
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NAIL DYSTROPHY
• Color changes
– Mee’s lines - transverse white
– hyperpigmentation
• Beau’s lines - transverse
grooves/lines
– related to the effect of
chemotherapy causing
decreased nail growth
• Paronychia -inflammation of
the nail fold
– Seen with cetuximab
Beau’s lines
Mortimer, NJ, Mills, J. Images in clinical medicine: Beau's
lines. N Engl J Med 2004; 351:1778.
Cardiac Toxicity
• Risk factors
– Previous chest radiation, hypertension, anthracyclines alone or in
combination with other cardiotoxic drugs like herceptin
• Acute
– electrocardiogram changes, arrhythmias within hours
• Chronic:
– CHF not easily treated with digitalis
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Cardiac Toxicity
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SURVEILLANCE
– EKG, ECHO, CK, AspAt and LHD activity in serum
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PREVENTION
– Monitor and Limit cumulative dose of cardiotoxi drugs
• doxorubicin below 450 mg/m2 to 550 mg/m2
• cumulative dose of daunorubicin below 600 mg/m2
– Attention to correct administration  duration, concentration, dose
interval
– administration of dexrazoxane ( Cardioxane )
BLADDER TOXICITY
• Caused by urotoxic metabolite of cyclophosphamide or
ifosfomide leading to hemorrhagic cystitis
• SYMPTOMS may mimick UTI – dysuria, urgency, microscopic
or gross hematuria
• PREVENTION OF HEMORHHAGIC CYSTITIS
– intensive i.v. hydratation
– diuresis stimulation
– Mesna at 160% the dose of cyclophospamide –
binds acrolein
TUMOR LYSIS SYNDROME (TLS)
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Seen when patients with rapidly dividing and bulky tumors are given effective therapy
– Can occur before treatment
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Lab shows  hyperuricemia, hyperphosphatemia, hyperkalemia and symptomatic
hypocalcemia
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Renal failure may result from uric acic crystalization
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PREVENTION AND THERAPY
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Hyperhydration (watch lung and lung)
urine alkalization to keep pH > 7
Rasburicase if active TLS  recombinated uric oxydase which converts uricacid to
soluble allantoin
Allopurinol to prevent in high risk patients
Dialysis as needed for electrolyte and volume derrangement
Neurologic toxicity
Peripheral neurotoxicity
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Symptoms  Painful burning sensation, progressive paresthesia, motor
weakness, urinary retention, paralytic ileus
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Classic drug etiology – platinum, taxanes, velcade, vinca alkaloids
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No good prentive strategy == avoid cold exposure, glutamine, vit B6
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D/C or reduce causative drug and try neurontin, elavil and others
Central nervous system toxicity
• Metothrexate at high dose or intrathecal may cause mengitis type sx
Bleomycin toxicity
• Etiology unclear but ? low levels of bleomycin hydrolase in lungs and skin
tissues leaving to sensitivity
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• lungs
– progressive fibrosis, chronic interstitial inflammation
• Drug dose incident  <450mg 3-5% >450mg 10%
– risk factors: age, emphysema, renal failure, previous radiotherapy to the chest,
oxygen administration
• Skin
– ~50% pts have erythema, peeling, ulceration
• systemic toxicity: ~1% of lymphoma pts develop hyperthermia,
hypotension, cardiovascular collapse (release of endogenous pyrogens?)
LATE COMPLICATIONS
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Functional disruption of any organ systems
- CNS neurologic, intellectual (chemo brain) and psychosocial sequelae
- liver
- kidney**
- heart **
- lungs **
- pancreas
- gastrointestinal tract
- skeleton
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Gonadal toxicity
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males
- Leydig cell hypofunction  low testosterone
- azoospermia/oligospermia  infertility
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Females  premature menopause  infertility
genetic aberrations leading to secondary malignancy
SECONDARY MALIGNANCY
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Depends on several factors
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Age of onset of chemotherapy
Type of chemotherapy
Intensity of treatment
Combination with radiation therapy
In a cohort of 5,519 British patients treated for with Hodgkin’s disease between
1963 through 1993
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322 malignancies occurred
Relative risks of GI, lung, breast, , bone & soft tissue cancers, leukemia correlate with younger age at treatment
Gastrointestinal cancer risk after mixed-modality treatment = 3.3
lung cancer risks after chemotherapy = 3.3 and after mixed modality = 4.3
breast cancer after radiotherapy without chemotherapy = 2.5
leukemia after chemotherapy = 31.6 and mixed-modality treatment = 38.1
For ages younger than 25 years
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RR for GI cancer = 18.7 after mixed-modality treatment, 14.4 for breast cancer after radiotherapy, and 85.2% for leukemia after chemotherapy with or without
radiotherapy
Absolute excess risks and cumulative risks of solid cancers and leukemia were greater at older ages
Swerdlow, AJ et al. JCO February 1, 2000 vol. 18 no. 3
It not as bad as it sounds !!
Questions