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Welcome! This site aims to be the premier site for information on, the reporting of, and
the improved detection, management and hence outcome for extravasation injuries. Please be aware that this website is always under construction! Therefore please check back regularly for new features and information. If you have any comments, or if there's something you would like to see on the website, please email us -Thanks!

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This service was made possible by a number of unrestricted educational grants from the UK pharmaceutical industry and .

Could you make a donation to the National Extravasation Information Service to allow our work to continue? Please donate here! Andrew Stanley, 1990-2007 This site last revised on Tuesday 6th February 2007 The National Extravasation Information Service, 2000-2007.

What is Extravasation?
The leakage of intravenous drugs from the vein into the surrounding tissue.31 Extravasation injury usually refers to the damage caused by leakage of solutions from the vein to the surrounding tissue spaces during intravenous administration. Once an extravasation has occurred, damage can continue for months and involve nerves, tendons and joints. If treatment is delayed, surgical debridement, skin grafting, and even amputation may be the unfortunate consequences.60

Taxotere extravasation

Doxorubicin extravasation

Taxol extravasation

This page last updated 16/04/2004

Extravasation Incidence
Extravasation is not as rare as many people think:

In children, up to 58% of intravenous lines may 'tissue'.75 2% of Medical Defence Union cases involving anaesthetic-related events between 19701982 (excluding deaths) were due to extravasation injuries.76 5% of patients who received a course of cytotoxic injections experienced extravasations.77

Recognising an extravasation

Pain at the intravenous site may be modest or severe, usually burning or stinging.92 There may be erythema, swelling and tenderness, and lack of blood return from the cannula.30 Not all of these symptoms may be present. Local blistering is indicative of at least a partial-thickness skin injury.92 There may also be mottling and darkening of the skin, persistent pain, and firm induration.60,61 Early firm induration, with or without tenderness, has been shown to be a reliable sign of eventual ulceration.92 When the full thickness of the skin is damaged, the surface may appear very white and cold with no capillary filling,62 and later may develop a dry, black eschar.92 Ulceration is not usually evident until one or two weeks after the injury when the eschar sloughs to reveal the underlying ulcer cavity.92 Ulcers have a typical necrotic, yellowish fibrotic base with a surrounding rim of persistent erythema.92

This page last updated 16/05/2005

Risk Management

Since the beginning of 1990, health authorities have been responsible for monitoring claims of medical negligence arising within the NHS hospital service. By far the largest number of claims, over 80% in 1989, are solely attributable to hospital doctors,86 largely because these clinicians are more likely than community professionals to be involved in specialities such as surgery and anaesthetics and other complex invasive procedures that frequently involve intravenous cannulation. NHS Trusts are now actively seeking risk management advice and services, and will need to comply with requirements of the civil justice reforms implemented in April 1999.87 The introduction to the NHS of Clinical Governance has made Chief Executives explicitly accountable for quality of clinical care and standards of practice in their organisations. In the USA, chemotherapy extravasations comprise a highly litigious area of oncology practice.88 In the UK, 2% of Medical Defence Union (MDU) cases involving anaestheticrelated injuries between 1970-1982 (excluding deaths) were due to extravasation.89 Between 1982-1986, the MDU dealt with three or four claims a year arising from extravasation injuries in premature infants, some of which resulted in permanent scarring.90 Litigation is increasing in the UK and medical negligence currently costs the NHS 300 million a year 91 compared with 23 million settled by the MDU for 759 claims in 1989.86 Taking all incidents into consideration, about 1% of in-patients experience negligent accidents to the point of claim but it is estimated that the overall rate of injuries or adverse outcomes possibly attributable to negligent medical management is considerably higher.87 Proactive risk management is being strongly promoted by the NHS Litigation Authority which also administers the Clinical Negligence Scheme for NHS Trusts. Clinical risk management involves identification, analysis and control of risks by initiating and documenting explicit and standardised care processes and monitoring variances against defined parameters.87 The control of risk is a crucial part of the quality package and it is essential that systems are in place at every level to ensure good practice and continuous improvements in clinical care.
Extravasation injuries may occur even in the most closely monitored situations. A study 32 which investigated extravasation over a five-week period in a UK hospital, established an incidence of 39%, almost double that of previously published reports. Lack of evidence that adequate precautions were taken, or failure to deal promptly and appropriately with a suspected or actual extravasation, could make a claim for negligence indefensible.

This page last updated 04/05/2005

The National Extravasation Information Service, 2000-2005.

Treating Extravasation Injuries

The many papers on this subject present a diversity of views but there is not enough consensus to formulate an algorithmic approach to treatment based on the physicochemical properties of the groups of agents or to predict which cases may progress to significant tissue necrosis. The

following information is based on current available evidence. Units are advised to formulate a policy to deal promptly with extravasation which is relevant to the drugs and infusates used regularly. To view the West Midlands Regional Chemotherapy Services extravasation treatment protocol, formulated by St. Chad's Unit, City Hospital, Birmingham UK, click here To view details of David Gault's 'flush-out' technique, please click here

Heat and Cold

8,13,14,16,20,23,30,36,45,78,79 These have been used on the principle that:

Heat induces vasodilation, increasing drug distribution and absorption 60,88 and decreasing local drug concentrations.59,64 Cold causes vasoconstriction, localising the extravasation 60 and allowing time for local vascular and lymphatic systems to disperse the agent.88 With the exception of vinca alkaloids, topical cooling seems to be more effective than topical warming in the management of cytotoxic and noncytotoxic vesicants.88 In practice, the application of moist heat has lead to maceration and necrosis.62

These have been used to reduce inflammation

As intradermal or subcutaneous injections and topically as steroid creams. As single treatments and in combination with other agents. Evidence suggests that corticosteroids are not helpful in the extravasation of antineoplastic agents because inflammation is not prominent in the aetiology of tissues necrosis.

Some of these are recommended by the drug manufacturers.

Phentolamine (an alpha-adrenergic blacking agent relaxing smooth vascular muscles) has been used as an antidote to vasopressor extravasation. (ABPI
Compendium 1998-9)

Topical glyceryl trinitrate (vasodilator) for parenteral nutrition. 93 Sodium thiosulphate (direct inactivation) for mustine.(ABPI Compendium 1998-9) Dimethyl sulphoxide (an oxygen-free radical scavenger) for daunorubicin, 11 mitomycin 4 and doxorubicin. 94 Dexrazoxane (Savene TM) for anthracycline extravasation

Indications for surgical excision of the extravasated area:

Clear cut full-thickness skin necrosis with or without frank ulceration 92 or intractable pain. 95 Wide excision including a margin of normal tissue ensures a satisfactory graft or flap 61although deep ulceration may involve tendons or nerves. 92 Patients frequently end up with extension contractures regardless of how wound closure is achieved. 92 Early surgical excision is controversial since only about a third of known vesicant extravasations will ulcerate.96
The National Extravasation Information Service, 2000-2006.

This page last updated 8th May 2006

DOCUMENTATION AND REPORTING OF EXTRAVASATION It is important that a complete history of an extravasation event is documented, with diagrams and photographs, in the patient's notes. Observation and documentation of the injury should be on a daily basis for the first few days, extended then to weekly observation on a planned follow-up. In an attempt to collate and analyse data on extravasation events in a large number of patients, a 'Green Card' scheme for reporting extravasation incidences, their treatment and outcome, is being co-ordinated through the St Chad's Unit, City Hospital, Dudley Road, Birmingham, UK. 1. Aims and objectives of the Green Card scheme

To obtain accurate statistics on the number of incidents categorised by extravasating drug and type of treatment. To collect data on treatment methods and antidotes being used for extravasation incidents. To obtain accurate information on the outcome of incidents. To feed back information on treatments and their effectiveness.

2. What do Green Cards ask for ?

Drug(s) involved. Circumstances of detection. Extent of the problem. Drugs used in the treatment. Procedure for treatment. Type of cannulation. Location and extent of the extravasation.

The Green Cards are intended to be user-friendly. The information is strictly confidential and the reporting centre and patient remain anonymous. The report cards are available by clicking here, or from hospital pharmacy departments or oncology units in the UK or can be obtained direct from the Extravasation Report Co-ordinator, c/o St Chad's Unit, City Hospital, Dudley Road, Birmingham, B18 7QH, UK. It is also possible to fill in and send an electronic version of the green card by clicking here - Green Card On-line
This page last updated 06/01/2004

The National Extravasation Information Service, 2000-2004.

This page last updated 06/01/2004

The National Extravasation Information Service, 2000-2004.

Extravasation Risk Factors - The Drug or Infusate

Soft tissue damage following extravasation may be due to a number of factors related to the physicochemical properties of the drug or infusate. The following agents have been known to

cause extravasation injuries, but the lists are by no means definitive. Some agents have properties which would place them into more than one category. The most important input that pharmacy can have is by consideration of the drugs themselves and by characterising their extravasation risk. It is now well documented that a number of physico-chemical factors influence, and usually increase, the extravasation risk of individual drugs. These are:

the ability to bind directly to DNA (most cytotoxic drugs do this) an ability to kill replicating cells of which such drugs also include the cytotoxic and anti-viral agents an ability to cause tissue or vascular dilatation the pH, osmolarity and excipience in the formulation of the drug

These parameters are more specifically defined as pH outside the range 5.5. - 8.5 and osmolarity greater than that of plasma, 290 mosmol/L and formulation components such as alcohol, polyethylene glycol and Tweens. Other formulation related parameters include the concentration and volume of the solutions to be administered. Unfortunately, these two parameters are contradictory to each other in so far as the smaller the volume the less the likelihood of extravasation but the greater the concentration, the higher the risk of extravasation, or the greater the damage should any extravasation caused. As the commonest way to decrease the volume is to increase the concentration, juggling these two factors becomes more of an art than a science.

Please click here to view a table of cytotoxic drugs, classified according to their potential to cause serious necrosis when extravasated.

Osmolality. 18 29
In order for the extravasated compound to do damage, lethal or sub-lethal, it must move out from the initial site of extravasation. The fact that this movement occurs is evident when we consider

that the extravasation area is often considerably larger than the immediate post incidence area or relative to the volume extravasated. Although there is little direct literature on the effect of time from occurance to either treatment or extent of maximum injury, all authors make the generalised statement that the sooner an extravasation injury is treated, the better the outcome, and the smaller the affected area. However our ability to define and characterise the mechanism and rate of movement of individual compounds in the subcutaneous tissues will allow us to better predict the extent of extravasation injuries. Learning Point An understanding of drug or infusate cellular transport process may allow us to better predict the spectrum of damage that may be expected. Some forms of transport mechanism may directly cause cell death because of the rate at which they affect the local cellular environment . Osmotic pressure is such a factor and this is directly related to the osmolality of the administered drug. Osmotic pressure can cause cell death and hence tissue necrosis by cell implosion from hypertonic solutions, or cell explosion from hypotonic solutions, however the former of these cellular fates is by far the more common. Some substances have the potential to cause tissue damage by having an osmolality greater than that of serum (281-289 mOsmol/L) 63 Hyperosmolar substances such as hypertonic glucose solutions or X-ray contrast media draw fluid from cells resulting in cell death by dehydration whereas calcium and potassium salts cause cell death by fluid overload. Hypertonic solutions which contain ions and are also acidic are particularly damaging to tissues because they are capable of killing cells by precipitating cell proteins. 42 Calcium chloride, for example, has caused full thickness skin necrosis, and hypertonic saline is the most common sclerosant associated with necrosis. Inexperienced sclerotherapists (< 500 treatments) reported a 5% incidence of post-sclerotherapy necrosis. Hyperosmolar agents
Hypertonic glucose Hypertonic saline Potassium chloride Calcium chloride Sodium bicarbonate Parenteral nutrition X-ray contrast media Antibiotics

In a series of 96 patients, mean age 10 years (premature - 70 years), 47 extravasations involved hyperosmolar agents and 14 of these were of parenteral nutrition. Parenteral nutrition extravasation is reported more often in children, 45 and can cause skin sloughs 62 and limb contractures particularly in premature infants. Four injuries were due to sodium bicarbonate which is also highly alkaline, resulting in two babies having digits amputated.

pH 27 29 32 45
The pH of a substance outside of the physiologic range (the pH of blood is 7.35 - 7.45) may have an adverse effect on tissue. 45 66 Thiopentone and phenytoin, for example, are highly alkaline and have caused severe injuries including amputations. 67 The replacement of thiopentone 5% solution with 2.5% solution followed reviews of extravasation reported to the Medical Defense Union and Medical Protection Society. Acid and alkaline agents
Thiopentone, pH 10.5 Methohexitone Etomidate Phenytoin, pH 12 Amphotericin Methylene blue

Vascular Tone
Vascular regulators (vasoconstrictors) can cause ischaemic necrosis by restricting local blood flow, resulting in severe tissue damage. 62 Dopamine extravasation appears to be a particular problem in neonatal intensive care units. 68 Vasodilators may exacerbate the effects of extravasation by increasing local blood flow and enlarging the area of injury. Vascular regulators
Adrenaline Noradrenaline Metaraminol Dopamine Dobutamine Vasopressin Prostaglandins


Cellular Toxicity
Some substances have a direct toxic effect on tissues. Many antineoplastic agents are vesicant (ie. produce blisters), 30 60 and as well as causing immediate injury may also bind to tissue DNA 11 so that the drug is continually released from dying to healthy cells, resulting in a slow increase in ulcer size over time. Doxorubicin, for example, has been shown to remain in tissue for 5 months after extravasation 69 which means that the injury can present late with extensive tissue destruction. 70 Ulcers caused by these highly vesicant agents usually do not heal and often require plastic surgery and skin grafting. 4 Cellular toxic agents
Doxorubicin Daunorubicin Vincristine Vinblastine Mitomycin Mustine Paclitaxel Azathioprine Acyclovir
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Classification of cytotoxic drugs according to their potential to cause serious necrosis when extravasated
Please note that the groupings have been reversed as of October 2005 - this is in order to facilitate the formulation of a grading system for extravasation risk - the higher the grouping, the higher the risk of causing severe and serious tissue damage. For any queries, please contact Andrew Stanley.

Neutrals: Group 1

Inflammitants: Group 2

Irritants: Group 3

Exfoliants: Group 4

Vesicants: Group 5

Asparaginase Bleomycin Cladribine Cyclophosphamide Cytarabine Edroclomab Fludarabine Gemcitabine Ifosfamide Melphalan Pentostatin Rituximab Thiotepa Beta-Interferons Aldesleukin (IL-2) Trastuzemab

Etoposide Phosphate Fluorouracil Methotrexate Raltitrexed

Carboplatin Etoposide Irinotecan Teniposide

Aclarubicin Cisplatin Daunorubicin Liposomal Docetaxel Doxorubicin Liposomal Floxuridine Mitozantrone Oxaliplatin Topotecan

Amsacrine Carmustine Dacarbazine Dactinomycin Daunorubucin Doxorubicin Epirubicin Idarubicin Mitomycin Mustine Paclitaxel Streptozocin Treosulfan Vinblastine Vincristine Vindesine Vinorelbine

Extravasation Risk Factors - The Patient

Despite the theoretically correct sites for cannula location, a number of other patient factors come into play. Disease parameters such as lymphodema in breast disease, or other underlying physiological conditions, such as diabetes and peripheral circulatory diseases such as Raynaud's disease; can all modify this theory. Patients who have had previous radiation therapy at the site of injection may develop severe local reactions from extravasated cytotoxic drugs. This is known as recall injury and has been noted in patients who have received doxorubicin.16 Cytotoxic drugs also have the potential to cause cutaneous abnormalities in areas that have been damaged previously by radiation, even of the areas are distant from the injection site. Furthermore, areas of previous surgery where the underlying tissue is likely to be fibrosed and toughened all dramatically increase the risk of extravasation. Because of the toxic chemical nature of many cytotoxic drugs and because of the stress and trauma involved in the cannulation process, combined with the fact that chemotherapy is given over a number of cycles on a three-weekly or even weekly basis; it is thought by many that the sites of cannulation should be alternated. A final factor to be worked into this complicated equation is the patient's preference. Often patients do not wish to be cannulated in their dominant hand and, in fact, there is some evidence to suggest that this is a more complicated, more traumatic process anyway because the underlying muscular structures of the dominant hand or arm are better developed and therefore apply greater pressure to the vascular structures which they surround.

Infants and Young Children 20 29 36 43 45

Most extravasations in children occur in infants under 6 months. 43 Severe damage is more common in neonates and young children than in adults. 62 Infants in special care baby units are particularly at risk because of their immature skin, the frequent need for prolonged antibiotic therapy, intravenous

electrolyte and nutritional supplementation, 43 and because they often have infusions through peripheral veins. 29 Infants and young children may not be able to localise and report pain. 71

The Elderly 16 18 32

These patients may pull or interfere with their cannulas because of confusion. They may be unable to report pain due to conditions which reduce pain sensation. Fragile skin and veins, and general debility may increase susceptibility to extravasation. 59

Patients Unable to Communicate 24 25 32 45

Reduced levels of conciousness or verbalisation difficulties may result in extravasations going unnoticed. Those at risk include :

Patients under general anaesthesia. 61 63 Patients intubated in the intensive care unit. 61 Heavily sedated or comatose patients. 63 Patients undergoing cardiac resuscitation. 63 Stroke or paralysed patients.
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Extravasation Risk Factors - The disease

Veins of people receiving chemotherapy are often fragile, mobile, and difficult to cannulate. 24,

Patients who receive chemotherapy at the same site as radiotherapy may experience a reactivation of skin toxicity known as 'recall' phenomenon.4, 14, 30, 34, 39, 48-58 Patients who have had an extravasation and recieve further chemotherapy in a different site may experience an exacerbation of tissue damage in the original site. Radical mastectomy, axillary surgery or lymph node dissection may impair circulation in a particular limb. This reduces venous flow and may allow intravenous solutions to pool and leak around the site of cannulation. 45

Peripheral Vascular Disease 18, 22, 36, 45, 59

Atherosclerosis may cause a reduction in venous flow with risk of leakage at the intravenous site. Patients may also be debilitated with reduced tissue and venous tone.

Raynaud's Phenomenon 16, 18, 32

Arterial spasm may compromise peripheral circulation and reduce venous flow.

Diabetes 16, 18, 32, 36

Patients with peripheral neuropathy may not experience the pain of an infusate leaking into the subcutaneous tissues.

Superior Vena Cava Syndrome 36, 60

These patients have elevated venous pressure which may predispose to leakage at the intravenous site.

Repeated Intravenous Infusions and/or Injections 14, 26, 33, 36

These may thrombose vessels and limit the number of accessible veins. Substance abusers may be particular risk.
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Extravasation Risk Factors - The Site

Once the appropriate cannulation device has been selected, a site for cannulation has to be chosen. This must be a site where the cannula can be inserted easily and fastened securely, observed easily and one which will not come under stress if the patient or administrator moves. Taking these factors into account, the most appropriate site for location of a cannula is considered to be the forearm. However, it has to be accepted that this is not always going to be an available site for cannulation. The vessels in the dorsum of the hand are probably the next most appropriate location for cannulation. As a general rule joints and creases should be avoided as these often represent a 'small' anatomical space, with nerves and tendons (often with little 'covering') present. Extravasation is usually due to leakage around the original puncture site at which the cannula enters the vein.

Sites most often implicated in extravasation injuries include the dorsum of the hand and foot, 61, 62 ankle,62 antecubital fossa,62 and near joints 30 or joint spaces 60 where there is little soft tissue protection for underlying structures.64 Such sites as the antecubital fossa should be avoided. Limbs with local vascular problems such as lymphoedema may have reduced venous flow causing pooling and potential leakage of infusates around the site of cannulation. 30 61 Avoid sites of previous radiotherapy because of 'recall' phenomenon. 58 Peripheral rather than central venous administration of antineoplastic agents is more likely to be associated with frequent cannulation which is a risk factor for extravasation.. Phlebitis induced by the acidity of an infusate may lead to vasoconstriction and reduce flow around the infusion site. This may cause a rise in intraluminal pressure and result in leakage.
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Extravasation Risk Factors - Concurrent Medication

The following medications prescribed concurrently with an intravenous solution may increase the risk of extravasation.

Medicatio Risk n
May exacerbate extravasation or cause a Antifibrinolytics compartmental injury by increasing local bleeding

Vasodilators Hormone Therapy Steroids Diuretics May increase local blood flow and enlarge the area of injury Vasodilating properties Vasodilating properties May increase local blood flow

Antihistamine May constrict capillaries and arterioles, resulting s in ischaemic injury Analgesics Reduced pain sensation may cause less reporting of extravasations

IV antibiotics Repeated venous insult may thrombose vessels

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Extravasation Risk Factors - The Technique

The elimination of human error can be considered to be impossible. In excess of 100,000 doses of chemotherapy and over 1,000,000 IVs are in progress each day, inevitably leading to some degree of human error. However, risk associated with these factors should be minimised by the use of good training and educational policy, not only as stand-alone courses, but, importantly on a continuing educational basis. One of the greatest skills that individuals can bring to the administration of chemotherapy is the fact that it is routine for them. It is neither appropriate nor is it safe practice to administer

chemotherapy on a 'when required' basis. It is a blind process where no two administrations will be similar, it is thus as much an art as a science. More rigorous scientific thought can govern the selection of cannula; it inherently makes sense and has been demonstrated in a number of studies and through the National Extravasation Register, that rigid steel cannulas lead to more problems than flexible Teflon or Silicone cannulas. The selection of device or cannula is also influenced by the competing issues of biology and physics. Flexible cannulas are supplied in a variety of widths and lengths and the biology of veins means that the smaller and shorter the cannula the less the trauma associated with the cannulation process. However, the physics of short narrow pipes means that smaller diameter pipes increase the resistance and decrease the flow of the fluid through them. Or conversely, the pressure of delivery has to be increased. The insertion of a cannula necessitates the puncture of the vein wall. This wall is relatively fragile. If the pressure of the blood is greater than that of the fluid entering the vein via the cannula,there is a risk of back-flow into the cannula, or of rupture of the vein around the cannula edge, leading to leakage. Vein walls contain small holes and therefore the greater the pressure of the incoming fluid, the greater is the chance of wall rupture. There needs to be a series of professional judgements. For example, if the quantity of the necessary chemotherapy to be administered is a 2 mg / 2ml dose of vincristine, then probably a small paediatric cannula is appropriate. The science and technology of cannula have developed rapidly and there are now a number of high-tech developments, e.g. the Silicon/Teflon IV cannula, and the cannula materials that soften once exposed to the warmer internal body temperature of 37.

More extravasations occur at night and often go unnoticed 62 , however data from the National Extravasation Information Service green card reporting database shows that 44% of extravasations occur between the hours of 2pm and 10pm, 10% occur between 10pm and 6am and 38% occur between 6am and 2pm. 97 Multiple attempts at venipuncture after failing to cannulate a vein is associated with extravasations. 60, 61

Inexperienced personnel may have a higher risk, particularly with cytotoxic administration. Covering the site of an intravenous cannula with sterile drapes or occlusive dressings may hide an extravasation. Fluid forced by gravity during manual administrations or by infusion pump into a limited tissue space may cause compression and result in a compartmental injury. Infusion pumps with a high maximum flow pressure are more likely to produce injury through extravasation than volumetric cassette pumps which have a maximum flow pressure of <= 20lb/in. 60 Mechanical power injection of contrast media (median range of injection 2.5 mL/sec) as opposed to drip-infusion or hand-injection technique results in a higher frequency of extravasations. 18 Steel butterfly needles have been shown to cause extravasations twice as often as Teflon (TM) cannulas. 65

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Diagnosis Of Extravasation Injury

It is important when diagnosing extravasation that a misdiagnosis is not made. This is because the treatment is physiologically traumatic to the body and may involve the administration of drugs which, in their own right, could cause or potentiate extravasation. Early detection of extravasation is crucial. Common misdiagnoses are made because the observer is not differentiating discoloration reactions in the vein, venous shock, flare or phlebitis reactions of the vein wall and / or anaphylaxis. This is complicated further as some cytotoxics are highly coloured agents and if the vein in question is particularly superficial then a bright red solution injected into the vein may cause local discoloration. Furthermore, cytotoxics are often administered cool, at best at room temperature. They are then administered fairly rapidly into blood at a temperature of 37C. The greater the thermal gradient between the drug solution and the blood the greater the stress on the vein and often contraction and / or venus spasm is observed due to the thermal shock. It is also important to differentiate extravasation from other intravenous phenomena such as phlebitis and / or anaphylaxis. Phlebitis, (inflammation of the vein) often occurs despite correct administration due to the nature of some of the agents involved either because their formulation had an irritant component e.g. etoposide, or because the pH of the formulation is particularly acidic or alkaline e.g. doxorubicin and epirubicin. Here a transient, but well pronounced inflammation along the line of the vein will occur and this may track for some considerable distance. Anaphylaxis will have a central component of cardiovascular nature along with pulmonary complications, but often starts at the local site of injection. A less traumatic form of anaphylaxis is the hypersensitivity reaction. This was not well observed or recognised with the oncology drugs until the recent introduction of the taxains, both of these due to the nature of their formulation often cause local and / or central hypersensitivity. Once these alternative diagnoses have been considered, and excluded, the practitioner should go on to consider the diagnosis of extravasation.
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Symptoms Of Extravasation
Extravasation should be suspected when :

The patient complains of burning, stinging, pain or any acute change at the injection site. The patient is often the first person to become aware that something is wrong with their IV therapy, so instruct them at the beginning of treatment to inform staff of any acute change during treatment. Explain the reason for this in a way which is not frightening but conveys the need for the patient's input and participation. Give reassurance that, if a leakage of drug

should occur, it would probably not cause serious problems if the infusion is promptly stopped and the correct treatment instituted. Patients who are unable to communicate should be particularly closely observed.

Induration, erythema, venous discoloration or swelling is observed at the site (discoloration alone may not indicate extravasation as doxorubicin, epirubicin and mitozantrone have been reported to produce this). No blood return is obtained. A lack of blood return from the cannula is commonly quoted as a sign that extravasation has occurred. It is however, the most misleading of all signs and has been implicated in a number of serious incidences. This occurs because although there has been extravasation injury and the cannula has become displaced, the act of trying to draw blood back to test for blood return moves the cannula back into the vein. Thus blood is returned, however, there is a hole in the vein wall in the proximity of the cannula tip. So when administration recommences, a larger and more significant extravasation injury ensues. Alternatively, the bevel of the needle can puncture the vein wall during venepuncture, allowing drug to escape into the tissue whilst the lumen of the needle may still remain in the blood vessel and allow adequate blood return. The flow rate is reduced. A reduced rate may be observed when using an infusion pump, so close observation is necessary. Increased resistance to the administration, once possible changes in the position of the body e.g. bending of wrist or elbow, or cannula support e.g. the bandaging, have been excluded as possible causes of the increased resistance, then a displaced cannula and hence extravasation are the next most likely causes. This is often one of the first signs of a problem or of pre-extravasation syndrome.

The Extravasation Syndrome

1. Pre-extravasation syndrome. In general, this is either pre-extravasation syndrome or a type I or type II extravasation injury. The pre-extravasation syndrome (PES) often involves little or no leakage, but particularly severe phlebitis and / or local hypersensitivity together with a number of other local risk factors e.g. difficult cannulation, one (but not multiple) patient symptoms, and is probably the easiest to treat by withdrawing IV therapy immediately to prevent further deterioration to a fullblown type I or type II extravasation. It should however, be remembered that if patients have shown a susceptibility towards pre-extravasation syndrome, further administration should proceed with extreme caution and ideally in the contra-lateral limb to where the problem was diagnosed. 2. Type I extravasations. Type I extravasation injuries raise a bleb or blister and have a defined area of increased firmness around the injury site. Type I injuries are most commonly associated with rapid intravenous bolus-type

injections where the pressure applied by the person administering the drugs causes fluid to collect around the injury site. Type I injuries also occur when IV infusions are administered through over-pressurised pumps. 3. Type II extravasations. Type II extravasation injuries are those characterised by soft, diffuse 'soggy' tissue- type injuries, where obvious dispersal into the intracellular space has occurred. This type of injury is most commonly associated with the gravity-fed IV infusion, or a bolus injection given into the side-arm of a free-flowing IV infusion, which has become subtly or partially dislodged. The treatment of both of these types of injury is the same. However, the success at different points in the treatment pathway can be dramatically different.
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Prevention or Minimisation of the Problems of Extravasation

The position, size and age of the venepuncture site are the factors which have greatest bearing on the likelihood of problems occurring. However, if the following points are borne in mind, the likelihood of extravasation can be significantly reduced.

For slow infusion of high-risk drugs, a central line or drum catheter should be used To ensure patency of a peripheral IV site, it is best to administer cytotoxics through a recently-sited cannula. Site the cannula so it cannot become dislodged; use the forearm and avoid, if possible, sites near joints. Administer vesicants by slow IV push into the side-arm port of a fast-running IV infusion of compatible solution. The most vesicant drug should be administered first. Assess a peripheral site continually for signs of redness or swelling. Verify patency of the IV site prior to vesicant infusion and regularly throughout; if there are any doubts, stop and investigate. Resite the cannula if the patency of the cannulation is still not entirely satisfactory. Ask the patient to report any sensations of burning or pain in the infusion site. Some investigators suggest delaying the administration of antiemetics until after vesicant administration. The sedative and anti-inflammatory effects of antiemetics often mask the early warning signs of extravasation and may impede the patient's ability to report any sensation at the infusion site. Never hurry. Administer drugs slowly to allow the drug to be diluted by the carrier solution and to allow careful assessment of the IV site. Document carefully the rate of administration, location and condition of site, verification of patency, and patient's responses, on giving any potentially extravasable drugs.

If vein diameter or vein collapse are a problem, then the use of glyceryl trinitrate patches distal to the cannula may be helpful.

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The National Extravasation Information Service, 2000-2004.

Extravasation Flush-out Technique

In brief, the treatment can be carried out either under local or general anaesthetic. If the treatment is to be carried out under local anaesthetic this is infused into the subcutaneous space both beneath the zone of extravasation and around it. Then into this zone is directed dilute Hyaluronidase. One vial containing 1500 units is diluted down with 10cc of saline and injected throughout the zone. Once numbness of the area has been established, four small stab incisions around the zone of extravasation injury are made. It is essential to have an infusion cannula which has a sealed or blunt end and side holes to flush out this zone. Such cannulae are widely available for use in rapid infusion prior to liposuction. Through the subcutaneous space beneath the area of extravasation, normal saline is infused. It is planned that the saline go in through one of the stab incisions and exit through the others. At various times throughout the procedure, volumes of saline will collect in the subcutaneous space above and below the treatment zone and this fluid needs milking down to exit through the stab incisions. A thorough flush out of the extravasation space is required. Large volumes of saline, up to 500mls are usually flushed through in 20cc of 30cc aliquots using a syringe and a blunt ended cannula. After the flush out a layer of Jelonet and Betadine soaked gauze is applied to the wound and the limb wrapped in a padded bandage and elevated for twenty-four hours. The stab incisions are never sutured and are allowed to close spontaneously. This flush out technique is now established as the most effective way of removing extravasated material and it is well worth invoking the surgical maxim when in doubt get it out. In seriously debilitated patients, for example those with neutropenia, a short course of prophylactic antibiotics is recommended. Flush-out technique reproduced by kind permission of Mr David Gault Mr David Gault FRCS Consultant Plastic Surgeon The Portland Hospital London W1W 5AH
This page last updated 8th May 2006

The National Extravasation Information Service, 2000-2006.1

Extravasation Audit IV Monitoring

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Time Cannulated Size of Cannula Make of Cannula Person Cannulating Ease of Cannulation (on a scale of 1 to 10, where 1 is Very Easy and 10 is Extremely Difficult) State of the Veins (on a scale of 1 to 10, where 1 is Very Healthy and 10 is Collapsed) No of Attempts at Cannulation Cannula finally placed in Reason for Cannula Failure Patient's Age Site of Cannula (Please enter coordinates)

[Grade each criterion against the standard scales shown in the table below] Colour Feel Flow Sensation 0 hrs +4 hrs +8 hrs +12 hrs +16 hrs +20 hrs +24 hrs +28 hrs +32 hrs +36 hrs +40 hrs +44

hrs +48 hrs +52 hrs +56 hrs +60 hrs +64 hrs +68 hrs +72 hrs





No adverse sensation Can feel flow through cannula but no discomfort Discomfort, but not really painful Painful

1 2 3 4

No discolouration of Fat 'juicy' veins, no vein or surrounding Normal pain area Vein looks slightly red Slower than when Firm and fixed, no started, but not pain interrupted

Vein and surrounding Tender and irritable. tissue look red +/Especially painful Partial Flow inflamed on palpation Frank phlebitic Sclerotic and discolouration of vein No Flow fibrous, very painful and tissues L. Bressler November, 1997 Antineoplastic Drugs - General Principles Of Use


Antineoplastic drugs - general principles of use General kinetic considerations for Chemothearapeutic Agents Drug interaction with Chemotherapeutic Agents

INTRODUCTION The following discussion reviews several general considerations surrounding the use of antineoplastic drugs: myelosuppression, kinetics and therapeutic drug monitoring, and drug interactions. These topics are presented independently from one another and are intended to provide an introduction to various practical aspects of antineoplastic drug use. OBJECTIVES 1. Discuss the common patterns of myelosuppression and common patterns of timing of antineoplastic drug regimens. 2. List those antineoplastic drugs which are not myelosuppressive. 3. Discuss the current role of therapeutic drug monitoring in oncology patients. 4. Be able to recognize and prevent undesirable clinically significant drug interactions with antineoplastic drugs. REQUIRED READING NONE SUGGESTED READING

Balmer C, Valley AW. Basic principles of cancer treatment and cancer chemotherapy. In: DiPiro JT, Talbert RT, Yee GC, Matzke, GR, Wells BG, Posey LM, editors.

Pharmacotherapy: A Pathophysiologic Approach. Stamford: Appleton & Lange. 1997:2403-2465. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocytemacrophage colony-stimulating factor. N Engl J Med 1992;237:28-35, 99-106.


MYELOSUPPRESSION = depression of bone marrow elements

Myelosuppression occurs with many chemotherapeutic agents because cells in the bone marrow are continually proliferating. It is of importance for obvious reasons: suppression of white blood cells can lead to INFECTION; suppression of platelets can lead to BLEEDING; suppression of red blood cells can lead to ANEMIA. The severity of depression of the different cell lines and the rapidity with which that depression is seen are a function of the circulating life of the different cells. Thus, effects on granulocytes and platelets are more severe, and occur earlier than effects on red blood cells. PATTERNS OF MYELOSUPPRESSION: NADIR = low point. On the average, the nadir white blood cell count is reached about 10 days following a single dose of most alkylators, antimetabolites or antibiotic chemotherapeutic agents. Recovery of peripheral counts follows. This pattern becomes somewhat obscured when multiple doses or multiple drugs are given. Drugs are commonly given in cycles (eg. every 3 or 4 weeks), allowing time for recovery of normal cells like those of the bone marrow. PLURIPOTENT STEM CELLS in the bone marrow (earlier precursors) have a low rate of cell proliferation and are thus less likely to be affected by many drugs. But granulocyte precursors (later, committed, precursors), as well as platelet and red blood cell precursors, in the bone marrow are depleted by chemotherapy. More mature, nonproliferating (even later) precursors continue to differentiate into mature cells within the first several days after chemotherapy. When these cells live out their lifespan, the precursor supply is depleted and peripheral counts fall to a low point, the nadir. Counts then recover within three to four weeks, after feedback stimulates the stem cells in the marrow to increase proliferation. Chemotherapy given at the time pluripotent stem cells increase their proliferation could cause permanent bone marrow damage. Not infrequently, drugs are given on days 1 and 8 of a 28 day cycle. The second dose of chemotherapy, one week after the first, is tolerated because the pluripotent stem cells

have not yet increased their proliferation (ie. the second treatment is given BEFORE the peripheral count has reached its nadir) Some drugs (BUSULFAN, NITROSOUREAS, MITOMYCIN-C) can cause more DELAYED and PROLONGED myelosuppression. They appear to be less selective, and may damage the slowly proliferating stem cells. Commonly, the intervals between doses or courses of these drugs are longer than those discussed above. Some drugs are NONMYELOSUPPRESSIVE. These include BLEOMYCIN, VINCRISTINE, ASPARAGINASE, CISPLATIN and STEROIDS. Colony stimulating factors (granulocyte colony stimulating factor [GCSF] and granulocyte-macrophage colony stimulating factor [GMCSF]) are being used to prevent (and sometimes to treat) chemotherapy-induced granulocytopenia. The drugs are given parenterally, either subcutaneously or intravenously. The high cost of these factors would seem to support their use in specified circumstances (eg. patients who have had neutropenia and fever after previous cycles of the same chemotherapy, patients who have had chemotherapy delayed because of neutropenia, mobilization prior to and to facilitate marrow recovery after bone marrow/stem cell transplantation). Commercially available colony stimulating factors don't ameliorate thrombocytopenia, although megakaryocyte growth and development factor is under investigation. GENERAL KINETIC CONSIDERATIONS FOR CHEMOTHERAPEUTIC AGENTS In general, monitoring of drug concentrations does not currently accompany the clinical use of most chemotherapeutic agents. Historically, ASSAY DEVELOPMENT was a major LIMITING FACTOR. There is a PAUCITY of data documenting BLOOD LEVEL EFFICACY or BLOOD LEVEL - TOXICITY relationships, although research in this area is increasing. An EXCEPTION to this is METHOTREXATE. Methotrexate toxicity is clearly related to blood levels and duration for which that blood level is maintained. Methotrexate levels are usually obtained in conjunction with HIGH DOSE METHOTREXATE and LEUCOVORIN RESCUE. Post high dose methotrexate levels are used to adjust leucovorin doses (ie. prolong the duration and/or increase the dose). Occasionally, methotrexate levels are used to characterize methotrexate kinetics in individual patients, with subsequent adjustment in methotrexate doses. Several guidelines have been proposed for dosage adjustment of CARBOPLATIN. These guidelines take in to account RENAL FUNCTION, and PREVIOUS MYELOSUPPRESSIVE TREATMENT. They were derived using an endpoint of toxicity (thrombocytopenia). Increasingly, carboplatin is dosed using an endpoint of desired AUC (Dose = AUC[CrCl + 25]. To date, there is a better correlation between carboplatin AUC and toxicity than between AUC and therapeutic effect. AUC dosing is being studied for other cytotoxic drugs, although carboplatin is the drug most frequently dosed based on AUC in "routine" practice.

Achievement of "therapeutic" blood levels extrapolated from animal data is also being used increasingly as a goal in dosage escalation in Phase I studies of antineoplastic drugs. (ie. instead of escalating by a predetermined percentage) DRUG INTERACTIONS WITH CHEMOTHERAPEUTIC AGENTS Interactions with METHOTREXATE - Several cases of methotrexate toxicity, including some with fatal outcomes, have been attributed to drug interactions. Drugs reported have included: ASPIRIN, COTRIMOXAZOLE, PENICILLIN, NSAIDS (INDOMETHACIN, KETOPROFEN). Although several different mechanisms have been suggested, one mechanism that might be common to all of these drugs is inhibition of tubular secretion of methotrexate. This would result in prolonged excretion of methotrexate and enhanced toxicity. If a person on methotrexate is to receive a drug that potentially inhibits tubular secretion (eg. weak acids), or is reported to interact by another mechanism, the drug could be added 12-24 hours after methotrexate. (In some cases patients are started on both drugs concurrently. It is obviously difficult to estimate how much methotrexate toxicity might be due to a drug interaction when we haven't observed the degree of toxicity due to methotrexate alone. In such cases, patients should be monitored keeping in mind that adverse effects might be more severe than generally expected from a given dose of methotrexate.) Patients receiving methotrexate should be questioned about concurrent medications and adjustments made as necessary (eg. change aspirin to acetaminophen, if possible; delay a dose until 12-24 hours after methotrexate, if possible; etc.) A different interaction involving methotrexate and NITROUS OXIDE was reported to be responsible for severe toxicity observed during the first year of a perioperative adjuvant breast cancer trial. Nitrous oxide inhibits homocysteine methyltransferase which inhibits formation of one of the reduced folate precursors. In other words, nitrous oxide exerts an additive effect with methotrexate on folate metabolism. This interaction might be clinically significant in patients who are receiving methotrexate at the time they get nitrous oxide anesthesia. Interactions with PROCARBAZINE - Three types of interactions with procarbazine have been described. First procarbazine is a MONOAMINE OXIDASE (MAO) INHIBITOR. There is documentation in animals that procarbazine does indeed inhibit MAO. The clinical significance of procarbazine MAO inhibition in humans is not known. Reported reactions that have been attributed to MAO inhibition include an "intensely itchy skin eruption" and a "manic reaction". The classic MAO inhibitor interaction that we would be concerned about, of course, is hypertensive crisis precipitated by foods with high tyramine content. There are no reports of this reaction (where procarbazine is the MAO inhibitor). It is generally recommended to avoid those foods containing high amounts of tyramine, keeping in mind that this effect is poorly documented. Examples of such foods include some cheeses and some wines, fermented sausages, pickled herring, caviar and yeast

extracts. Note that baked goods do not contain very much tyramine and are unlikely to cause a problem. Second, procarbazine is reported to cause an ALCOHOL "flush" or "Antabuse-like" reaction. The documentation for this interaction comes from early reports of the use of procarbazine. Several patients were reported to have facial flushing when they drank alcohol. Most of these patients were taking continuous daily procarbazine. This is not how procarbazine is usually given today. From these reports, we can't tell how many patients didn't get a flush, or how many might have facial flushing from alcohol without procarbazine. At any rate, there doesn't appear to be evidence of a more severe "Antabuse reaction". Lastly, procarbazine can cause CNS DEPRESSION and this is said to be additive with other CNS depressants. Many patients receiving procarbazine receive other CNS depressants (eg. analgesics, antiemetics). Patients should be monitored for sedation. Use of the two drugs together is not contraindicated. Interactions with 6-MERCAPTOPURINE - The interaction of 6-mercaptopurine (6-MP) or azathioprine with ALLOPURINOL is probably the most well known of interactions with antineoplastic agents. 6-MP (or azathioprine) toxicity (thrombocytopenia, granulocytopenia) is enhanced and may be fatal. The dose of 6-MP or azathioprine should be decreased to one-third to one-fourth the normal amount when allopurinol is used concurrently. Several kinetic analyses have failed to document the interaction although there are multiple case reports of clinical toxicity presumably due to the combination. These analyses utilized IV 6-MP. More recently, the mechanism of the interaction has been further delineated and it has been shown to be important with oral, and not IV, 6-MP. (6-MP is generally given orally.) Allopurinol inhibits the first-pass metabolism of orally administered 6-MP: After oral 6-MP, the entire dose travels via the portal circulation to the liver where a large portion is metabolized by xanthine oxidase before reaching the systemic circulation. Thus, bioavailability is low. Allopurinol inhibits xanthine oxidase, thereby increasing the plasma concentration of 6-MP. (As IV 6-MP is rapidly distributed, only a fraction of it is metabolized initially by hepatic xanthine oxidase. Thus changes in xanthine oxidase won't be as important when 6-MP is administered by this route.) Interactions with PHENYTOIN - Several reports describe patients on phenytoin whose phenytoin concentrations dropped shortly after receiving various chemotherapeutic agents. Doses were increased in some cases, and within several weeks after chemotherapy, patients developed phenytoin toxicity. The mechanism of the initial decrease in phenytoin concentration is not clear (both a decrease in absorption and an increase in metabolism have been proposed). But the pattern is the same in many reported cases, providing support for the occurrence of a drug interaction. Patients on phenytoin should have blood concentrations measured 24-72 hours after receiving chemotherapy. If concentrations are low and dose increases are clinically indicated, follow-up levels should be obtained after chemotherapy to allow for downward adjustment and prevent toxicity.

Interactions with LEVAMISOLE - Levamisole is reported to interact with alcohol. The documentation for this interaction is scanty. In the large trial of 5-FU and levamisole for adjuvant therapy in Dukes Stage C colon cancer, adverse consequences from alcohol intake were not discussed.

Previous The College of Pharmacy The University of Illinois at Chicago


Syllabus Last modified: Dec 19, 1997 Extravasation Injuries L. Bressler November, 1997 OBJECTIVES 1. List those antineoplastic drugs that are vesicants. 2. Discuss the differentiation of extravasations from other venous reactions. 3. Recommend, in writing, treatment for extravasation of specific vesicant antineoplastic agents. REQUIRED READING NONE SUGGESTED READING 1. Larson DL: What is the appropriate management of tissue extravasation of antitumor agents?; Plastic and Reconstr Surg 75:397-402, 1985 2. Dorr RT: Discussion - What is the appropriate management of tissue extravasation of antitumor agents?; Plastic and Reconstr Surg 75:403-405, 1985


I. EXTRAVASATION = leakage of fluid outside of the vasculature into the perivascular and subcutaneous spaces; infiltration. Some substances, upon leakage into subcutaneous tissue, have the potential to cause severe tissue damage and even necrosis. These substances are known as VESICANTS. The following chemotherapeutic agents are vesicants:

actinomycin-D daunorubicin doxorubicin idarubicin mechlorethamine mitomycin-C paclitaxel streptozocin vinblastine vincristine vinorelbine

Some chemotherapeutic agents can cause pain or burning on administration, even though they may remain in the vasculature:

carmustine (BCNU) dacarbazine (DTIC)

Pain or burning can be minimized by infusing these drugs slowly, as dilute solutions (eg. 100-250ml over 30-60 minutes, as opposed to IV push injections) II. OTHER VENOUS REACTIONS A. MECHLORETHAMINE (nitrogen mustard) frequently causes phlebitis, irritating the vein independent of the possibility of extravasation. Some clinicians find that the use of hydrocortisone prior to or during (separated by saline flush) injection of mechlorethamine preserves the integrity of the vessel. This is a subjective finding. B.

5-FLUOROURACIL frequently causes darkening of the veins. This is referred to as "serpentine veins". It may be embarrassing for patients, although it is merely a discoloration. That is, the vein(s) can still be utilized for administration of chemotherapy, etc. This venous discoloration is particularly prominent in black patients. C. DOXORUBICIN (as well as DAUNORUBICIN) can cause redness and itching along the distribution of the vein through which it has been administered. This is known as a "flare". Usually the flare is self-limited. It disappears in several minutes to half an hour with or without treatment (antihistamines, steroids). The cause is not known, although it has been suggested that the incidence is less when the diluent for doxorubicin is normal saline instead of water for injection. Rarely, the flare has been associated with systemic allergic symptoms. Management involves making sure a systemic allergic reaction is not present, and making sure the reaction does not represent an extravasation. III. Several factors may influence the occurrence of or the severity of extravasation injuries. These factors include the location, size and fragility of the vessel, the age of the patient, site(s) of previous venipuncture, lymph node dissections, and the concentration of drug. These should be considered when selecting venous sites or ways to administer vesicant drugs. Practically speaking, however, one may have to use less than preferred sites in patients with poor or limited venous access. Fragile, low flow, or small diameter vessels, or previously irradiated sites may all have relatively decreased vascularity. Thus, extravasated fluid is more likely to remain concentrated in a given area. Use of vessels close to tendons or muscles can lead to greater functional loss in the event of extravasation of a vesicant agent. Administration of drug distal to the site of a recent venipuncture can lead to leakage of the drug as it passes the venipuncture site. The size of subsequent ulceration following extravasation of vesicant agents is related to the concentration and the total amount of drug that has extravasated. In an animal model, a critical concentration of doxorubicin was determined to be 0.01-0.02mg/ml. That is, when doxorubicin was diluted to this concentration, and volume of extravasated drug kept constant, the size of the subsequent ulcer was significantly decreased from that seen with more concentrated solutions. Note that pain is not necessarily present at the time of extravasation. Thus absence of pain does not rule out an extravasation. When extravasation cannot be comfortably ruled out, drug administration should be discontinued and restarted in another vessel.

PATTERNS OF INJURY - The onset of injury is earlier with vinca alkaloids and mechlorethamine, and later with anthracyclines (eg. doxorubicin). The vinca alkaloids tend to produce blistering, not necessarily necrosis. Mechlorethamine leads to ulceration which reaches its maximum severity faster than that seen with anthracyclines. Tissue damage from anthracyclines is progressive over weeks to months. A full thickness ulcer can be seen and damage can extend to underlying structures like muscles and tendons. IV. MANAGEMENT OF EXTRAVASATION A. The goal of treatment is to prevent severe tissue damage and preserve function. B. The majority of extravasations are suspected (eg. all of the sudden, blood return diminishes), when venous patency/blood return is checked frequently. C. Primary prevention (see above): choice of vessel technique IV push injections may be preferred when possible. Infusions may be more likely to be left unattended, allowing for leakage of a greater amount of fluid before the extravasation is detected.

D. Aspirate back fluid, to avoid extravasation of any more fluid remaining in the needle/catheter. Then remove the needle. E. Aspirate any bleb if possible. F. Administer antidote. G.

Follow up. Continued pain or ulceration after 1-2 weeks is an indication for surgery/skin grafting. (Plastic) surgery should be consulted at this point. H. ANTIDOTES 1. SODIUM THIOSULFATE 1/6M (4ml 10% sodium thiosulfate + 6ml water = 1/6M). Instill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g). Sodium thiosulfate is recommended as an antidote for extravasation of MECHLORETHAMINE. It provides a substrate for alkylation by mechlorethamine, preventing the alkylation and subsequent destruction in subcutaneous tissue. 2. HYALURONIDASE 150U (1ml). Instill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g). Hyaluronidase is recommended as an antidote for extravasation of VINCRISTINE, VINBLASTINE, and VINORELBINE. It breaks down hyaluronic acid ("cement") in connective/soft tissue, allowing for dispersion of the extravasated drug. 3. DIMETHYLSULFOXIDE (DMSO) 50-70% solution 1.5ml. Apply topically (ie. "paint" on the skin) QID x 14 days. Leave uncovered. DMSO has been recommended as an antidote for extravasation of DOXORUBICIN and DAUNORUBICIN as well as MITOMYCIN. There is conflicting data in animals regarding its effectiveness. Some reports of prevention/decreased ulcer formation were obtained when DMSO was used in conjunction with Vitamin E. There is one series of patients reported in whom topical application of 99% DMSO was thought to have prevented ulceration. Little other information is presented (eg. amount of drug extravasated, whether or not cold was used). Note that the only commercially available concentration of DMSO is 50%. DMSO may work by virtue of its free radical scavenging property. 4. COLD - Apply cold packs for 20 minutes QID x 3 days. Cold is recommended as an antidote for extravasation of DOXORUBICIN and DAUNORUBICIN. Initially, cold was suggested as a general measure for extravasation of a variety of drugs. The rationale for cold was vasoconstriction, thereby "containing" the drug at the site of extravasation and minimizing the size of the subsequent ulceration. Studies in animal models, however, have shown that the concentration of doxorubicin at the site of extravasation was not different from that at a distal site following the application of cold. But ulceration was still not seen. Thus it appears that cold prevents ulceration from doxorubicin or daunorubicin by a mechanism other than vasoconstriction and "containing" the drug. This mechanism has been suggested to be decreased cellular uptake of drug at lower temperatures - the same rationale as that for the use of scalp cooling to prevent alopecia.

5. HEAT - Apply heat packs for 20 minutes QID x 3 days. Heat is recommended, in conjunction with hyaluronidase, as an antidote for extravasation of VINCRISTINE and VINBLASTINE. Initially, heat was suggested as a general measure for extravasation of a variety of drugs. The rationale for heat was vasodilation, thereby "diluting" the drug and minimizing the size of the subsequent ulcer. It seems unlikely that heat can result in a change in concentration of the magnitude noted above to decrease ulcer size. Yet, in the mouse model heat did decrease ulceration due to extravasation of vinca alkaloids, and not that due to anthracyclines. 6. SUMMARY - Although several drugs have been well studied in animals (eg. doxorubicin), there is less data available on the management of extravasation of some of the other agents. The following represents my recommendations for acute treatment of extravasation of vesicant antineoplastic agents: doxorubicin, daunorubicin, idarubicin, mitomycin, actinomycin - cold " DMSO vincristine, vinblastine, vinorelbine - hyaluronidase and heat mechlorethamine - sodium thiosulfate streptozocin - cold

paclitaxel - recent reports indicate that paclitaxel is a vesicant, although there are also reports of extravasation without resulting necrosis; there is as yet no universally recommended treatment for paclitaxel extravasation; my recommendation would be to treat it like extravasation of the vinca alkaloids

Previous The College of Pharmacy The University of Illinois at Chicago


Syllabus Last modified: Dec 19, 1997

Occupational Exposure Risks L. Bressler November, 1997


Occupational Exposure Risks


Effects on Pregnancy Outcomes Selected Recommendations

OBJECTIVES 1. Describe the risks, potential or actual, related to occupational exposure to cytotoxic drugs. 2. Discuss the outcomes that have been reported in the literature and know the difference between potential and actual risks. 3. Develop a written plan for minimizing occupational exposure to cytotoxic drugs. Explain the rationale for each step included in such a plan. REQUIRED READING 1. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs; Am J Hosp Pharm 47:1033-1049, 1990 SUGGESTED READING OCCUPATIONAL EXPOSURE RISKS Three "negative outcomes" or risks of occupational exposure to cytotoxic drugs might be: MUTAGENICITY, CARCINOGENICITY and ADVERSE OUTCOMES OF PREGNANCY. MUTAGENICITY - causing an alteration in one or more genes (ie. a change in DNA) DNA repair is an ongoing process. For our purposes, the importance of mutagenic properties of cytotoxic drugs lies in the fact that many carcinogens are mutagens. Mutagenicity is easier to study than carcinogenicity. CARCINOGENICITY - causing cancer In ANIMALS, some cytotoxic drugs are carcinogenic. Clinically, cytotoxic drugs have been implicated as carcinogens in PATIENTS RECEIVING THERAPEUTIC DOSES OF THESE DRUGS. Most commonly, ALKYLATING AGENTS (eg. chlorambucil, nitrogen mustard, melphalan) have been reported to cause SECONDARY LEUKEMIAS. More equivocal is a relationship between antibiotics and carcinogenicity, and the antimetabolites are thought to be the "safest" with regard to carcinogenicity. There are no conclusive reports of cancers developing in health personnel as a result of occupational exposure to cytotoxic drugs. NONE

Obviously, occupational exposure is much, much less than therapeutic exposure. ROUTES of occupational exposure are via INHALATION of aerosolized particles and TRANSCUTANEOUS absorption. Various manipulations in the preparation and administration of cytotoxic drugs could lead to exposure by these routes. Aerosolization might occur when one breaks open an ampul, withdraws solution form a vial, or injects liquid into a powder. Transcutaneous absorption could occur following spills on the skin. Drug "contamination" in the environment around areas of preparation has been documented (ie. aerosolization has been measured). Anecdotal reports of adverse effects (eg. dizziness) in health professionals working with cytotoxic drugs prompted much attention to this issue in recent years. More controlled studies (albeit with limitations related to urine mutagenicity studies) demonstrated exposure to drugs in health professionals, and demonstrated the protective effect of vertical-flow biological-safety cabinets. What is not known is the "safe level" of occupational exposure. Is exposure cumulative??? Is there a level of exposure above which irreversible damage might occur??? Several methods have been used for detecting low levels of exposure to potentially carcinogenic substances: 1. AMES TEST FOR MUTAGENICITY: Utilizes a strain of Salmonella bacteria sensitive to mutagenic changes. The bacteria require histidine to grow. In the test system, urine from the subject "exposed" is incubated with the bacteria. Bacterial growth in a histidinefree medium indicates that the Salmonella has mutated, thus there are "mutagenic substances" in the urine. Both positive and negative results have been reported using urinary mutagenicity tests. Some of the discrepancy may be that, in fact, negative results represent prevention/minimizing exposure. Timing might also be a factor. The mutagenic substance must be excreted into the urine and this might occur at various times following exposure, depending on the particular drug. Cigarette smoke, other noncytotoxic drugs, or some dietary factors may also be responsible for mutagenic activity in the urine, resulting in false positive urine mutagenicity tests. 2. Analytical methods (eg. HPLC) for determination of CYTOTOXIC DRUG (or metabolite) CONCENTRATION in BLOOD or URINE. These methods have been developed primarily for use in patients receiving therapeutic doses of cytotoxic drugs. They may lack the sensitivity to detect the low levels assumed to be associated with occupational exposure. 3. CYTOGENETIC EFFECTS - analysis of CHROMOSOMAL DAMAGE (eg. structural chromosome aberrations [CA], sister chromatid exchanges [SCE]) in peripheral blood lymphocytes.

Both positive and negative results have been reported. The persistence of the cytogenetic effect also depends on the type of damage (ie. SCE are short-lived while CA persist for years). In addition, there may be a wide distribution of SCE in normal individuals (ie. SCE without exposure to cytotoxic drugs). 4. Measurement of NUCLEIC ACID ADDUCTS - ie. determination of drug/DNA complex in the urine, has been suggested as a means of monitoring occupational exposure. At present this technique is not perfected to the point of being useful in the workplace. None of these methods for detecting low levels of exposure are routinely utilized in the workplace. There is no standard "test" for detecting exposure or monitoring for potential adverse consequences that can be recommended at the present time. EFFECTS ON PREGNANCY OUTCOMES Several papers have addressed the incidence of SPONTANEOUS ABORTIONS and MALFORMATIONS in the offspring of health professionals with occupational exposure to cytotoxic drugs. The conclusions have met with some questions and concerns. A study in Finland examined outcomes in nurses exposed to anesthetic gases, sterilizing gases and soaps, x-rays and cytotoxic drugs. Data on exposure were obtained retrospectively by means of questionnaires sent to head nurses. Cytotoxic exposure in the first trimester was reported to be associated with malformations in offspring. The same investigators, in a subsequent study, reported an increased risk of spontaneous abortions (not malformations) in nurses exposed to cytotoxic drugs. Again, data were obtained retrospectively by questionnaire. One wonders about the ability to recall how many does per week were prepared several years prior. Spontaneous abortions occurred in women who also had (other) risk factors for spontaneous abortion. In both studies, nurses were responsible for preparing, as well as administering, cytotoxic drugs. Both studies covered a period in time before attempts at minimizing exposure were recommended in the literature. QUANTITATIVE ASSESSMENT OF RISK - We cannot quantitate the risk of exposure at this time. Much of the risk appears to be POTENTIAL (based on known effects of therapeutic doses in patients, or animal data), NOT ACTUAL. However, because of the seriousness of the potential risk, it makes sense to minimize occupational exposure to cytotoxic drugs as much as possible. SELECT RECOMMENDATIONS A VERTICAL FLOW BIOLOGICAL SAFETY CABINET (as opposed to horizontal laminar flow) should be used for preparation of cytotoxic drugs. This offers protection of the product AND the operator. Most commonly used is a Class II biological safety

cabinet, in which 30% of the air is filtered and recirculated (or alternatively, vented to the outside). When no vertical flow hood is available, it has been recommended that a quiet work space, away from heating and cooling vents and other personnel be used. (ie. not a horizontal flow hood) GLOVES - SURGICAL LATEX GLOVES appear to offer the best protection. In general, the shorter the contact time (with drug) and the thicker the glove, the less penetration through the glove. Gloves should be changed after 30 minutes of continuous wearing (or sooner if a spill occurs). GOWNS - closed front and cuffs TECHNIQUES Usual ASEPTIC TECHNIQUE NEGATIVE PRESSURE to withdraw solutions from vials (ie. inject less air than the volume to remove.) This will minimize aerosolization. Alternatively, several devices that absorb or prevent aerosolization have been marketed for use in the preparation of cytotoxic drugs. For related issues (eg. pregnancy), the policies and procedures at specific institutions, as well as current laws, should be reviewed

Neurotoxicity From Chemotherapy L. Bressler November, 1997OBJECTIVES 1. Describe, briefly, the manifestations of neurotoxicity seen with several antineoplastic drugs. 2. Discuss the implications (or lack thereof) for treatment of chemotherapy-induced neurotoxicity. REQUIRED READING NONE

SUGGESTED READING 1. Weiss HD et al: Neurotoxicity of commonly used antineoplastic agents; N Engl J Med 291:75-81 (1974) and 291:127-133 (1974) 2. Kaplan RS, Wiernik PH: Neurotoxicity of antineoplastic drugs; Sem Onc 9:103-130 (1982) NEUROTOXICITY FROM CHEMOTHERAPY Several antineoplastic drugs can cause distinct neurologic side effects. Often there is no drug treatment for these toxicities. The decision to discontinue treatment because of toxicity may be subjective: How severe are the symptoms? How bothersome are they to the patient? Is the patient responding to therapy? With this introduction, then, the discussion that follows serves to familiarize the reader with the neurotoxic side effects seen with different drugs. The reader should be able to answer questions regarding the likelihood of occurrence of specific effects with specific drugs.

5-FLUOROURACIL (5-FU) 5-FU has been reported to cause neurotoxicity in about 1% of patients receiving the drug. 5-FU causes CEREBELLAR toxicity, and patients present with ATAXIA of the trunk or extremities, DYSMETRIA, coarse NYSTAGMUS and, subjectively, DIZZINESS. Although cerebellar toxicity has been observed in association with a variety of doses and schedules of 5-FU, there appears to be a higher incidence with higher weekly doses (ie. greater than 15mg/kg/week) or more intense daily doses. The syndrome is reversible within one to six weeks after stopping therapy -in some cases doses have been reduced, in some cases intervals between treatments have been prolonged, or in some cases, treatment schedules haven't been altered at all. Symptoms do not necessarily recur with subsequent doses. It has been suggested that 5-FU cerebellar toxicity is due to accumulation of FLUOROCITRATE, a neurotoxic metabolite, in the CNS. However, it has also been noted that the combination of thymidine and 5-FU may cause more neurotoxicity than 5FU alone - and thymidine blocks catabolism of 5-FU, decreasing the amount of fluorocitrate produced. CYTARABINE (Ara-C) Ara-C causes central nervous system toxicity when it is administered in high doses (eg. 3gm/m2, in contrast to "standard" doses of about 100mg/m2). Toxicity is primarily CEREBELLAR, manifest as NYSTAGMUS, truncal ATAXIA, DYSMETRIA, DYSARTHRIA, DYSDIADOCHOKINESIA. Occasionally, CEREBRAL manifestations are seen: headache, somnolence, seizures, altered personality, difficulty with

calculations. Cerebral toxicity is rare without cerebellar toxicity. Symptoms begin within three to eight days of beginning treatment, and usually last for three to ten days. Occasionally, symptoms persist for longer than a month. This persistence seems to be more likely in patients older than 50 years. VINCA ALKALOIDS - VINCRISTINE (VCR) and VINBLASTINE (VLB) Although both drugs are neurotoxic, neurotoxicity is the dose-limiting toxicity for VCR. Myelosuppression is dose-limiting for VLB. Thus VCR is quantitatively more neurotoxic and the clinical manifestations described below are seen primarily with VCR. The earliest and most common manifestation of VCR neuropathy is decreased Achilles tendon reflex. This occurs in about 100% of patients, frequently after only one or two does. The earliest symptoms noted by the patient are usually paresthesias like NUMBNESS and TINGLING in hands or feet. Both loss of deep tendon reflexes and sensory symptoms are slowly reversible upon discontinuation of the drug. With continued dosing, motor involvement is seen: AREFLEXIA, MOTOR WEAKNESS, and gait disorders such as FOOT DROP. Motor neuropathy may be PAINFUL. Another common manifestation of VCR neurotoxicity, seen in about 50% of patients, is CONSTIPATION. It can occur within a few days of a dose and may cause abdominal pain. VCR can cause fecal impaction high in the colon. Patients on VCR often require laxatives. Occasionally patients may experience severe JAW PAIN after the first or second dose of VCR. This represents neuropathy involving the trigeminal nerve. It disappears over a few days but may require analgesics. The jaw pain doesn't usually recur with subsequent doses. HOARSENESS, due to vocal cord paralysis, may be another manifestation of VCR neuropathy. ORTHOSTATIC HYPOTENSION due to autonomic dysfunction may also be seen. PACLITAXEL Paclitaxel is a common cause of peripheral neuropathy. In addition, myalgias/arthralgias are often seen following infusions. Opioids, adjuvant analgesics, and nonsedating antihistamines have all been suggested to treat these reversible myalgias/arthralgias. PROCARBAZINE A common form of neurological disturbance reported with procarbazine was alteration in the level of consciousness. Alteration may range from mild drowsiness to somnolence and confusion to profound stupor. Rarely, hallucinations or manic psychosis have been reported. Paresthesias of the extremities and painful myopathies have also been reported. It seems that much of the neurotoxicity reported with procarbazine was seen with continuous daily dosing, not a common schedule today. CNS depression is also said to be additive with other CNS depressants. However, since many CNS depressants might be used in patients receiving procarbazine (eg. antiemetics, analgesics), it should be noted that this doesn't represent a contraindication. Again,

CNS toxicity is not usually of much clinical importance with the current use of procarbazine. CISPLATIN As nephrotoxicity from cisplatin became more easily preventable, attention focused on neurotoxicity, seen especially after high cumulative doses. Cisplatin causes a somewhat dose-related SENSORY NEUROPATHY. Early signs (300-400mg/m2 cumulative dose) include DECREASED VIBRATORY SENSATION and DECREASED DEEP TENDON REFLEX in the ankle. With continued therapy, findings progress proximally and PARESTHESIAS may develop. Neuropathy may be DISABLING and recovery may be very slow. AMIFOSTINE may minimize cisplatin-induced neurotoxicity. It is important to consider functional and subjective improvement, as well as objective improvement, in evaluating such protectants. L-ASPARAGINASE L-asparaginase-induced neurotoxicity manifests as CEREBRAL DYSFUNCTION with disturbances in the degree (LETHARGY, SOMNOLENCE, STUPOR, COMA) or quality (CONFUSION, DEPRESSION, HALLUCINATIONS, PERSONALITY CHANGES) of consciousness. The incidence appears to be about 25-50% in adults. It usually occurs within about a day of drug administration and improves within a few days after treatment. It is not clearly dose-related. Neurotoxicity is thought to be due to metabolic abnormalities induced by l-asparaginase (eg. increased levels of aspartic and glutamic acids and ammonia, and decreased levels of asparagine and glutamine). IFOSFAMIDE Ifosfamide, unlike the related compound cyclophosphamide, has been reported to cause neurotoxicity in up to 30% of patients. Manifestations include ALTERATIONS IN CONSCIOUSNESS, ATAXIA, MYOCLONUS, SEIZURES, and COMA. Fatal neurotoxicity has been reported. Several factors have been suggested as increasing the risk of development of neurotoxicity, including low albumin, elevated creatinine, and pelvic disease. These are not universally accepted as risk factors, however. It has been suggested that toxicity is due to high serum chloroacetaldehyde, via either increased production or decreased elimination. Discontinuation of the drug when signs and symptoms are mild seems more likely to lead to reversibility than continued exposure to drug. Several other ALKYLATING AGENTS have been implicated as causes of neurotoxicity. Toxicity has been reported with high doses (eg. in preparation for bone marrow transplant, overdose) of MECHLORETHAMINE or CHLORAMBUCIL. Lastly, several neurotoxic syndromes have been reported after the use of INTRATHECAL METHOTREXATE. They may be related, at least in part, to prolonged high CSF levels.

MENINGEAL IRRITATION or ARACHNOIDITIS has been reported to occur in up to 61% of patients. Symptoms (stiff neck, headache, nausea, vomiting, fever, CSF pleocytosis) occur 2-4 hours after intrathecal injection and last for 12-72 hours. PARAPLEGIA due to intrathecal methotrexate may be transient or permanent. Intrathecal CYTARABINE has also been implicated. This is not a common form of toxicity. Onset has been reported to be from minutes to hours after intrathecal injection. Improvement has been noted from 48 hours to 5 months, and in some cases, not at all. Finally, CHRONIC ENCEPHALOPATHIC SYNDROMES have developed in patients receiving intrathecal methotrexate. Intrathecal CYTARABINE and THIOTEPA and cranial IRRADIATION as well as systemic methotrexate have all been implicated.

The Pulmonary Toxicity of Antineoplastic Agents Terry L. Stonich, Pharm.D. (with modifications by L. Bressler) Spring , 1998

Introduction Mechanisms of pulmonary injury Risk factors Clinical Syndromes Diagnosis Example Other Antineoplastic agents Conclusion

OBJECTIVES 1. List five proposed mechanisms of pulmonary injury induced by antineoplastic agents. 2. List five risk factors for development of antineoplastic induced pulmonary toxicity. 3. Discuss three clinical syndromes of pulmonary toxicity identified with the antineoplastic agents. 4. Discuss the incidence, risk factors, treatment and outcome of bleomycin induced pulmonary toxicity.

5. List the major categories of antineoplastic agents reported to cause pulmonary injury. REQUIRED READING NONE SUGGESTED READING 1. Cooper J et al: Drug induced pulmonary disease - Part I: Cytotoxic drugs; Am Rev Resp Dis 133:321-340 (1986) 2. DeVita V et al (eds): Cancer - Principles and Practice of Oncology, 3rd Edition, 21622219 (1989) 3. Ginsbery S et al: The pulmonary toxicity of antineoplastic agents; Sem Oncol 9(1):3451 (1982) 4. Batist G, Andrews J: Pulmonary toxicity of antineoplastic drugs; J Am Med Assoc 246(13):1449-1453 (1981) I. INTRODUCTION Although antineoplastic agents play an invaluable role in the treatment of malignancies, there are toxicities inherent to their use. A serious and sometimes dose limiting toxicity is pulmonary injury. II. MECHANISMS OF PULMONARY INJURY Pulmonary toxicity secondary to antineoplastic drugs may be due to a variety of mechanisms. There are five major postulates to explain the development of this toxicity. Generally it is thought that antineoplastics induce pulmonary injury by disturbing homeostatic mechanisms (ie. causing an imbalance between inflammatory reactions that may cause pulmonary damage and protective detoxification reactions) for the following systems: A. Oxidant/Antioxidant System Oxidant molecules (eg. O2, H2O2, OH, HOCl) that are formed within phagocytic cells such as monocytes, macrophages and neutrophils may participate in redox reactions resulting in fatty acid oxidation that can lead to membrane instability and perhaps autologous cytotoxicity. Similarly, it is thought that these oxidant species may initiate damaging inflammatory reactions. Normally, antioxidant defense mechanisms (superoxide dismutase, glutathione peroxidase, alpha tocopherol) provide the necessary balance to offset the oxidant effects. When antineoplastic drugs are administered, there may be a disturbance of this homeostasis resulting in pulmonary injury.

B. Immunologic System Even in the "healthy" state, pulmonary host cells can exaggerate toxic reactions caused by exposure to substances that initiate or activate the immunologic system. Pulmonary cells release mediators that activate and attract inflammatory cell types like eosinophils, monocytes, neutrophils, etc. To counterbalance the amplified effects of the immunologic system that may result in pulmonary tissue damage, other tolerant cells (eg. lymphocytes, alveolar macrophages) exist. It is postulated that when cytotoxic drugs are administered, there is a disturbance of this usual homeostasis of toxic reaction and tolerant suppressor cells, resulting in pulmonary injury. C. Matrix Repair System Normally, proliferation of fibroblasts leading to collagen deposition is helpful in repairing or limiting cell injury. However, excessive deposition of collagen can result in structure impairment. It has been postulated that when antineoplastic drugs are administered, the homeostatic control of fibroblast proliferation and collagen deposition is disrupted. D. Proteolytic System Neutrophils, macrophages, and other inflammatory cells produce a number of proteolytic enzymes that are associated with a myriad of pulmonary disturbances. Proteolytic enzymes are normally controlled or inactivated by protease inhibitors that are mediated by oxidant molecules. It is thought that although antineoplastic drug parent molecules do not affect this homeostasis, their oxidant radicals may inactivate protease inhibitors, thereby allowing proteolytic enzymes to function unopposed. E. Central Nervous System The CNS is thought to provide some control over pulmonary capillary permeability. It has been postulated that cytotoxic drugs may affect the hypothalamus and medulla in such a way that permeability is increased. III. RISK FACTORS FOR DEVELOPMENT OF PULMONARY TOXICITY As has been discussed, antineoplastic drugs do induce pulmonary toxicity. However, it should be realized that not all patients receiving these agents experience this toxicity. To identify those patients at risk, five major predisposing factors for development of pulmonary toxicity should be noted. A. Cumulative Dose Cytotoxic agents that are directly toxic to the lungs generally exhibit increasing toxicity with increasing dose. This is believed to be a result of drug accumulation in the lung itself. Two patterns of dose related pulmonary toxicity are usually clinically observed:

1. A threshold effect wherein there is a marked increase beyond a specific amount of drug received. For example, when total lifetime dose of bleomycin exceeds 450-500 units, there is a definite increase in risk for development of pulmonary toxicity. Pulmonary toxicity secondary to busulfan, in the absence of other predisposing factors, has only been noted with total doses >500mg. 2. A linear effect wherein there is a constantly increasing risk for the development of pulmonary toxicity as more drug is administered (eg. carmustine). B. Age A normal physiologic phenomenon that has been observed with aging is a decrease in the effectiveness of the antioxidant defense system. Therefore, as a patient ages, he/she would be expected to be more susceptible to pulmonary toxicity from certain cytotoxic drugs. To date, however, age has been shown to be a risk factor only for the development of bleomycin-induced pulmonary disease. C. Radiation Radiation therapy results in the production of oxidant species that lead to pulmonary damage. When antineoplastic agents (eg. bleomycin, mitomycin, busulfan) that also affect the oxidant/antioxidant homeostasis are administered, there may be synergistic toxicity. D. Oxygen Therapy Reactive oxidant metabolites (eg. O2, H2O2, OH) are produced when high concentrations of oxygen are administered. Synergistic toxicity may also be possible between high concentrations of O2 and drugs that can disrupt the normal oxidant/antioxidant homeostasis. This appears to be the case with bleomycin, cyclophosphamide and mitomycin. E. Multidrug Regimens Although not clearly defined, the incidence and severity of pulmonary toxicity may increase with multidrug regimens. Typically, these chemotherapy regimens include bleomycin, mitomycin, cyclophos- phamide, methotrexate, or carmustine. It has not been determined whether any single drug is the causative agent or if the interaction of these antineoplastics results in enhanced toxicity. IV. CLINICAL SYNDROMES IDENTIFIED Pulmonary toxicity induced by antineoplastic agents is manifested in three typical clinical patterns. Although they will be described individually, there may be certain patients that present with symptoms from more than one pattern. A. Chronic Pneumonitis/Fibrosis

This presentation is observed most frequently and has been reported with virtually all antineoplastic drugs associated with pulmonary toxicity. However, it should be noted that it is not usually associated with antimetabolites. With this manifestation of pulmonary damage, the patient experiences slow, progressive (ie. weeks to months) dyspnea on exertion, a nonproductive cough and fatigue. Based on clinical utility and assessment of severity, the antineoplastic drug may be discontinued in an attempt to manage this toxicity. Steroids have been administered to enhance resolution of this syndrome, but documentation of their efficacy is anecdotal. B. Hypersensitivity Reactions These reactions are commonly associated with bleomycin, methotrexate, and procarbazine, and are manifested as an acute syndrome (ie. hours to days) consisting of dyspnea, fever, and nonproductive cough. Peripheral and/or pulmonary eosinophilia with pulmonary infiltrates can be observed. Usual treatment of these hypersensitivity reactions includes drug discontinuation and steroid administration, resulting in a good prognosis for the affected patient. C. Noncardiogenic Pulmonary Edema This pattern of pulmonary toxicity is a very rare and acute complication associated with the use of cytarabine, methotrexate, and cyclophosphamide. Prognosis in these instances is variable. V. DIAGNOSIS The definitive diagnosis of cytotoxic drug induced pulmonary toxicity is difficult since a detailed history of drug administration in the absence of other situations that may lead to pulmonary damage is required. However, the following have been reported: A. Chest X-ray changes consistent with progressive pulmonary fibrosis; however, a patient may have a normal X-ray even when histologically demonstrated pulmonary damage is present. B. Pulmonary histopathologic features including endothelial cell damage, fibroblast proliferation, and epithelial abnormalities C. Arterial blood gases revealing hypoxia with hypocapnia D. Pulmonary function abnormalities: typically a restrictive process is seen, with a reduced diffusion capacity for carbon monoxide, decreased total lung capacity, and other ventilatory defects. VI. EXAMPLE - BLEOMYCIN The model for antineoplastic-induced pulmonary damage, both interstitial pneumonitis/pulmonary fibrosis and hypersensitivity, is bleomycin, which will be used for illustrative purposes.

A. Incidence Literature reports of the incidence of bleomycin pulmonary toxicity vary from 2-40% of all patients receiving the drug. It is thought that these differences in occurrence may be due to differences in risk factors in the populations studied. It has been suggested that a realistic estimate of patients affected is near 10% of those receiving bleomycin. Of this population, 10% will die due to pulmonary toxicity, resulting in an overall fatality of 1% of patients treated. B. Risk Factors 1. Age - older patients (ie. >70) are more sensitive to bleomycin-induced pulmonary toxicity. However, younger patients, especially those receiving high cumulative doses, are still at risk. 2. Cumulative Dose - at approximately 450-500 total units, the incidence of pulmonary toxicity sharply increases. It should be noted, however, that caution should be exercised in all patients at even lower cumulative doses since contributing risk factors may be present. 3. Radiotherapy - lowest effective doses of radiotherapy should be administered since there is a synergistic phenomenon that occurs. It should be noted that this synergism is seen regardless of sequence of therapy administration (ie. radiation followed by bleomycin or bleomycin followed by radiation). 4. Oxygen Therapy - only clinically necessary oxygen supplementation should be provided to patients who have received bleomycin since this contributes to the development of pulmonary fibrosis. 5. Multidrug Regimens - close monitoring is warranted when bleomycin is administered as part of a multidrug regimen, especially those containing cyclophosphamide. 6. Route of Administration - although further documentation is required, it is thought that continuous infusion of bleomycin may decrease the incidence of pulmonary toxicity. 7. Organ Failure - Delayed excretion of bleomycin is seen in patients with renal failure. This has been reported to lead to an increased sensitivity to pulmonary toxicity. This relationship is inconclusive. C. Treatment No single or specific treatment is accepted as a standard in managing bleomycininduced pulmonary toxicity. For those patients experiencing chronic pneumonitis/fibrosis, discontinuation of the drug should be considered when a rapid decline in pulmonary function (especially CO diffusion capacity) is observed. For those patients experiencing hypersensitivity reactions, bleomycin discontinuation with steroid

therapy is usually recommended. VII. OTHER ANTINEOPLASTIC AGENTS REPORTED TO INDUCE PULMONARY DAMAGE Several other antineoplastic drugs or drug classes have been reported in the literature to induce pulmonary damage. These include: MITOMYCIN, NITROSOUREAS (BCNU, CCNU), ALKYLATING AGENTS (BUSULFAN, CYCLOPHOSPHAMIDE, CHLORAMBUCIL, MELPHALAN), ANTIMETABOLITES (METHOTREXATE, AZATHIOPRINE, 6-MERCAPTOPURINE, CYTARABINE), VINCA ALKALOIDS, PROCARBAZINE, and FLUDARABINE. VIII. CONCLUSION The pulmonary toxicities associated with chemotherapy administration can pose significant problems in the management of cancer patients. Methods to prevent pulmonary toxicity and standard, effective management of the toxicity once it occurs must still be developed.

GU and Electrolyte Toxicities L. Bressler November, 1997 I. TUMOR LYSIS SYNDROME Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. It is due to the rapid release of the intracellular contents of tumor cells. Tumor lysis syndrome is seen with large tumor burdens with high growth fractions that are very sensitive to chemotherapy. Examples include high-grade lymphomas and leukemias with high leukocyte

counts. Tumor lysis syndrome is seen less often with solid tumors. It can be treated/prevented with HYDRATION, ALLOPURINOL 300-900 mg/day, and URINARY ALKALINIZATION to pH > 7. (This can be achieved with 50-lOO mEq sodium bicarbonate per liter of fluid, with subsequent adjustment based on urine pH.) Dialysis may be required. A. HYPERURICEMIA results from the action of xanthine oxidase on hypoxanthine and xanthine. It can lead to URATE NEPHROPATHY with resultant renal failure. B. HYPERKALEMIA associated with tumor lysis syndrome can lead to ARRHYTHMIAS. It can be treated with KAYEXALATE. C. HYPERPHOSPHATEMIA can also lead to renal failure. D. HYPOCALCEMIA results from hyperphosphatemia. It can lead to MUSCLE CRAMPS, ARRHYTHMIAS, or TETANY. Hypocalcemia may be treated with CALCIUM GLUCONATE. II. STERILE HEMORRHAGIC CYSTITIS It is seen with cyclophosphamide and ifosfamide. It is thought to be due to an alkylating metabolite, acrolein. Hemorrhagic cystitis has been seen after single high doses or prolonged low doses. Patients may be asymptomatic or they may present with symptoms of cystitis (eg. burning, frequency). Hematuria may be microscopic (detectable only on urinalysis) or gross . The potential danger accompanying hemorrhagic cystitis is BLOOD LOSS. HYDRATION is commonly employed to prevent hemorrhagic cystitis from cyclophosphamide. When possible, the drug should be given early in the day, followed by hydration and FREQUENT VOIDING (eg. every few hours). MESNA is always given with ifosfamide (and it may be used with cyclophosphamide) to prevent hemorrhagic cystitis. MESNA provides a substrate for acrolein to alkylate.

III. HYPOMAGNESEMIA FROM CISPLATIN is a common electrolyte abnormality. Magnesium falls in many patients who receive cisplatin. Unless it is very low (eg.< 1) or accompanied by hypocalcemia, hypomagnesemia is usually asymptomatic. Although magnesium replacement is frequently undertaken, it is of questionable value in the absence of other electrolyte abnormalities. Urinary magnesium loss is increased and frequently continues even after cisplatin therapy is stopped. Thus administered magnesium may simply be lost in the urine. It has been suggested that treatment is only necessary in patients who have other electrolyte abnormalities, or who are symptomatic.


It has been seen following high doses (eg. usually after doses of > 50mg/kg). It is characterized by a decrease in urine output occurring 6 to 8 hours after drug administration, weight gain, increase in urine osmoiality and decrease in serum osmolality. The syndrome, resembling SIADH, is generally self-limiting. Furosemide can be given to preserve urine output and prevent symptomatic hyponatremia; potassium would be required to prevent hypokalemia. (Note that the possibility of this syndrome does not preclude the hydration suggested above to prevent hemorrhagic cystitis. The latter is much more common, and the former has been reported primarily after high doses.) V. CISPLATIN NEPHROTOXICITY In the past, nephrotoxicity secondary to tubular damage, was the dose-limiting toxicity of cisplatin. Increases in BUN and creatinine, and decreases in CrCl may be seen shortly after cisplatin therapy. Usually, with doses < 100mg/m2 , nephrotoxicity is mild and reversible. It is no longer the doselimiting toxicity, as it may be prevented or minimized by the use of hydration immediately before and following drug administration. Mannitol has also been used to ensure diuresis and prevent nephrotoxicity, as has furosemide. Caution should be taken so as not to dehydrate patients if diuresis is greater than hydration. Hypertonic saline has been used to prevent nephrotoxicity from higher doses of cisplatin (eg. 40mg/m2/day x 5 days). DDTC (diethyldithiocarbamate), a heavy metal chelator, has also been used as an investigational agent to prevent cisplatin nephrotoxicity. Amifostine, a recently marketed protectant, is reported to decrease the nephrotoxicity (as well as some other toxicities) of cisplatin or other alkylators. Its exact place in therapy remains to be determined. Currently it is approved for use with cisplatin in advanced ovarian or non-small cell lung cancer. Frequent monitoring for hypotension is required and amifostine can worsen the nausea and vomiting seen with cisplatin. VI. Nephrotoxicity It has been associated with HIGH DOSE METHOTREXATE. High dose usually refers to doses > 1 gm/m2 and is given in conjunction with leucovorin. Nephrotoxicity is thought to be due to precipitation of the metabolite of methotrexate in an acidic urine, leading to renal tubular injury. Acute renal failure due to obstruction can result. Further, elimination of methotrexate will be inhibited, leading to severe toxicity. Nephrotoxicity can be prevented with hydration (eg. 3L/m2 x 24 hours) and urinary alkalinization to maintain urine pH >= 6.5.

VII. MITOMYCIN It has been associated with renal failure due to a hemolytic-uremic syndrome. There is no consistently effective treatment, although recovery has been seen after temporary dialysis.

VIII. STREPTOZOCIN It is a nitrosourea derivative, is also associated with renal failure. The earliest sign is hypophosphatemia, and the most frequent sign is proteinuria. Urinalyses should precede each dose of streptozocin. If the drug is stopped early (ie. when mild proteinuria is the only abnormality), toxicity is reversible. If the drug is continued, increases in BUN and creatinine can follow, and nephrotoxicity can be irreversible.

IX. Renal failure is associated with nitrosoureas (BCNU, CCNU). Azotemia and increases in creatinine have been seen following prolonged use and high cumulative doses (eg. 1200 mg/m2). Most reports are in children treated for brain tumors.

GI Toxicity From Chemotherapy L. Bressler November, 1997 I. Explanation of terms II. Vomiting mechanisms III. Consequences of inadequately treated nausea and vomiting IV. Emetic Mechanisms of chemotherapeutic agents V. Antiemetics VI. Conclusions/Guidelines VII. Suggestions VIII. Stomatitis IX. Other GI toxicities: Diarrhea OBJECTIVES

1. Discuss the (potential) mechanisms of chemotherapy-induced nausea and vomiting. 2. Discuss the mechanism(s) of antiemetic drugs.

3. Discuss the phenomena of anticipatory nausea and vomiting. 4. Select an antiemetic regimen, noting patient specific concerns (eg. type of chemotherapy, patient preferences). 5. Discuss the side effects of antiemetic treatments, and be able to prevent or minimize them. 6. Discuss the mechanism of chemotherapy-induced stomatitis. 7. Suggest, in writing, a rational treatment for chemotherapy-induced stomatitis. 8. List those chemotherapeutic agents commonly associated with diarrhea. 9. Suggest, in writing, a rational treatment for chemotherapy-induced diarrhea. REQUIRED READING NONE SUGGESTED READING NONE

I. Explanation of terms A. NAUSEA - a psychic experience of human beings which may or may not be associated with vomiting. It is a subjective phenomenon difficult to identify in experimental animals. B. VOMITING - EMESIS; the forceful expulsion of the gastro-intestinal contents through the mouth. C. RETCHING - the labored rhythmic activity of respiratory musculature which usually precedes or accompanies vomiting. Retching is not ordinarily accompanied by opening of the mouth. II. Vomiting mechanisms A. VOMITING CENTER (VC) - The VC coordinates the act of vomiting. It is located in the reticular formation in the medulla. The VC is anatomically close to other loci in the medulla, specifically, those concerned with salivation, spasmodic respiratory movements (eg. retching), the inspiratory and expiratory centers, and the vasomotor

center. Activities of all of these centers are involved in the motor expression of vomiting. Drugs don't usually stimulate the VC directly. Instead, the VC receives input from the chemoreceptor trigger zone (CTZ), from the so-called "periphery", from higher brain centers and from the vestibular apparatus. B. CTZ - The CTZ is located in the floor of the fourth ventricle in the medullary surface. It is more superficially located than the VC. It is exposed to both blood and CSF, and it is sensitive, as the name implies, to emetic chemicals. Many drugs that cause nausea and vomiting, but by no means all, do so via stimulation of the CTZ. The prototype for studying CTZ stimulation (eg. in animals) is apomorphine. C. "PERIPHERY" - "Peripheral" input to the VC is through vagal and sympathetic afferents, originating primarily in the pharynx and GI tract. Note that parenterally administered drugs can cause nausea and vomiting by this mechanism. The prototype for studying peripheral stimulation of the VC (eg. in animals) is intragastric copper sulfate. D. HIGHER BRAIN CENTERS - Higher brain centers can also provide input to the VC. This may be in response to such stimuli as taste and smell. Higher brain centers probably are involved in NAUSEA, as well as in the development of ANTICIPATORY NAUSEA and VOMITING. E. VESTIBULAR APPARATUS - The vestibular apparatus provides input to the VC, probably by way of the CTZ. It is important in motion sickness, but is thought not to have a major role in chemotherapy-induced nausea and vomiting. A multitude of neurotransmitters and receptors may be involved in the transmission of impulses to the VC. Of recent interest is the role of SEROTONIN in chemotherapyinduced nausea and vomiting. NAUSEA and VOMITING are SEPARATE phenomena. It may be that an emetic stimulus divides, producing vomiting, as described above, and nausea, a central phenomenon. III. Consequences of inadequately treated nausea and vomiting

A. NONCOMPLIANCE with chemotherapy 1. Noncompliance due to nausea and vomiting has been estimated to occur in as many as 25-50% of patients. 2. Noncompliance is of particular concern in patients with potentially curable diseases (eg. Hodgkins, testicular cancer).

B. PATIENT DISCOMFORT 1. Time off from work or school, with resultant financial consequences. 2. Disruption of personal life. C. MEDICAL COMPLICATIONS 1. ESOPHAGEAL TEAR (Mallory-Weiss syndrome) or pathologic BONE FRACTURE from violent or repeated retching or vomiting. 2. DEHYDRATION 3. Prolonged ANOREXIA and MALNUTRITION may compromise the patient's ability to tolerate normal dosages of chemotherapy. 4. METABOLIC ABNORMALITIES from vomiting: metabolic alkalosis, hypokalemia, hypochloremia 5. ANTICIPATORY NAUSEA and/or VOMITING a. Anticipatory nausea and/or vomiting are nausea or vomiting that occur before administration of, and in anticipation of, chemotherapy. b. Anticipatory symptoms have been reported in as many as one-third of patients receiving chemotherapy. c. Anticipatory symptoms are a conditioned response. The best treatment for anticipatory nausea/vomiting is prevention, by minimizing post chemotherapy nausea and vomiting in the first place.

IV. EMETIC MECHANISMS of chemotherapeutic agents A. Emetic mechanisms (from those mechanisms and neurotransmitters discussed above) are known for only a few drugs. 1. NITROGEN MUSTARD emesis in dogs is mediated through the CTZ, and in cats, through the periphery and higher brain centers. 2. CISPLATIN emesis is mediated through the periphery and appears to be related to serotonin. 3. For most other drugs, the mechanism of emetic effect is unknown. In some cases, emetic mechanism is inferred indirectly from results of antiemetic use.

B. It is likely that there are several mechanisms for chemotherapy-induced nausea and vomiting, perhaps even more than one mechanism for the same drug. This makes it unlikely that any one antiemetic will be successful against all chemotherapy-induced nausea and vomiting, and also supplies a rationale for combination antiemetic therapy.

V. ANTIEMETICS A. PHENOTHIAZINES 1. Proposed antiemetic mechanism: blockade of dopamine receptors in the CTZ. 2. Piperazines (PROCHLORPERAZINE, THIETHYLPERAZINE, PERPHENAZINE) are the most potent antiemetics (among the phenothiazines) but also have the greatest tendency to cause extrapyramidal side effects (EPS). 3. Piperidines (THIORIDAZINE) are poor antiemetics. 4. Aliphatics (CHLORPROMAZINE) are less potent than piperazines, but are associated with less EPS. Chlorpromazine is often preferred in children for this reason (less EPS). 5. GUIDELINES for use a. Phenothiazines are often successful in minimizing nausea and vomiting from drugs with LOW to MODERATE EMETOGENIC POTENTIAL (eg. METHOTREXATE, 5FLUOROURACIL). b. Use a variety of dosage forms: parenteral, oral, rectal suppositories (eg. in case patients can't keep down oral medications). c. Duration of antiemetic effect is three to four hours, less than the usual recommended dosing intervals. Antiemetics can often be given at these more frequent dosing intervals. d. Occasionally, doses higher than those usually recommended may be administered, and may be more effective (eg. prochlorperazine 30-40mg as a short IV infusion). e. SIDE EFFECTS accompanying short-term use i. EPS - ACUTE DYSTONIC REACTIONS (spasms of the neck or back, with torticollis or opisthotonos in severe cases; difficulty swallowing, trismus, protrusion of the tongue or oculogyric crisis). ii. EPS - AKATHISIA - motor restlessness ranging from a feeling of inner disquiet to inability to sit or lie quietly (agitation, jitteriness) or to sleep.

iii. EPS - TREATMENT - DIPHENHYDRAMINE 25-50mg PO or parenterally (ie. if swallowing is difficult) or BENZTROPINE 2mg PO or parenterally. BENZODIAZEPINES may also be useful for akathisia. iv. autonomic effects - hypotension, dry mouth, urinary retention v. SEDATION B. BUTYROPHENONES - DROPERIDOL and HALOPERIDOL 1. Proposed antiemetic mechanism: blockade of dopamine receptors in the CTZ. 2. Clinically, butyrophenones are used as more "potent" antiemetics than phenothiazines. This is somewhat empiric. Higher doses of phenothiazines may be just as "potent". (see above) 3. SIDE EFFECTS are qualitatively similar to phenothiazines. The doses are less well defined. 4. Suggested STARTING DOSES: DROPERIDOL 1.25mg IV push or IM; HALOPERIDOL 2.5mg IV push or IM (these are not necessarily equipotent and are somewhat empirically derived; IV doses may also be given as short infusions). Doses may repeated at four hour intervals and increased or decreased based on efficacy and side effects. Oral haloperidol might be used by patients at home, following parenteral dosing. C. METOCLOPRAMIDE 1. High doses are more effective than low (standard, eg. 10mg QID) doses for chemotherapy-induced nausea and vomiting. High doses block serotonin receptors as well as dopamine receptors. 2. A commonly reported dose/schedule is 2mg/kg in 50ml D5W or 0.9% NaCl infused over 15-30 minutes. This dose is repeated at approximately two hour intervals for a total of five times. a. Oral metoclopramide is less convenient to use, being only available in 10mg tablets. b. Lower and higher doses of IV metoclopramide (eg. 1-3mg/kg) have also been used. Higher doses might be used for outpatients who can only receive one or two (as opposed to five) doses. 3. EPS, similar to those seen with phenothiazines and butyrophenones, also occur with metoclopramide, as metoclopramide also blocks dopamine receptors in the CTZ.

4. In addition, metoclopramide has a PERIPHERAL EFFECT, enhancing forward motility of the GI tract (ie. the "opposite" of vomiting). This may also result in DIARRHEA. 5. SEDATION is also reported with metoclopramide. D. STEROIDS 1. Steroids have been reported to have an antiemetic effect, although the mechanism remains speculative. In addition, most literature supports the use of dexamethasone in combination with other agents for highly emetogenic chemotherapy. 2. Much of the literature documenting a beneficial effect of steroids describes patients who received chemotherapy that was not clearly highly emetogenic (eg. CYCLOPHOSPHAMIDE, METHOTREXATE, 5-FLUOROURACIL). 3. The steroids most commonly used are DEXAMETHASONE and METHYLPREDNISOLONE (one suggested dose of dexamethasone: 20mg IV then 10mg PO every six hours for 24 hours). 4. Short term use of steroids in this setting isn't accompanied by many side effects. PERINEAL BURNING has been reported with IV injection of steroids. This can be minimized by prolonging the rate of injection. E. CANNABINOIDS 1. THC (DRONABINOL) is marketed for chemotherapy-induced nausea and vomiting unresponsive to more "standard" treatment. It is also recommended for delayed or prolonged nausea and vomiting (symptoms lasting longer than 24 hours, usually following treatment with cisplatin). This latter use probably requires better documentation before it can be accepted as "standard". 2. The antiemetic mechanism is unclear; THC may act at higher brain centers that transmit impulses to the vomiting center. 3. Usual dose of THC is 5-10mg/m2 PO every three to four hours. Doses for delayed or prolonged nausea or vomiting are generally lower (eg. 2.5-5mg twice a day). 4. The most common SIDE EFFECTS are DROWSINESS and a "HIGH". Dizziness and reddening of the eyes are also seen. 5. The cost of THC can be prohibitive - thus, it remains a useful second or third choice antiemetic. F. BENZODIAZEPINES

1. Benzodiazepines are frequently used in combination, or sometimes alone, to treat chemotherapy-induced nausea and vomiting. a. Benzodiazepines provide an ANTIANXIETY effect, quite useful in nervous patients. b. Benzodiazepines produce ANTEROGRADE AMNESIA, leaving the patient with a "fuzzy" recollection of the time of chemotherapy and shortly thereafter. This may help to PREVENT ANTICIPATORY NAUSEA and VOMITING. c. Benzodiazepines have been reported to have a separate ANTIEMETIC effect. The mechanism of such an effect is unclear. Perhaps it is an antinausea effect, acting on the psychic component. 2. LORAZEPAM has been used in various doses and by various routes of administration (eg. 0.05mg/kg IM, 3mg PO, 4mg IV). 3. ALPRAZOLAM has been reported to be useful in patients with anticipatory symptoms, when given beginning the night before chemotherapy. G. SEROTONIN ANTAGONISTS 1. Recent literature has focused on serotonin as a mediator in chemotherapy-induced nausea and vomiting. 2. Selective antagonists of serotonin at the S3 (serotonin3) receptor (ondansetron, granisetron) have become among the most widely used antiemetics. Dolasetron was very recently marketed. a. Results with serotonin receptor antagonists are quite positive for nausea and vomiting due to cisplatin as well as other chemotherapeutic agents, although they are very expensive to use. b. Serotonin receptor antagonists have no antidopaminergic activity and therefore do not cause EPS. They also ar not sedating. They are very well tolerated; the most common SIDE EFFECT reported is HEADACHE. c. The recommended dose of ondansetron is 32mg IV as a single dose or 0.15mg/kg IV as a short infusion before chemotherapy and 4 and 8 hours after chemotherapy. Other, widely used, lower doses may be similarly effective although there is less literature support for them. Oral tablets are marketed for cyclophosphamide-containing chemotherapy regimens. The oral dosage form is also likely to be used for "follow-up" after IV dosing in patients receiving other chemotherapeutic agents (eg. cisplatin). d. The recommended dose of granisetron is 10mcg/kg over 5 minutes, as a single IV dose before chemotherapy. Oral granisetron is also recommended instead of a

parenteral serotonin antagonist. Whether such use is, indeed, as effective and less costly than parenteral agents is still being debated. e. Ondansetron and granisetron appear to be equivalent in efficacy.(Dolasetron is probably of similar effectiveness.) There is however, little comparative data using 10mcg/kg of granisetron and 32mg of ondansetron. Most of the supportive literature for granisetron describes higher doses (3mg or 40mcg/kg). Cost to individual institutions or buying groups may be the ultimate determinant in the choice of serotonin receptor antagonist. I would not recommend either of these drugs for most mildly or moderately emetogenic chemotherapy regimens, specific patient concerns notwithstanding.

VI. CONCLUSIONS/GUIDELINES A. CISPLATIN is the most highly emetogenic drug, causing nausea and vomiting in 90% or more (but not 100%) of patients. B. Other HIGHLY EMETOGENIC drugs include DTIC, DOXORUBICIN, NITROGEN MUSTARD, and IFOSFAMIDE. C. DTIC is often given daily for five days. Nausea and vomiting commonly decrease over the five day period. D. BLEOMYCIN and VINCRISTINE cause almost no nausea or vomiting E. Nausea/vomiting that are not anticipatory do not occur immediately. The shortest "lag time" is about 30-60 minutes, and "lag time" may be six hours or longer (eg. after CYCLOPHOSPHAMIDE). It should be remembered, however, that anticipatory nausea and vomiting still cause much discomfort for patients and may still require treatment. F. Nausea/vomiting, when they do occur, commonly IMPROVE WITHIN 24 HOURS. G.

The EXCEPTION to this is CISPLATIN, following which nausea, vomiting, or anorexia may last for a week or more. H. Nausea/vomiting from CISPLATIN are DECREASED by giving the drug as a PROLONGED INFUSION (eg. 24 hours). I. Antiemetics should be started BEFORE chemotherapy administration - well before nausea and vomiting might be expected to be seen. J. Many of the antiemetics discussed above are used acutely, before chemotherapy. Attention should be paid to follow-up with oral or rectal medications, lower doses, or even continued dosing with the same drug. This assures treatment throughout the expected duration of nausea and vomiting, or in the event of delayed or prolonged symptoms. Having said that, it is commonly believed that most antiemetics display decreased effectiveness when given over multiple days (eg. with daily x five cisplatin). Consistent follow-up with appropriate adjustments is important. K. The choice of antiemetic is OFTEN EMPIRIC. The literature supports the use of any of a number of drugs, even if a pharmacologic rationale (ie. based on mechanism of nausea and vomiting of the particular chemotherapeutic agent[s]) is absent. L. The subjective nature of nausea and the degree of patient discomfort often seen may justify this empiric approach. M. Nausea and vomiting are DISTINCT ENTITIES. They may occur together or separately. The presence of (and disappearance of) nausea must be evaluated separately from vomiting. N. ANTICIPATORY NAUSEA and VOMITING are very real phenomena. The way to prevent them would appear to be to prevent post chemotherapy nausea and vomiting from occurring in the first place.

O. SIDE EFFECTS play an important role in the patient's overall assessment of antiemetic effectiveness. Patients may prefer a drug that, objectively, has not helped that much, over a drug with side effects that they find intolerable. P. Consider the patient's needs - do they want to be awake or asleep? Do they have a companion if they are at home, or with whom they can travel to and from an outpatient facility? Are they at risk of aspiration? Make sure sleeping patients lift their heads so as not to aspirate if they vomit. Q. DEXAMETHASONE/METOCLOPRAMIDE is the most widely used combination for DELAYED nausea and vomiting. Low doses of metoclopramide are used in this setting.

VII. SUGGESTIONS (see K above)

A. The following regimens can be used for highly emetogenic chemotherapy. Some of these regimens (ie. haloperidol and lorazepam) can be very sedating. This may be beneficial, but certainly needs to be considered in view of the patients' desires, responsibilities, etc.:

metoclopramide haloperidol/lorazepam high dose prochlorperazine ondansetron or granisetron or dolasetron chlorpromazine/secobarbital*

*secobarbital can provide effects qualitatively like those of lorazepam B. For less highly emetogenic chemotherapy:

droperidol prochlorperazine dexamethasone

C. THC as second line treatment for either of the above categories

D. DIPHENHYDRAMINE prophylactically with any of the above to prevent EPS and/or increase sedation. E. Dexamethasone in combination with those regimens listed in A above


As is the case with myelosuppression and alopecia, stomatitis (oral mucositis) results from the effects of chemotherapy on rapidly proliferating tissues - in this case, epithelium in the mouth. Although mucositis can involve the esophagus, ileum or colon, stomatitis is the most common. Stomatitis is PAINFUL, which may IMPAIR NUTRITIONAL INTAKE. In addition, mucosal breaks predispose to secondary INFECTIONS. Among the chemotherapeutic agents most likely to cause stomatitis are 5FLUOROURACIL, METHOTREXATE, BLEOMYCIN and DOXORUBICIN. SYMPTOMS of stomatitis generally begin 3-4 days after chemotherapy. They include tingling, dryness, pain, burning, sensitivity of teeth and gums, dysphagia and impaired taste. Symptoms progress, becoming the most severe within a week. Lesions appear as an ULCERATION with ERYTHEMATOUS BORDERS. The lips, tongue, gums, buccal mucosa, palate or floor of the mouth may be involved. The lesions slowly HEAL (barring infection) in 7-10 days. TREATMENT of stomatitis is SYMPTOMATIC - PAIN RELIEF and HYGIENE. Various agents, alone or in combination, have been used. None have been studied in a comparative fashion so superiority of one treatment over another cannot be stated. VISCOUS LIDOCAINE and DICLONINE 0.5% are used for LOCAL ANESTHESIA. A common combination is DIPHENHYDRAMINE/KAOLIN-PECTIN in equal parts. Although diphenhydramine is reported to have local anesthetic properties, documentation of this effect with the concentrations used clinically is scanty. Kaolinpectin "soothes" or "coats", and prolongs the contact time of other agents with the oral mucosa. Sometimes combinations may mask the unpleasant taste of viscous lidocaine. For example: VISCOUS LIDOCAINE/MAALOX/MOUTHWASH (alcohol free if possible). MAALOX probably works as the kaolin-pectin above, and MOUTHWASH provides an ANTISEPTIC as well as a FLAVOR. Alcohol in mouthwashes may intensify burning or drying.

Extemporaneously prepared suspensions of SUCRALFATE have been described for use in stomatitis. It is suggested that sucralfate may help heal oral lesions. This is similar to its effects in peptic ulcer disease. A suspension of ALLOPURINOL has been used to minimize stomatitis due to 5fluorouracil (5-FU). This is based on the premise that allopurinol results in inhibition of one of the activation pathways of 5-FU (ie. a form of biochemical modulation). CHLORHEXIDINE GLUCONATE (Peridex?) may be used to decrease secondary infections in stomatitis. It has been reported to decrease plaque and gingivitis as well as decreasing mucositis and bacteria. The dose is 15cc three times a day (swish & spit). TANNIC ACID (Zilactin?) is available without a prescription and may provide relief for painful stomatitis. After an initial burning sensation, it forms a thin protective film that can often withstand eating and drinking. Patient acceptability is obviously an important consideration in choosing a treatment for symptomatic relief of stomatitis. Patients must also be cautioned so as not to aspirate food, bite their tongue, etc., following the use of local anesthetics. It may be necessary to swallow the anesthetic (eg. lidocaine) in order to reach some painful lesions, requiring a greater volume than that which can be dabbed on a more easily accessible lesion. Systemic side effects (eg. seizures) have been reported following the use of viscous lidocaine. Patients should use the minimum amount necessary to provide relief.

IX. OTHER GI TOXICITIES: DIARRHEA Several chemotherapeutic agents are associated with the development of diarrhea. Although alterations in colonic mucosa are a likely mechanism for such, there may be other contributing factors as well. Diarrhea can be severe, with resultant fluid and electrolyte disturbances, and even fatality. Two of the most common causes of diarrhea include 5-FLUOROURACIL and IRINOTECAN. Management of 5-FU-induced diarrhea is usually nonspecific and includes opioids (loperamide, diphenoxylate), kaolin-pectin, or, occasionally, octreotide. IRINOTECAN is associated with acute diarrhea (eg. during or shortly after drug administration) that is thought to be cholinergic mediated. It is recommended that such diarrhea be treated with atropine. "High dose" loperamide is recommended for late irinotecan-induced diarrhea (eg. 4mg at the onset of diarrhea, then 2mg every 2 hours until diarrhea-free for 12 hours).

Chemotherapy - Induced Cardiac Toxicity L. Bressler November, 1997 OBJECTIVES 1. List the antineoplastic drugs implicated in causing cardiac toxicity. 2. Describe the clinical picture(s) of antineoplastic-induced cardiac toxicity (including risk factors, onset, manifestations, treatment, course, etc.). REQUIRED READING NONE SUGGESTED READING 1. Speyer JL et al.: Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer; N Engl J Med 319:745-752, 1988

CHEMOTHERAPY-INDUCED CARDIAC TOXICITY I. The most well-known cause of chemotherapy-induced cardiotoxicity is DOXORUBICIN (ADRIAMYCIN). There are different manifestations of doxorubicin cardiotoxicity: ARRHYTHMIAS - Arrhythmias are reported to occur acutely -during or within 24 hours of doxorubicin administration. The most common electrocardiographic (ECG) abnormalities reported are nonspecific ST-T wave changes, decreased QRS voltage, sinus tachycardia, supraventricular tachyarrhythmias, premature ventricular and atrial contractions, T-wave abnormalities and QT interval prolongation. Rarely, sudden death and life-threatening ventricular arrhythmias have been reported. Arrhythmias appear to be more common in patients with abnormalities on baseline ECG. Drug treatment is

generally not required, and future treatment is usually not compromised. For our purposes, the important aspect is recognizing that arrhythmias may be drug-induced. CHRONIC CARDIOMYOPATHY - This is the most severe form of doxorubicin cardiotoxicity and has been the subject of many discussions/trials in the literature. Cardiomyopathy is DOSE-RELATED. Overall, the incidence is reported to be less than 1% at cumulative doses less than 550mg/m2, and up to 30% at cumulative doses 5601155mg/m2. Morphologic damage increases progressively with increasing doses, although the progression is slower in some individuals and faster in others. CARDIAC FUNCTION, HOWEVER, MAY REMAIN RELATIVELY NORMAL UNTIL A FAIR AMOUNT OF MORPHOLOGIC DAMAGE HAS OCCURRED. Morphologic damage has been quantitated by pathologists from samples obtained by myocardial biopsy. The cellular lesions are known as "myofibrillar dropout". Myofibrillar dropout consists of swelling of the sarcoplasmic reticulum and, with more advanced stages of damage, complete loss of myofibrils. The quantitation system goes from 0 to 3 (increasing numbers implying more damage to a greater number of cells). Effects on clinical function may be seen at biopsy scores of 2.5. Since some patients may receive high doses of doxorubicin without ever developing cardiomyopathy and some develop cardiomyopathy at relatively low doses (ie. less than 550mg/m2 total dose), it would be beneficial to predict the development in individual patients. RISK FACTORS for the development of cardiomyopathy include TOTAL DOSE 450mg/m2 or more, MEDIASTINAL IRRADIATION, AGE greater than 70 years. Other risk factors may be pre-existing cardiac disease and treatment with cyclophosphamide. Myocardial biopsies can be done in high risk patients, before the development of clinical cardiomyopathy, to predict whether or not they can safely receive more drug. With biopsy scores less than 2.5, the chance of developing congestive heart failure (CHF) if 100mg/m2 more drug is given is less than 10%. This chance increases to 10-25% with grade 2.5 and to more than 25% with grade 3. So if patients with grade 2 don't receive any more drug, there is little likelihood of their developing CHF. Myocardial biopsies are not routinely available in most institutions. Ejection fraction (EF) determined by radionuclide scanning has been suggested as the best noninvasive monitoring tool. For example, baseline EF can be obtained in patients with risk factors. Then subsequent determinations (eg. every other dose or every 100mg/m2) can lead to decision points: EF less than 45%, decrease in EF of greater than 5% to less than 50%, failure of EF to increase by at least 5% with exercise. These points may be indications to stop the drug or obtain a biopsy, if possible. Other guidelines are available that incorporate a baseline EF in all patients (ie. not just high risk patients). It should be noted that frequently, these decisions may not even need to be made (ie. total dose for an entire course of therapy is <450mg/m2 in a patient with no other risk factors, the disease progresses before a total of 450mg/m2, etc.).

The CLINICAL MANIFESTATIONS of doxorubicin cardiomyopathy are those of severe biventricular CHF. Because of the progressive morphologic changes and the persistence of changes for a long time, symptoms have been reported to occur any time up to months after stopping the drug. Although CHF has been reported to have a high mortality rate, successful treatment is possible. Therefore symptoms of CHF should be managed as CHF due to other causes. The incidence of cardiotoxicity has been reported to be less when doxorubicin is given as a PROLONGED INFUSION (ie. 96 hours) or in LOW WEEKLY doses instead of higher doses every three weeks. Various attempts have also been made to prevent cardiotoxicity. The most promising method of preventing doxorubicin cardiomyopathy appears to be DEXRAZOXANE (ICRF-187). It is thought to block the formation of oxygen free radicals by chelating complexes between doxorubicin and iron. Doxorubicin can be reduced to a semiquinone free radical that can react with molecular oxygen to yield free radicals: superoxide, hydroxyl. Iron must be present for these reactions to result in significant damage. Doxorubicin binds to iron and the iron-doxorubicin complex catalyzes the free radical reactions. Classical free radical scavengers (tocopherol, N-acetylcysteine) do not block the reactions but ICRF-187, which is an iron chelator, can. In a randomized study, patients receiving doxorubicin-containing chemotherapy plus ICRF-187 had no biopsy scores of 2 or greater and a lower incidence of clinical CHF than the group receiving chemotherapy alone. Because of concern for a possible decrease in the antitumor effect of the anthracycline, dexrazoxane is indicated AFTER a total cumulative dose of 300mg/m2 doxorubicin.

II. DAUNOMYCIN causes much the same type of cardiomyopathy as doxorubicin. The incidence has been reported to be 1.5% at a total dose of 600mg/m2 and 12% at 1000mg/m2.

III. IDARUBICIN (IDAMYCIN) is associated with cardiac toxicity similar to that seen with doxorubicin or daunomycin.

IV. MITOXANTRONE is associated with cardiomyopathy, especially in patients who have received previous doxorubicin, but the incidence is less than that seen with doxorubicin. Cumulative dose recommendations for minimizing the occurrence of cardiomyopathy are 160mg/m2 in patients without prior doxorubicin and 100mg/m2 in patients with prior doxorubicin. These cutoffs are also viewed in light of the patients underlying disease and the need for continued drug. (approximate equivalent doses are 60mg/m2 doxorubicin and 12mg/m2 mitoxantrone)

Other anthracyclines currently under study may, in some cases, be less cardiotoxic than doxorubicin. Similarly, the LIPOSOMAL ANTHRACYCLINES may be less cardiotoxic.

V. 5-FLUOROURACIL (5-FU) has been implicated as a cause of cardiotoxicity. The toxicity manifests as ischemic pain within hours of a dose. Myocardial infarction has been reported. Electrocardiogram changes consistent with ischemia and response/prevention with nitrates have been noted. The toxicity is not clearly dose related, although it has been suggested that the incidence is considerably higher when 5-FU is given as a continuous infusion rather than a bolus (10% versus about 1%). Some patients have received further treatment safely, but the need for 5-FU in the face of cardiotoxicity may obviously be re-evaluated. VI. CYCLOPHOSPHAMIDE has been reported to cause cardiac necrosis resulting in the acute or subacute development of CHF. This has been seen in some patients after the use of very high does (120-140mg/kg) in preparation for bone marrow transplant. CYCLOPHOSPHAMIDE as well as the VINCA ALKALOIDS have also been reported to cause ischemic cardiac toxicity.

Malignant Effusions L. Bressler November, 1997


Malignant Pleural Effusions Malignant Pericardial Effusions Malignant Peritoneal Effusions

OBJECTIVES 1. Discuss, briefly, the factors responsible for the development of malignant effusions. 2. Discuss the treatments used in the management of malignant effusions. REQUIRED READING

NONE SUGGESTED READING NONE I. MALIGNANT PLEURAL EFFUSIONS The pleural space normally contains about 5-20ml of fluid. Usually the concentration of protein in this fluid is <2gm/dl. Factors that promote increased collection of fluid in this space (ie. a pleural effusion) include: increased capillary permeability, increased hydrostatic pressure (eg. in CHF), increased negative intrapleural pressure (eg. atelectasis), decreased oncotic pressure (eg. hypoalbuminemia), or increased pleural fluid oncotic pressure (eg. with pleural tumor growth). Impaired pleural lymphatic drainage also leads to accumulation of pleural fluid. The most important factors contributing to the development of MALIGNANT PLEURAL EFFUSIONS are INCREASED CAPILLARY PERMEABILITY (from inflammation or disruption of capillary endothelium) and IMPAIRED LYMPHATIC DRAINAGE due to obstruction by tumor. These factors most commonly result from direct invasion of the pleural space by primary or metastatic tumor. The most common tumors causing malignant pleural effusions are: LUNG CANCER, BREAST CANCER and LYMPHOMAS. SYMPTOMS associated with malignant pleural effusions include: DYSPNEA, COUGH and CHEST PAIN. Dyspnea is due to pleural compression. Cough is nonproductive. It is caused by compression of the bronchial walls by fluid. Inflammation of the parietal pleura results in pleuritic chest pain. The severity of symptoms is related to the rapidity with which the fluid accumulates rather than to the amount of fluid. Most effusions have more than 500ml of fluid. THORACENTESIS, the removal of the pleural fluid through a chest tube, is both diagnostic and therapeutic. The fluid is sent for analysis: cytology (to look for the presence of malignant cells), protein (>3gm/dl in malignant effusions), specific gravity (>1.025 in malignant effusions), pleural/serum LDH (>0.6 in malignant effusions). Symptoms will improve with thoracentesis, but fluid removal alone will not generally be successful in controlling the effusion (ie. the recurrence rate in people treated with thoracentesis alone and followed for one month is 97%, with the majority of recurrences seen in 1-3 days). SCLEROSIS - This procedure produces fibrosis and obliterates small pleural blood vessels. It is done after the space occupied by the effusion is obliterated by

thoracentesis followed by suction drainage. The purpose of sclerosis is to PREVENT REACCUMULATION. The following agents have been used for sclerotherapy:


The cytotoxic drugs work by producing fibrosis, NOT BY EXERTING AN ANTINEOPLASTIC EFFECT. Systemic side effects (bone marrow suppression) can be seen with the intrapleural administration of cytotoxic drugs. TETRACYCLINE was among the most commonly used agents for sclerotherapy until recently, when the only parenteral preparation was removed from the market by the manufacturer. A variety of other agents have been recommended in its place. The following represents some general information about the intrapleural administration of some of these agents. Individual procedures should be reviewed for each drug if needed. Patients are premedicated with opioid analgesics about 1/2 hour before treatment

Bleomycin 60 units in 50ml D5W or NaCl, or doxycycline 500mg in 30ml NaCl, or mitoxantrone 30mg in 50-100ml NaCl, or nitrogen mustard (mechlorethamine) 20mg in 50-150ml NaCl, or thiotepa 3045mg in NaCl is instilled through the chest tube.

Lidocaine 100-300mg has been added to solutions to provide local anesthesia.

The patient changes positions every 15 minutes for several hours (eg. lying flat, right side up, etc.).

The chest tube clamp is removed and fluid drains, with suction, for about 24 hours.

The chest tube drains by gravity, and when drainage is decreased (ie. to 50-100ml/day) and the lung remains re-expanded, the chest tube is removed.

Note: The above is intended as a general overview of the sequence of events commonly observed in the management of malignant effusions. It is not intended as a step-by-step guide. TALC for pleurodesis is enjoying a resurgence in use in various centers. The procedure for insufflation is different than that described above, and is usually done in an operating room setting. The goals of sclerosis are the same. II. MALIGNANT PERICARDIAL EFFUSIONS Malignant pericardial effusions are most common in BREAST and LUNG CANCERS. Heart or pericardial involvement is also seen in leukemia, Hodgkins or non-Hodgkins lymphomas, melanoma, gastrointestinal cancers and sarcomas. Fluid accumulates in the pericardial space as a result of OBSTRUCTION OF LYMPHATIC and VENOUS DRAINAGE OF THE HEART. Symptoms of pericardial effusions include DYSPNEA, COUGH, CHEST PAIN, ORTHOPNEA, PALPITATIONS, WEAKNESS, FATIGUE and DIZZINESS. CARDIAC TAMPONADE is the most severe form of presentation. The occurrence of symptoms depends on how fast the fluid accumulates, how much fluid accumulates and underlying ventricular function. TREATMENT of malignant pericardial effusions may involve PERICARDIOCENTESIS and SCLEROTHERAPY (eg. doxycycline, bleomycin, etc., similar to that discussed above for pleural effusions), or SURGERY. III. MALIGNANT PERITONEAL EFFUSIONS When drugs are used in the management of malignant peritoneal effusions, SCLEROTHERAPY may also be similar to that noted above.

Pain Management in Cancer Patients L. Bressler November, 1997

I. II. III. IV. V. VI.

Subjective nature of pain Opioid analgesics Special considerations Side effects of opioid analgesics Other drugs Tolerance and dependence with opioid analgesics

OBJECTIVES 1. Discuss factors influencing pain in cancer patients. 2. Discuss the subjective nature of pain. 3. Discuss the possible sites of action of opioid analgesics. 4. Be able to choose an opioid analgesic regimen based upon specific patient concerns (eg. renal function, age). 5. Be able to adjust an analgesic regimen based upon therapeutic response and/or side effects. 6. Discuss common side effects associated with opioid analgesics, and ways to minimize or prevent them. 7. Discuss the role(s) of other, non-opioid drugs in the management of pain in cancer patients. REQUIRED READING 1. Levy MH: Pharmacologic treatment of cancer pain; N Engl J Med 335:1124-1132, 1996 SUGGESTED READING 1. Reisine T, Pasternak G: Opioid Analgesics and Antagonists, in The Pharmacological Basis of Therapeutics (eds. Hardman, Limbird, Molinoff, Ruddon, Gilman), McGraw Hill, 1996, p.521-555 PAIN MANAGEMENT IN CANCER PATIENTS I. SUBJECTIVE NATURE OF PAIN A. Basically, there are two components of pain. The first component is the sensory input to the central nervous system (CNS) that results in recognition of the sensation of pain. Under controlled laboratory conditions, the amount of stimulus required to produce

such a sensation (ie. PAIN THRESHOLD) would be very similar in all subjects. However, this sensation, produced outside of a pathological setting, is not "pain". By definition, pain is subjective. It is defined as a sensory and emotional experience. The second component is the REACTIVE, SUBJECTIVE COMPONENT. It is the reaction to the first component - the meaning or the interpretation of the pain. It is influenced by the setting in which the pain occurs (eg. more fear might be evoked by "crushing" chest pain than by the same quality and intensity of pain in another part of the body) and by the experiences, attitudes and beliefs of the patient. The reactive component varies widely from person to person and it would seem, then, that it is the reactive component that we are dealing with when patients complain of pain, and when we treat pain. B. ACUTE versus CHRONIC PAIN Acute pain serves as a warning to patients to seek medical attention. Frequently, acute pain can be "understood", in that one knows the cause. A healing period can anticipated. Such is not the case with chronic pain, especially that due to cancer. It serves no useful purpose and its presence cannot be "rationalized" or "understood". The subjective component is obviously very important in chronic pain due to cancer. Twycross describes this quite well: "Chronic pain differs from acute pain in that it is a situation rather than an event, it is impossible to predict when it will end, it usually gets worse rather than better, it appears to be entirely meaningless and frequently expands to occupy the patient's whole attention, isolating him from the world around. Consequently, there is a greater likelihood of a negative pain-potentiating psychological component in chronic pain than in acute pain. Depression, anxiety, fear, mental isolation, other unrelieved symptoms, and pain itself will all tend to exacerbate the total experience of pain. To relieve the pain, all these factors must be considered." There are few or no OBJECTIVE SIGNS of chronic pain. PAIN IS WHAT THE PATIENT SAYS HURTS. II. OPIOID ANALGESICS are the mainstay for treatment of chronic pain due to cancer A. MECHANISM - opioid analgesics exert their effects by binding to opiate receptors. 1. Transmission of pain impulses to the brain may be altered following opioid binding at the receptor. 2. The reactive component of pain may be altered following opioid binding at the receptor. Some areas of the brain rich in opiate receptors are those relating to mood and behavior.

B. GUIDELINES FOR USE 1. For patients with persistent, severe pain, medication on a SCHEDULED BASIS rather than PRN is generally preferred. It is easier to prevent pain from recurring than to treat it once it has recurred. The anxiety component increases as the last dose is wearing off and pain must be experienced before the next dose is given. This exacerbates the pain and makes it more difficult to eradicate with subsequent doses. 2. PO:PARENTERAL RATIO - Due to a first-pass effect, all of the opioids are more effective when given parenterally than when given orally. The ratio of oral to parenteral effectiveness of morphine is reported to be 1:6 (ie. six times the parenteral dose is required to achieve the same effect orally). This and other estimates are based on single dose studies. Chronic oral use seems instead to result in a ratio closer to 1:2 or 1:3. A helpful "rule of thumb" is to use 1:2 or 1:3 as the PO:PARENTERAL RATIO for all opioids, as a starting point. Thus, when switching a patient from oral to parenteral, doses can be halved (or decreased to one-third), and when switching from parenteral to oral, doses can be doubled (or tripled). This "rule of thumb" also makes calculating equianalgesic doses easier - if all of the drugs have a similar PO:PARENTERAL potency ratio, parenteral equianalgesic doses (ie. equivalent to 10mg morphine SQ) can be applied, proportionately, to oral opioids as well. C. EQUIANALGESIC DOSES DRUG ROUTES OF ADMINISTRATION APPROXIMATE EQUIANALGESIC DOSES* codeine hydromorphone PO, parenteral PO, parenteral PR levorphanol meperidine methadone morphine oxycodone PO, parenteral PO, parenteral PO, parenteral PO, parenteral PR PO 2mg 100mg 10mg 10mg 15mg 4-6 hours 2-4 hours 6-12 hours 3-4 hours 4-6 hours 120mg 2mg 4-6 hours 2-5 hours APPROXIMATE DURATION

* parenteral doses equianalgesic to morphine sulfate 10mg SQ Again, the same equianalgesic doses would apply to oral opioids, if one uses the PO:PARENTERAL potency ratio of 1:2 or 1:3 for all opioids, as mentioned previously. The table of equianalgesic doses provides GUIDELINES for switching from one opioid to another. Determination of equianalgesic doses was not done in patients with chronic pain due to cancer and the doses are approximate.

D. STARTING DOSES Common starting doses for opioid-naive patients are shown in the table. These doses are not necessarily equianalgesic. They are determined by experience of the prescriber, dosage forms and sizes available, and individual patient characteristics (eg. patients 70 years or older may start with lower doses of opioid as they may be more sensitive to the therapeutic effect, as well as to side effects). COMMON STARTING DOSES OPIOID-NAIVE PATIENTS codeine hydromorphone levorphanol meperidine methadone morphine oxycodone E. If an opioid is to be started in a patient who is not opioid-naive, the dose equianalgesic to the previous opioid should be estimated. This can be used as a starting point, keeping in mind that the dose might have to be increased (eg. maybe the previous opioid or dose was ineffective) or decreased (eg. maybe tolerance developed to the previous analgesic and there was not complete cross tolerance with the new opioid. See below) F. CHANGING DOSES 30mg 2mg 2mg 50mg 5mg 10mg 5mg

Similarly, increments in opioid dose are conveniently made taking into account the dosage forms and sizes available. Furthermore, the per cent increase is higher when the doses are lower, and lower at higher doses. For example, consider a patient being started on morphine sulfate solution, 2mg/ml. A common starting dose would be 10mg (one teaspoonful). If 10mg didn't provide satisfactory relief, the dose might be increased 100% - 20mg (two teaspoonsful). On the other hand, in a patient receiving 100mg of morphine, the dose might be increased to 120 or 140mg. G. MAXIMUM DOSE There is no absolute maximum dose of opioids for chronic pain due to cancer. Since tolerance develops to respiratory depression (see below), doses can be increased gradually to maximize pain control. As long as patients are getting some relief, and side effects are at an acceptable level, opioid doses can be increased. When patients are getting no relief, or side effects are greater than analgesic effect, opioid doses should not be further increased. Instead, a new drug should be instituted. Patients may display individual variation in analgesic response to the same drug. Such variation cannot be accurately predicted. H. DURATION OF ANALGESIC ACTION Approximate durations of analgesic action are shown in the table above. Duration of pain relief can vary among individuals, and does not appear to correlate well with halflife. In general, the only "long acting" opioid is methadone, which may provide pain relief for six or eight or even twelve hours. It is not unusual for patients taking "short acting" opioids (ie. everything other than methadone or perhaps, levorphanol) to report that pain relief lasts for only three or two or even one hour. SUSTAINED RELEASE morphine preparations (MS Contin?, Oramorph SR?) and oxycodone (Oxycontin?) have recommended dosing intervals of eight or twelve hours. Kadian? is a sustained release morphine capsule that is indicated for Q 24 hour dosing. These preparations have demonstrated bioavailability equivalent to immediate release products. Since evidence of a blood level-response relationship for morphine in chronic pain is equivocal, it is not clear that this bioavailability truly predicts duration of pain relief. The manufacturers recommend that the dose be increased (rather than the interval be shortened) in the event that the duration of pain relief is inadequate. Clinically, this does prolong the duration, although the total daily dose may be greater than the previous, immediate release, total daily dose. The long acting morphine capsule reportedly can be opened and the contents placed in food or a feeding tube without destroying the sustained release mechanism. The duration of respiratory depression (as well as miosis) from METHADONE is considerably longer than the duration of analgesia. The potential exists then, for frequent, repeated dosing with resultant cumulative toxicity. If methadone does not provide pain relief for at least six hours, its use should be re-evaluated since it is not

"long acting" in this case. It should not be given any more frequently than every six hours. Transdermal FENTANYL is marketed for the treatment of chronic pain, with a recommended dosing interval of 72 hours. Clinical observations seem to indicate that the manufacturer's conversion guidelines from other opioids are rather conservative, and that the duration of pain relief may be shorter than 72 hours. Although the place of this preparation in cancer pain therapy is still not clearly defined, it would seem to be useful in select populations (eg. patients who can't take solid oral dosage forms, patients with feeding tubes). Twycross, reporting on pain management in hundreds of terminally ill cancer patients, also recommends increasing the dose of immediate release morphine when effective analgesia is maintained for less than four hours. I. MONITORING PARAMETERS EFFICACY - What degree of pain relief is obtained? How long does the degree of relief obtained last? (ie. duration of analgesia) If the degree of relief is inadequate, an increase in dose may be attempted. If the degree of relief is adequate but the duration is shorter than the prescribed dosing interval, a decrease in interval may be attempted. Alternatively, the dose may be increased to prolong the duration of pain relief, as discussed above. How OFTEN should efficacy be ASSESSED? Daily might be ideal. In the case of severe pain, efficacy should be assessed following one dose. More practical in an outpatient setting is assessment after several days on a regular dose. HOW should EFFICACY be ASSESSED? Ask the patient. Remember, pain is subjective. An observer cannot accurately measure pain (or pain relief). A numeric pain rating scale may be useful - either verbal or written. A patient may define an "8" out of 10 as unbearable pain. A decrease to a "3" or "4" may be quite acceptable. Other similar pain assessment scales may also be utilized. OVERALL ASSESSMENTS or GLOBAL ASSESSMENTS made by patients likely take in to account other than just analgesic efficacy. A drug may work very well but if the patient considers the side effects unacceptable, their overall assessment may be negative. SIDE EFFECTS - Ask the patient about common side effects: CONSTIPATION; SEDATION - Sedation occurs early on and usually improves within several days. New onset of sedation in a patient previously stable on an opioid is unlikely due to the opioid (unless the patient has acutely deteriorated); CONFUSION - Confusion also occurs early on and should improve. Confusion is seen more often with methadone and more often in the elderly. III. SPECIAL CONSIDERATIONS

A. COMBINATIONS Remember ASPIRIN and ACETAMINOPHEN in Percodan?, Percocet?/Tylox?, Vicodin? and others. Patients taking acetaminophen 1gm every four hours and not getting adequate pain relief could be switched to another drug so as not to increase acetaminophen. Hepatotoxicity has been reported with chronic regular use of therapeutic doses of acetaminophen. B. CONTINUOUS INFUSIONS of opioid (morphine, hydromorphone) - Morphine doses reported have ranged from 1mg to several grams per hour. As is the case with intermittent administration, there is no absolute maximum dose. Continuous infusions benefit patients requiring frequent dosing or patients who can't take medication orally. They have been administered intravenously or subcutaneously. Infusion rates should be controlled by infusion control devices. Several guidelines are available for dosing continuous opioid infusions: 2.5mg morphine IV push every 10 minutes until relief. Then start continuous infusion at an hourly rate equal to the cumulative IV push dose. Alternatively, start at 1mg morphine/hour with subsequent adjustment based on degree of pain relief and side effects. Or, for patients on high opioid doses, calculate the 24 hour opioid dose, convert this dose to parenteral (morphine) and then divide by 24 to determine the hourly dose. C. Avoid METHADONE in the elderly, in patients with severe liver dysfunction (ie. patients thought to have decreased liver metabolizing capacity) and in patients with compromised pulmonary function. In the latter two groups of patients, the potential exists for cumulative toxicity with methadone. D. Avoid MEPERIDINE for chronic frequent use and in patients with renal dysfunction. Meperidine is metabolized to normeperidine which has CNS stimulatory activity and can cause seizures. Normeperidine accumulates in patients with renal dysfunction. However, there are also reports of neurotoxicity in very ill patients (but without renal failure) who received regular, frequent dosing with meperidine. There is some suggestion that CNS toxicity might also occur with FENTANYL, which is structurally similar to meperidine, and is metabolized to norfentanyl. MORPHINE-6GLUCURONIDE may also accumulate in patients with renal dysfunction or on high doses of morphine. It is thought to contribute the development of myoclonus.

E. HEROIN Orally administered heroin is no different than morphine. Indeed, it is metabolized to morphine. Parenterally administered heroin has greater solubility than morphine, thus more drug can be delivered in a small volume. This is important in patients with little or no muscle mass receiving frequent intramuscular injections. Dilaudid HP? offers a concentrated solution of parenteral opioid (10mg per ml), obviating the need for heroin. Newer, more concentrated strengths of morphine are also available for parenteral use. F. PROPOXYPHENE Qualitatively, propoxyphene binds to opiate receptors, resulting in the same effects as other opioid analgesics. Quantitatively, however, propoxyphene is much less potent than other opioids and is commonly considered with non-opioid analgesics. There are some situations in which propoxyphene may be particularly useful: Propoxyphene WON'T MASK A FEVER. Other non-opioid analgesics (aspirin and nonsteroidal antiinflammatory drugs, acetaminophen) have antipyretic activity. Propoxyphene DOESN'T INHIBIT PLATELET AGGREGATION. Inhibition of platelet aggregation occasionally limits the use of aspirin and many nonsteroidal anti-inflammatory drugs (but not acetaminophen). IV. SIDE EFFECTS OF OPIOID ANALGESICS A. RESPIRATORY DEPRESSION In equianalgesic doses, ALL OPIOIDS DEPRESS RESPIRATION TO THE SAME DEGREE. Clinically, respiratory depression may be seen as shallow and slow respirations. It has been reported that respiratory depression (decreased rate) was significant when it was accompanied by somnolence. Tolerance develops to respiratory depression, and usually, respiratory depression is not a problem when using opioids for chronic pain due to cancer. B. NAUSEA and VOMITING Opioids produce vomiting by stimulation of the chemoreceptor trigger zone (CTZ). There is also a VESTIBULAR component to GI symptoms, in that nausea and vomiting are seen more in ambulatory than in supine patients. PHENOTHIAZINES may help minimize nausea and vomiting (eg. prochlorperazine 10mg every 4 hours). ANTIHISTAMINES such as meclizine or dimenhydrinate can help minimize the vestibular component. Tolerance also develops to the nausea and vomiting. Symptoms commonly improve within about a week of regular opioid use. C. SEDATION -

Sedation may be seen with all of the opioids. It is more common in the elderly and with methadone. Tolerance also usually develops to opioid-induced sedation. D. CONSTIPATION Constipation occurs in a significant percentage of patients receiving opioids. Tolerance does not appear to develop to constipation. Regular use of stool softeners or bulk laxatives may minimize constipation. However, stimulant laxatives are often required on a chronic basis. E. SWEATING/PRURITUS Sweating is due to vasodilation, probably mediated by histamine release. Pruritus is also thought to be due to histamine release. Tolerance does not develop to sweating or pruritus. It is reported that fentanyl does not cause release of histamine. F. SEIZURES see above discussion of MEPERIDINE. MYOCLONIC JERKS are sometimes seen with morphine or other opioids, especially at high doses. They appear to be particularly discomforting for caregivers. Benzodiazepines have been used to treat myoclonic jerks. G. As is the case with analgesic response, there is UNPREDICTABLE INDIVIDUAL VARIATION IN TOXICITY. When one opioid produces unacceptable side effects, another opioid may be tolerated. V. OTHER DRUGS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS These drugs are commonly used for pain due to BONE METASTASES. It is proposed that PROSTAGLANDINS are involved in the development of bone metastases. Prostaglandins increase the sensitivity of pain receptors (nociceptors) to painful stimuli. Nonsteroidal anti-inflammatory drugs are frequently used in addition to opioids in the management of bone pain. B. TRICYCLIC ANTIDEPRESSANTS In experimental systems, SEROTONIN and DOPAMINE enhance morphine analgesia, and NOREPINEPHRINE antagonizes morphine analgesia. These findings, although not proven in pathologic pain, provide a rationale for the use of tricyclics. Clinically, tricyclics appear to be most effective in the management of PAINFUL NEUROPATHIES (eg. postherpetic neuralgia, infiltration of nerve by tumor).

C. PHENOTHIAZINES Based on the above information, theoretically, we might expect phenothiazines to be antianalgesic, as they block dopamine receptors. Probably, any "analgesic" effect is related to sedation, especially in anxious patients. A similar effect is probably seen with ANTIHISTAMINES. BENZODIAZEPINES may serve the same purpose in anxious patients. D. STIMULANTS COCAINE was added to Bromptons mixtures (traditionally, morphine or heroin + cocaine in an alcohol vehicle) to counteract the sedation from the opioid. In recent years, morphine sulfate solution has been found to have efficacy comparable to a Bromptons mixture. Further, with "standard" formulae, the ability to titrate the individual ingredients in Bromptons is diminished. Cocaine may be useful as a local anesthetic in patients with head and neck cancer, when absorbed through mucous membranes rather than swallowed. DEXTROAMPHETAMINE or METHYLPHENIDATE (5mg BID) may be useful in patients who have intolerable sedation but can't decrease the dose of opioid without compromising the analgesic effectiveness. E. ANTICONVULSANTS PHENYTOIN, CARBAMAZEPINE, and GABAPENTIN, as well as other anticonvulsants, are often used to treat neuropathic pain. They tend to decrease "shoots" in shooting, lancinating pain, not affecting underlying nociceptive pain. F. MEMBRANE STABILIZERS Like the anticonvulsants, LIDOCAINE and MEXILITENE have been suggested to be useful in neuropathic pain. G. NMDA antagonists (eg. dextromethorphan) are being studied for pain. Animal data suggests two beneficial effects: prevention of tolerance to the analgesic effect of opioids (see below) and relief of neuropathic pain. Their use is investigational at this time. VI. TOLERANCE AND DEPENDENCE WITH OPIOID ANALGESICS TOLERANCE - This refers to an increased amount of opioid necessary to produce the same effect previously seen with a smaller amount of opioid. Tolerance develops to several opioid side effects - RESPIRATORY DEPRESSION, NAUSEA and VOMITING, SEDATION and CONFUSION. Twycross states that tolerance to the analgesic effect is

not a clinical problem when opioids are used in chronic pain in cancer patients. When patients require more opioid, their disease can frequently be seen to be progressive. Foley notes that tolerance develops to the ANALGESIC EFFECT and that cross tolerance between opioids is not complete. In either case, side effects permitting, opioid doses can be increased when previous doses are no longer as effective. When switching drugs, the possibility of incomplete cross tolerance may be considered, and a smaller than equianalgesic dose be started accordingly. PHYSICAL DEPENDENCE implies that a withdrawal syndrome can be seen upon abrupt withdrawal of an opioid or upon administration of an opioid antagonist. Physical dependence is a property of the drug, not the patient. It is generally not a concern in chronic pain in cancer patients. Should the need for opioid be decreased or removed, a withdrawal syndrome can be avoided by tapering the opioid over several days. It has been noted that withdrawal reactions can be prevented if the dose of opioid is 25% of the previous day's dose. PSYCHOLOGICAL ADDICTION or PSYCHOLOGICAL DEPENDENCE results from a variety of personality, environmental, psychosocial, etc. factors. It does not result from simply exposure to the opioid for a legitimate medical purpose. ADDICTION is NOT A CONCERN AMONG CANCER PATIENTS WITH CHRONIC PAIN.

L. Bressler November, 1997 Cancer Associated Hypercalcemia

I. II.

Cancer associated Hypercalcemia Treatment

OBJECTIVES 1. Describe, in brief, the pathophysiologic changes associated with cancer associated hypercalcemia. 2. Discuss the mechanism(s) of the various treatment modalities for cancer associated hypercalcemia.

3. Be able to discuss relative advantages and disadvantages of the various treatment modalities for cancer associated hypercalcemia, and to recommend treatment for specific patients. REQUIRED READING NONE SUGGESTED READING 1. Bilezikian JP: Management of acute hypercalcemia; N Engl J Med 326:11961203,1992 2. Hall TG, Schaiff RAB: Update on the medical treatment of hypercalcemia of malignancy; Clin Pharm 12:117-125, 1993 CANCER ASSOCIATED HYPERCALCEMIA Hypercalcemia is reported to occur in 10-20% of patients with malignancies. Malignancy is one of the most common causes of hypercalcemia. Certain cancers are more likely than others to cause hypercalcemia. The most common cancers that are associated with the development of hypercalcemia are SQUAMOUS CELL LUNG CANCER, SQUAMOUS CELL HEAD AND NECK CANCERS, BREAST CANCER, MULTIPLE MYELOMA, T-CELL LYMPHOMAS, RENAL CELL CANCER, AND OVARIAN CANCER. Hypercalcemia may be associated with BONE METASTASES in patients with solid tumors eg. metastatic breast cancer. Increased BONE RESORPTION by OSTEOCLASTS leads to hypercalcemia. The increased bone resorption in this setting may be mediated by PROSTAGLANDINS or other factors. In addition, TUMOR CELLS may be able to RESORB BONE DIRECTLY. Hypercalcemia is also associated with HEMATOLOGIC MALIGNANCIES like multiple myeloma or T-cell lymphomas. Again, hypercalcemia in these cases results from increased BONE RESORPTION by OSTEOCLASTS, mediated by lymphokines. Most widely studied in recent years is hypercalcemia associated with SOLID TUMORS WITHOUT BONE METASTASES eg. squamous cell lung or head and neck cancers. Hypercalcemia in these cases is due to a systemic humoral factor(s) that is produced by the tumor, the so-called HUMORAL HYPERCALCEMIA OF MALIGNANCY (HHM). Recent investigations have identified parathyroid hormone-related protein (PTH-rP) as a probable mediator of HHM. PTH-rP may act in conjunction with other factors (eg. TRANSFORMING GROWTH FACTOR ALPHA, TUMOR NECROSIS FACTOR, INTERLEUKIN-1) to cause the effects seen in humoral hypercalcemia.

The proximal cause of hypercalcemia in all of these situations is increased bone resorption. However, the kidneys help to maintain calcium homeostasis by increasing urinary calcium excretion when bone resorption increases. Changes in renal handling of calcium, then, are important in precipitating hypercalcemia in patients with increased bone resorption. Normal calcium reabsorption in the proximal renal tubule is linked with sodium reabsorption and with volume status. Hypercalcemia is associated with a decreased effect of ADH on the renal tubules, leading to dehydration. Dehydration leads to a decrease in GFR, increasing sodium and thus calcium reabsorption, and worsening the hypercalcemia. Other factors like vomiting also may also contribute to precipitating or maintaining hypercalcemia. Normal total serum calcium is about 8.5-10.5mg/dl. About 40% is bound to proteins, mainly albumin. Fifteen percent is complexed to anions, and 45% is the free, ionized, active form. Formulae are available for correcting calcium concentrations for changes in albumin. These are supposed to estimate ionized, active calcium, although the correlation with measured ionized calcium is questionable. However, ionized calcium is usually not measured, and the formulae, based on albumin, are frequently used (eg. corrected serum calcium = [(4 - albumin) X 0.8] + measured serum calcium) Clinical manifestations of hypercalcemia include GI: nausea, vomiting, constipation; NEUROLOGIC: weakness, lethargy, confusion, coma; RENAL: polyuria, thirst. Symptoms may depend on the rate of rise of calcium eg. slow, gradual increases may be less symptomatic than abrupt increases. Progressive hypercalcemia can lead to death. Prompt treatment is initiated in patients who are symptomatic and/or whose calcium is very high (eg. > 13mg/dl). Other patients are treated, but perhaps less urgently. Remember also, that certain drugs can contribute to hypercalcemia (eg. thiazides, lithium). TREATMENT: The first line of treatment for cancer associated hypercalcemia is HYDRATION with SALINE. Hydration repletes volume, and increases calcium excretion. Promotion of sodium diuresis leads to calciuresis as noted above. Hydration over 2 days (2-8L/day, depending on hydration status, of 0.9% NaCl) can decrease serum calcium by approximately 2mg/dl. Note that unless other treatment is initiated, or the underlying malignancy treated, calcium will rise again. FUROSEMIDE may be used to prevent fluid overload from hydration eg. in patients with CHF. Furosemide also has a calciuric effect and has been suggested as a treatment in addition to, or following, hydration. Reports of successful lowering of calcium with furosemide involved very high doses along with large volumes of fluid, strict electrolyte monitoring and replacement, and intensive care monitoring. Outside of this setting, dehydration from furosemide can offset any calciuric benefit, and its use should probably be reserved for patients who can't tolerate hydration, as noted above.

BISPHOSPHONATES - Today, bisphosphonates are probably the most frequently used calcium-lowering agents. They (ETIDRONATE, PAMIDRONATE) prevent osteoclastic bone resorption, and they may directly inhibit osteoclasts. Etidronate can also impair bone formation. For prompt response, bisphosphonates are given IV. Pamidronate is more potent than etidronate, and is probably used more often, although its clear superiority is not well documented. The recommended dose of pamidronate is 60-90mg IV. With either bisphosphonate, calcium decreases in about 48 hours and over the next 2 to 3 days, may fall to normal. Although commonly recommended for administration over 24 hours, pamidronate has been safely administered by short infusion (eg. 0.5-3 hours), making it attractive for outpatient use. Bisphosphonates are relatively free of side effects. There are reports of elevations of serum creatinine with etidronate in large doses. The clinical importance of mild reversible elevations is not clear. Because of the reports, the recommendations are to avoid etidronate in patients with serum creatinine greater than 5, and to decrease the dose when creatinine is > 2.5. Clinically, however, bisphosphonates may be safe to use even before patients are completely rehydrated (eg. while their creatinine may still be elevated). Oral etidronate has been recommended for maintenance of normocalcemia. Its efficacy is less well established than that of parenteral bisphosphonates. Doses up to 20mg/kg/day have been used. Although inhibition of bone formation is a potential concern, many patients with cancer associated hypercalcemia have a limited survival, and will be unlikely to suffer long-term consequences. PLICAMYCIN (mithramycin) is commonly used to treat cancer associated hypercalcemia after hydration. The dose is 25mcg/kg and should be reduced in patients with renal dysfunction (eg. by 50%). Plicamycin may be given as an IV bolus or infusion. Most side effects of plicamycin are associated with higher or repeated doses (eg. 2550mcg/kg/day x 5). These side effects include thrombocytopenia, coagulopathy, hepatitis. The 25mcg/kg dose given once and perhaps repeated in 48 to 72 hours if necessary is well tolerated. Although calcium is lowered to normal levels in a majority of patients, the duration of normocalcemia is variable. When plicamycin provides normocalcemia for 7 days or more, it can also be a useful agent for maintaining lowered calcium. GALLIUM NITRATE is given as a continuous IV infusion (200mg/m2/day x 5 days). It appears to be effective in a large proportion of patients. In a comparative study with etidronate, the median duration of normocalcemia was 8 days. Overall, gallium was reported to be more effective than etidronate. Gallium should be used after rehydration. Higher doses have been associated with nephrotoxicity, and it is recommended that gallium not be used in patients with serum creatinine greater than 2.5. Its relative place in therapy is yet to be defined, keeping in mind factors such as cost, duration of effect and duration of treatment, potential for nephrotoxicity, etc. CALCITONIN is also used to lower serum calcium. It works within several hours, and may be useful in lowering calcium acutely. Calcitonin may also be used in patients with renal insufficiency or before rehydration. Resistance develops quickly to calcitonin, and

although some investigators suggest that steroids prolong the effectiveness, others have not found that to be the case. Calcitonin requires frequent parenteral administration (IV or SQ). These latter factors make calcitonin a less than optimal choice for maintenance of normocalcemia. Finally, CISPLATIN has been used to treat hypercalcemia associated with certain malignancies. It may provide several weeks of normocalcemia. However, it should not be used in patients with renal insufficiency. Cisplatin should only be given to patients who have been well hydrated. Maintenance of normocalcemia may be achieved with intermittent administration of some of the agents described above to lower calcium initially (eg. plicamycin, pamidronate). Maintenance with oral etidronate was discussed above. ORAL PHOSPHATE is also used to maintain normocalcemia, provided patients are not hyperphosphatemic. Neutral phosphate capsules should be emptied and mixed with liquid. The starting dose of phosphate is about 1gm/day in divided doses. Diarrhea frequently impairs dose escalation and/or compliance, thus minimizing effectiveness.

Hormonal Treatment - Introduction L. Bressler November, 1997

Hormonal treatment Introduction Hormones in breast cancer Principles of use of hormone treatment in breast cancer Hormones in prostate cancer

OBJECTIVES 1. Discuss the settings for use of different hormones and hormone-related treatments in oncology. 2. Discuss common side effects of hormonal therapy in cancer patients. REQUIRED READING NONE


HORMONAL TREATMENT - INTRODUCTION Hormonal therapy is used extensively in the treatment of breast cancer, prostate cancer and lymphoid malignancies, as well as in the management of several complications of cancer (eg. brain metastases). Occasionally, hormonal therapy is incorporated into chemotherapeutic regimens for other solid tumors, on the basis that the tumor may have some hormone dependency. Many steroid hormone effects are mediated through interaction with HORMONE RECEPTORS. The steroid binds to a specific receptor in the cytoplasm. The STEROID/RECEPTOR COMPLEX is then translocated to the nucleus of the cell where it alters cell function through interaction with RNA. Some effects of steroids are nonreceptor mediated (ie. direct steroid binding to nucleic acids). The significance of such effects is not completely understood, but may have implications especially as regards the role of glucocorticoids in leukemias, lymphomas and multiple myeloma. The following is a brief overview of the use of pharmacologic agents for hormonal treatment of breast cancer and prostate cancer. It is not to be interpreted as a review on the treatment of these cancers. HORMONES IN BREAST CANCER About 30% of patients with breast cancer respond to various hormonal manipulations. This figure almost doubles when patients are selected on the basis of positive ESTROGEN RECEPTORS. Positive PROGESTERONE RECEPTORS in addition to positive estrogen receptor status increases the response rate even further. (Hormone receptor positivity is a quantitative measurement, not merely presence or absence.) Patients with higher estrogen receptor positivity tend to be OLDER and have SLOWER GROWING tumors than receptor negative patients. Tumors that have estrogen (progesterone) receptor positivity may respond to various hormonal manipulations, additive or ablative: TAMOXIFEN - Tamoxifen is an ANTIESTROGEN that binds to estrogen receptors. It is very well tolerated. Usual dose is 10mg BID. There is little evidence for a doseresponse relationship, although occasional patients will respond to higher doses after progressing on a lower dose. Ocular toxicity has been reported, primarily when high

doses have been used. Menopausal symptoms may be seen, especially in premenopausal women. DIETHYLSTILBESTROL (DES) - DES is as effective as tamoxifen in advanced breast cancer, but with more side effects. Thus, tamoxifen is commonly the first line hormonal agent. The usual dose of DES in breast cancer is 5mg TID. This may be associated with nausea/vomiting, so treatment can be initiated with a lower dose (5mg/day) and gradually increased to full dose over 1-2 weeks. Other side effects include SODIUM and WATER RETENTION and THROMBOEMBOLIC complications. AMINOGLUTETHIMIDE (AG) - AG may be used as a second (occasionally first or third) line hormonal agent in breast cancer. AG blocks the conversion of cholesterol to delta9-pregnenolone, an early step in adrenal steroid synthesis. More important in breast cancer, AG blocks the peripheral (eg. in fat, muscle) conversion of androstenedione to estrogen. With continued use of AG, the former mechanism is overridden by a compensatory increase in ACTH, thus AG is used in conjunction with HYDROCORTISONE (HC) (to suppress the reflex increase in ACTH). The latter mechanism, however, continues. And this mechanism is probably more important in breast cancer. Most side effects of AG are seen within the first six weeks of treatment. These include LETHARGY, DIZZINESS and RASH. In most cases, the drug need not be discontinued. A common dosing schedule is: AG 250mg BID + HC 100mg/day x 2 weeks, then, AG 250mg QID + HC 40mg/day. AG dose is increased, as the drug induces its own metabolism. Higher initial doses of HC may help minimize occurrence of the rash due to AG. Newer agents (eg. ANASTROZOLE) are selective aromatase inhibitors. They work by the second mechanism noted above, and don't affect adrenal steroid synthesis. Their relative place in therapy remains to be determined. PROGESTINS (eg. MEGESTROL 40mg QID) and ANDROGENS (eg. FLUOXYMESTRONE) may be used as second or third line hormonal agents. Megestrol is usually very well tolerated, frequently causing subjective improvement (eg. patients feel better). The major side effects of megestrol are weight gain (which is often desirable) and sweating. (The occurrence of weight gain with megestrol has lead to its use in cancer and AIDS cachexia.) Androgens are more likely to be associated with adverse side effects such as masculinization. PRINCIPLES OF USE OF HORMONE TREATMENT IN BREAST CANCER Responsive tumors commonly respond to subsequent hormonal manipulations after response, then progression, with a previous hormone therapy. Response to hormonal therapy is slow (ie. it can't be evaluated for about 6-8 weeks). Fast growing tumors and/or visceral involvement respond less well to hormones.

All hormonal agents have the potential to cause a "FLARE" of the disease, an apparent worsening with increased bone pain, hypercalcemia, etc. This is not necessarily an indication to discontinue the drug, although manifestations (eg. hypercalcemia) should be corrected. Flare reactions, when they occur, do so with in the first few weeks of therapy. WITHDRAWAL RESPONSES (ie. response seen when hormone therapy is discontinued) may also be seen in hormonally responsive tumors. Most of the above applies to the use of hormones in advanced breast cancer. Tamoxifen is also used as adjuvant treatment (ie. to prevent recurrence after primary breast cancer) in certain populations. HORMONES IN PROSTATE CANCER Hormones (or orchiectomy) are generally used in symptomatic STAGE D PROSTATE CANCER. DES - 1mg/day - This dose causes less cardiovascular toxicity (edema, thrombosis, phlebitis) and is as effective as higher doses that have been tested. Sometimes 3mg/day is used in an attempt to decrease testosterone to castrate levels. The CLINICAL BENEFIT of 3mg versus 1mg is not clear. IMPOTENCE and DECREASED LIBIDO are associated with DES. Other side effects include NAUSEA, HOT FLASHES, and GYNECOMASTIA. Gynecomastia can be prevented by local irradiation to the breasts prior to starting treatment. LEUPROLIDE - Leuprolide was reported to be as effective and have less toxicity than 3mg/day of DES. Leuprolide is a long-acting analog of luteinizing hormone releasing hormone (LHRH), which inhibits gonadotropin (and thus testosterone) secretion with chronic use. Leuprolide is given by daily subcutaneous injection or monthly (or longer) depot IM injections. Leuprolide is also associated with IMPOTENCE. Another common side effect is HOT FLASHES. Some non-hormonal treatments used to treat menopausal hot flashes in women (eg. clonidine) may be useful. GOSERELIN - Goserelin is another LHRH analog. It is administered monthly as a subcutaneous implant into the upper abdominal wall. Side effects are similar to those seen with leuprolide. FLUTAMIDE - Flutamide is an ANTIANDROGEN that inhibits either androgen uptake into cells or the binding of androgen in the nucleus of target cells. Flutamide thus blocks the effects of both testicular and adrenal androgen. It may thus be used in combination with an LHRH agonist to achieve "TOTAL ANDROGEN BLOCKADE". Initial treatment with LHRH agonists results in an increase in gonadotropin secretion. This can cause a "flare", which can be dangerous in patients with IMPENDING SPINAL CORD COMPRESSION or URINARY TRACT OBSTRUCTION. Flutamide is used to BLOCK this INITIAL FLARE. Flutamide may also be used ALONE as hormonal therapy in symptomatic Stage D prostate cancer. The dose of flutamide is 250mg TID. In contrast

to other hormonal therapies, flutamide appears to PRESERVE LIBIDO and SEXUAL POTENCY. (This benefit is not seen when flutamide is combined with an LHRH agonist.) The only side effect reported to occur more often with flutamide in combination with LHRH agonist than with LHRH agonist alone is DIARRHEA. Other antiandrogens include NILUTAMIDE and BICALUTAMIDE. High doses of KETOCONAZOLE (ie. 400mg q 8 hours) have been used to treat prostate cancer. This is based on the ability of ketoconazole to block adrenal and testicular androgen synthesis. In contrast to breast cancer, responses to sequential hormonal therapies in prostate cancer are less common.