OHO-13(221-226) 11/16/02 11:30 AM Page 221 Chapter 13 Clinical trials Methodology in cancer 222 Quality of life 224 OHO-13(221-226) 11/16/02 11:30 AM Page 222 CLINICAL TRIALS 222 Methodology in cancer Introduction Clinical trials can be classi \201ed as: (cid:2) Phase I studies (cid:2) Phas e II studies (cid:2) Phase III studies In addition, some Phase III studies are sometimes re ferred to as Phase IV or post-marketing studies. No study should be started without a protocol that describes in detail: (cid:2) Aim of the study (cid:2) Patient eligibility criteria (cid:2) Screening and follow-up studies (cid:2) Treatment (cid:2) Criteria to score toxicity and activity In add ition, rules for informed consent procedures should be speci \201ed. All of these criteria have been speci \201ed in guidelines produced by the International Conference for Harmoni zation for Good Clinical Practice (ICH-GCP). Phase I studies Phase I studies are human toxicology studies. Their endpoint is safety and they usually include 15 \200\22330 patients. They are designed to de \201ne a feasible dos e for further studies. These studies begin at a dose that is expected to be safe in man. Th is dose is projected from toxicology studies in animals, most frequently rodent studies (al though other species are used). If there is no difference in the sensitivity between species, the start- ing dose of the st udy in humans is frequently 10% of the LD10 (the dose that is lethal to 10% of the animals exposed to it) in mice. Once this dose is found safe, it is escalated. Dose escalation is u sually between cohorts and infrequently in individual patients. It can be: (cid:2) Accordin g to the Fibonnaci method (dose is escalated in decreasing percentages of the previous dose i.e. 100%, 66%, 50%, 33%, 25%). (cid:2) According to pharmacokinetics (Pharmacokinetically Guided Dose Escalation or PGDE), using a method that combines statistics with the experien ce and expectations regarding side-effects (continuous reassessment method). (cid:2) Variation on these methods. OHO-13(221-226) 11/16/02 11:30 AM Page 223 METHODOLOGY IN CANCER 223 The aim of the Phase I study is to describe the side-effects that limit further dose escala tion (dose limiting toxicities or DLTs) and to recommend a dose for further studies with th e drug or the new administration method (maximal tolerated dose or MTD). Most often the MTD is the dose level just below that that induces DLTs. This approach assumes that there is a linear relationship between drug dose and therapeutic effect. For studies with biological agents the MTD may be different from the optimal dose due to a bell-shaped ef \201cacy curve. Phase II studies In Phase II studies anti-tumor activity of a new drug or method is the end point. There are various statistical designs, including 14 \200\22360 patients on average. In the case of new drugs, where the exposure of patients to potentially inactive agents sho uld still be avoided, the design is aimed to exclude activity with a level of certainty, in stead of showing activity. With the emergence of drugs that create tumor dormancy rather than cell kill, the endpoint of time to progression becomes important. This is the time from the start of treatment unti l the \201rst evidence of tumor progression. In addition, Phase II studies can provide in for- mation on side-effects related to cumulative drug dose. Phase III studies Phase III studies have either time to progression or survival time as the endpoint. Phase III studies always include randomization against a standard form of therap y (although this may be \200\230best supportive care \200\231 in some situations), where t he randomization is included to avoid bias. Toxicity is never a major endpoint in Phase III trials which can involve between 50 and several thousands of patients. Study monitoring Long-lasting accrual periods have clearly hampered the quality of data and the enthusiasm of investigators has been shown to color the results they report. Therefore it is important that protocols do optimally de \201ne issues such as: (cid:2) Measurabili ty of the disease (e.g. minimum size of lesions still considered measurable). (cid:2) Criteria to use for toxicology reporting (e.g. the WHO or NCI Common Toxicity Crite ria (CTC) grading systems) and moni- toring of data which relate to both the anti-tumor res ponse and side-effects. To improve quality of data from clinical trials the implementation of systemic treatment ch ecklists has proven to be of value. OHO-13(221-226) 11/16/02 11:30 AM Page 224 CLINICAL TRIALS 224 Quality of life Introduction Most cancer treatment produce unwanted toxicities that interfere with the pati ent \200\231s quality of life. In many cancers the bene \201ts of new treat- ments over ex isting approaches have been modest. Thus there have been few examples of new treatments for common cancers that afford a dramatic improvement in cure rate; rather, small but incremen tal improvements in overall survival have been made. As new cancer treatments are developed, randomized, controlled trials are conducted to eval uate them, and a common problem is the comparison of a novel intensive treatment regimen ag ainst a relatively less toxic standard. In such circumstances, if the survival gain from th e new treatment is reliably established but of modest magnitude, then it may be questioned whether the gain is worthwhile for individ- ual patients. Does a small improvement in media n survival com- pensate for additional discomfort (and risks) experienced by the patient? The discomfort referred to here will be a compound of items comprising features of the trea tment itself (e.g. surgery, radiotherapy, or chemotherapy). It will include aspects associa ted with: (cid:2) Duration of treatment (cid:2) Length of hospital stay (cid:2) Number of c linic visits (cid:2) Short- and long-term toxicities (cid:2) Less clinical aspects (perhaps less well-appreciated) summarized as quality of life (QoL) Just as treatment-related toxic ity must be documented and compared between therapeutic regimens, it is also mandatory to c ompare QoL in randomized, clinical trials. Assessing health-related QoL Several questionnaires for completion by patients have been de vel- oped. The EORTC Quality of Life Study Group have developed a core questionnaire, the E ORTC QLQ-C30, to which are added disease- speci \201c modules. The core questionnaire cont ains 30 questions and, for example, the associated lung cancer module, QLQ-LC13, contains 1 3 further questions. To simplify the analysis of QoL scores, some of the items on these ins truments are combined. For the QLQ-C30 there are \201ve function, three symptom, and one global health-status scales. A patient who scores high for global health-status/QoL is deem ed to have high QoL. OHO-13(221-226) 11/16/02 11:30 AM Page 225 QUALITY OF LIFE 225 Frequency of QoL questionnaires (cid:2) Baseline QoL after consent but before randomization (cid:2) Not too frequent to bur den patient (cid:2) Frequent during active treatment period (cid:2) Assess multiple scores for statistical analysis Dif \201culties in QoL assessment (cid:2) Compliance declines as patient becomes terminal (cid:2) Compliance may also be poor if patient feels well (cid:2) Surrogate, relative, nurse, physician can \201ll in form? \200\230Missing \200\231 data The missing response may result from an oversight by the pat ient but alternatively may be due to ambiguity in the question or the patient \200\231s rel uctance to answer the particular item. It is often important to the investigator to collect information on the impact of treatment on psycho-sexual aspects of the patient \200\231s Q oL, but patients may regard items relating to sexuality as embarrassing or not relevant. In such cases, the fact that such data is \200\230missing \200\231 will need to be reported. However, a trial nurse who is sensitive to the patient \200\231s wishes for privacy will o ften facilitate the collection of complete data. Clinical trials In planning a clinical trial it is fundamental to consider the number of pa tients required to demonstrate the anticipated change in treatment outcome. When survival i s the primary endpoint of the study, this may be expressed as the anticipated improvement i n median survival time or reduction in hazards ratio for the test group over the control. I n trials comparing treatments in terms of QoL, it is dif \201cult to quan- tify the \200 \230gain \200\231 (or \200\230loss \200\231) that may be anticipated with the test therapy . In addition, there will be many aspects of QoL that are measured and it may be dif \201c ult to predict which of these should be the primary endpoint variable that is required for sample size calculations. In prac- tice, QoL data are rarely used as the primary determinan t of trial size. There are important challenges in reporting QoL outcomes in clinical trial s. These include the description of compliance, sum- marizing longitudinal data in a comple te yet clinically meaningful way, balancing the multiple endpoints under consideration, and perhaps, most importantly, relating the \201ndings with regards to QoL to other treatmen t outcomes such as patient survival and treatment-related toxicity. Attempts have been made to integrate QoL and survival data into quality-adjusted life years (QALY). The duration of survival is adjusted according to periods of different levels of Q oL before OHO-13(221-226) 11/16/02 11:30 AM Page 226 CLINICAL TRIALS 226 summing to give the overall survival time for analysis. Thus, a month during which the QoL is high will contribute more to the QALY than will a month with a lower score. The \201na l QALY can then be used for a comparison between treatments, embracing both survival effect s and changes in QoL. However, this integration process has not been readily accepted \200 \224its application is clearly limited by the arbitrary choice of weights or values put ont o different levels of QoL. It should be recognized that including the measurement of QoL into cancer clinical trials a dds a considerable burden. This burden is felt immediately by the trial team as it may affe ct the basic trial design, the content of the protocol, and patient follow-up schedules. It may impact on patient numbers. Implementing the trial will burden the patients themselves and the clinical team. It will increase the volume of data to be collected and may adversel y affect the overall data quality. It will certainly increase the complexity of analysis an d report- ing. All this adds to overall trial costs. It is important to give due consideration to these factors when con- sidering whether or no t assessment of QoL is an essential part of a trial. In general however the dif \201cultie s are justi \201ed in cancer studies. OHO-14(227-248) 11/18/02 8:16 AM Page 227 Chapter 14 Principles of palliative care Pain control 228 Control of other symptoms 235 Supporting cancer patients 240 The \200\230 holistic \200\231 approach to cancer 244 Further reading 248 OHO-14(227-248) 11/18/02 8:16 AM Page 228 PRINCIPLES OF PALLIATIVE CARE 228 Pain control Introduction Roughly 80 \200\22390% of pain due to cancer can be relieved relatively simply with oral analgesics and adjuvant drugs in accordance with World Health Organization (WHO) guidelines. WHO guidelines should be used in combination with interdisciplinary management . Relief of pain at the expense of side-effects is unacceptable to most patients; therefore a variety of treatment modalities is required. Failure to control pain can result in many other problems e.g. fatigue, anorexia, depressio n, anxiety, constipation, nausea, and hope- lessness. It is more dif \201cult for the pati ent with pain to continue with demanding cytotoxic treatment and hospital visits. Pain cont rol is an obvious priority for patients with cancer, whether embarking on cura- tive or pal liative treatment. The commonest causes of uncontrolled cancer pain are: (cid:2) Lack of sophistication in patient assessment, resulting in mis- diagnosis of cause and type of pain and failure to detect general distress, which lowers the pain threshold. (cid:2) Lack of a systematic approach to analgesia. \200\230Panic prescribing \200\231 is more likely to result in unacceptable side-effects. (cid:2) Lack of knowledge of opioid pharmacology and of evidence for adjuvant analgesics an d non-steroidal anti-in \202ammatory drugs. (cid:2) Lack of sophistication in use of opioi ds and adjuvant analgesics, in particular, failure to prevent or treat drug side-effects. An accurate patient assessment underpins appropriate analgesic choice. If pain distress is greater than pain severity and this is not identi \201ed it means: (cid:2) The patient is especially susceptible to opioid toxicity (pain is the physiological antagonist to the side-effects of opioids). (cid:2) The \200\230pain \200\231 will never be adequately dealed with if pyschological distress is treated as a physical pain. (cid:2) Appropriate strength of analgesic cannot be chosen. Principles of the WHO ladder (cid:2) Strength of analgesic chosen (i.e. step of ladder) depends on severity of pain, not stage of disease. (cid:2) Adjuvant analgesic is chosen according to cause and type of pain. (cid:2) Opioids s hould generally be used in combination with non- opioids. OHO-14(227-248) 11/18/02 8:16 AM Page 229 PAIN CONTROL 229 Freedom from cancer pain Opioid for moderate to severe pain Non-opioid Adjuvant Pain persisting or increasing Opioid for mild to moderate pain Non-opioid Adjuvant Pain persisting or i ncreasing Non-opioid Adjuvant Pain The WHO analgesic \200\230ladder \200\231. (Reproduced with permission.) The prototype analgesics for each step of the analgesic ladder are: (cid:2) Step 1: paracet amol or non-steroidal anti-in \202ammatory drug (NSAID). (cid:2) Step 2: codeine or dextropropoxyphene + paracetamol or NSAID. (cid:2) Step 3: morphine or diamorphine + paracetamol or NSAID. Opioids should be prescribe d at regular intervals. Therapeutic doses should be given and codeine preparations with sub -therapeutic doses of codeine (<30 mg) should be avoided (e.g. codydramol, cocodamol, cocod aprin). Prescribed doses and indications for the common adjuvant anal- gesics are listed in the tab le. There is evidence for the tricyclic anti- depressants and carbamazepine in neuropathic pain but the former generally have fewer side-effects and should usually be used \201rst. There is strong evidence for the effectiveness of NSAIDs as anal- gesics; however, their us e will depend on the individual risk:bene \201t ratio. Those at high risk of side-effects are: age >60 years (cid:2) (cid:2) past history of peptic ulcer smokers concomitant steroid use (cid:2) (cid:2) O H 2 3 0 O 1 4 ( 2 2 7 2 4 8 Table 14.1 Adjuvant analgesics (drugs with a primary indication other than pain) ) Dosage Drug Side-effects Indications 1 1 NSAIDs e.g. ibuprofen, diclofenac naproxen See prescribing information for specific guidance Gastric irritation; \202uid retention; headache; vertigo; caution in renal impairment Bone metastases; soft tissue in \201ltration; liver pain / 1 8 / 0 2 Steroids e.g. dexamethasone 4 \200\22316 mg/day po, sc, iv Raised intracranial pressure; nerve compression; soft tissue in \201ltration; liver pain Gastric irritation if together with NSAID; \202uid retention; confusion; Cushingoid appea rance 8 : 1 6 Amitriptyline 25 mg nocte (starting dose) Titrate according to response and tolerability Nerve pain \200\224any type Sedation; dizziness; dry mouth; constipation; urinary retention A M P Carbamazepine 200 mg nocte (starting dose) Titrate according to response and tolerability Vertigo; constipation; rash Nerve pain \200\224any type a g e 2 3 0 OHO-14(227-248) 11/18/02 8:16 AM Page 231 PAIN CONTROL 231 There is no evidence as yet of the superiority of the selective Cox 2 inhibitors available. Sulindac has been favored for patients with renal impairment needing a NSAID. Effective use of morphine The keystone to using morphine for moderate to severe pain is in proper prescribing, patient reassessment, patient information, and prevention of side-effec ts. Ideally start with a quick-acting morphine preparation. This has onset of analgesia in 20 \200\22330 minutes, which peaks at 60 minutes, and, when the required dose for the individu al \200\231s pain is reached, will last four hours. This information should be given to the patient. Morphine may relieve pain completely, partially, or not at all. It was previously thought t hat some pains, especially neuropathic pain, were unresponsive to opioids. Clinical practic e and evidence from clinical trials tells us that opioid responsiveness is a continuum and no pain can be predicted as opioid-unresponsive. It is true that neuropathic pain often req uires larger doses of opioids and titration is limited because at higher doses unacceptable side-effects, especially sedation, are problematic. It is obvious that if side-effects of opioids are not prevented or mini- mized, especially sedation, then titration of opioids and subsequently pain control is not achieved. Review a nd rationalization of all drugs, especially drugs with sedative side-effects, is mandatory for successful titration of opioids. Monitoring of symptoms of opioid toxicity as part of r egular patient review will prevent much distress and also save on resources such as unneces sary hospital admissions with confusion, cerebral imaging, and blood analysis. Opioid toxic ity is a spectrum, which includes vivid dreams, shadows at the periphery of visual \201el ds, nightmares, hallucinations, agitation and confusion. These features can be associated w ith myoclonic jerks or even generalized seizures. The management of opioid toxicity is to reduce the dose of the opioid and reassess the pain syndrome, psychological factors, and Table 14.2 Preventing opioid toxicity Side-effect Management Constipation Regular codanthramer or codanthrusate Dry mouth Frequent sips of cool water and regular mouth washes Nausea/vomiting Haloperidol 1.5 \200\2233 mg nocte or metoclopramide 10 mg 8-hourly Sedation Explanation very important. Expect to settle in about 2 \200\2233 days. Avoid other sedatin g medication where possible OHO-14(227-248) 11/18/02 8:16 AM Page 232 PRINCIPLES OF PALLIATIVE CARE 232 Table 14.3 Management of dif \201cult pain Bone pain Palliative radiotherapy; NSAIDs with opioids titrated to control pain; consider bisphosphon ates Neuropathic (nerve) pain Titrate through analgesic ladder, remembering adjuvants (amitriptyline, carbamazepine, or s teroids); consider nerve block Rectal/vaginal/bladder pain Use standard analgesic ladder approach (+ nifedipine amitriptyline, steroids); consider nerve block, local anesthetic gel, steroid enemas Bed sores NSAIDs biochemistry as appropriate. Haloperidol (1.5 \200\2233 mg po/sc, repeated as necessary) ma y be required to manage the altered sensorium in the acute situation. Rehydrate as appropri ate \200\224patients who are opioid- toxic are usually dry-mouthed. Often pain is still controlled on the reduced dose of opioid. Sometimes an adjuvant drug ma y be needed. If the patient was using the opioid as an anxiolytic, another approach to anxi ety is needed. Occasionally opioid toxicity heralds renal dysfunction. In renal failure, a reduction in op ioid dose may need to be accompanied by a reduction in dosing frequency. Liver dysfunction usually has to be severe before opioids accumulate. Methadone is safer than morphine in sev ere liver dysfunction. NMDA antagonists N-methyl-D-aspartate (NMDA) antagonists have a role in some pains, especia lly neuropathic pain and dif \201cult in \202ammatory pains. Unfortunately, a convenient preparation is missing. However, SC or IV ketamine may be considered after seeking advice f rom a palliative care or pain team. Alternative opioids There are second-line opioids for moderate to severe cancer pain. The p otential bene \201t in a switch from one opioid to another is a better balance between ana lgesia and unwanted effects. There are no controlled trial data at present to indicate de \201nite bene \201ts of one opioid over another. However, the following is suggested: (cid :2) TTS-Fentanyl \200\224may cause less constipation than morphine. Suitable for stable pai n. Time to peak blood levels is 12 hrs (up to 48 hrs in some patients) and terminal half-li fe after patch removal is up to 24 hrs. It is usually unsuitable in uncontrolled pain. The manufacturer \200\231s conversion chart is about right. OHO-14(227-248) 11/18/02 8:16 AM Page 233 PAIN CONTROL 233 (cid:2) Hydromorphone \200\224useful if patient has cognitive impairment or hallucinations on morphine. May be useful in renal dysfunction because no known accumulation of active met abolites. Available as quick-acting and controlled-release capsules. Hydromorphone is about seven times as potent as morphine. (cid:2) Oxycodone \200\224similar bene \201ts to hydromorphone. It is about equipotent wit h morphine (2:3). Available as quick-acting and controlled-release preparations. (cid:2) Phenazocine \200\224useful if dysphoria with morphine. Size of tablets limits use (5 mg tablet is equivalent to 20 mg morphine). (cid:2) Methadone \200\224alternative to morphine. However, for the non- specialist, dif \201cult to titrate. Equianalgesic dose is variable; methadone can be up to 10 times as pot ent as morphine. When switching from one opioid to another, the equi-analgesic doses are not always easily p redictable because the relative potencies of the two drugs are the result of the complex va riables. Equi-analgesic doses are just for guidance and careful reassessment is required af ter an opioid switch. Incident pain Bone pain is, in fact, responsive to opioid analgesia. However, bone pain on movement can be dif \201cult to control with opioids alone. Pain is a physiological antago nist to the side-effects of opioids, and inter- mittent pain allows less titration of opioi ds since the patient is unacceptably sedated at rest. NSAIDs and radiotherapy are usually e ssential adjuncts where possible. It is appropriate to try a break- through dose of quick-a cting oral morphine 20 \200\22330 minutes before movement. However, surgical intervention ( e.g. for spinal stabiliza- tion or anesthetic block techniques) should be considered sooner rather than later. Bisphosphonates Bisphosphonates should be considered in bone pain secondary to breast carci noma an to multiple myeloma; intravenous pamidronate, in doses ranging from 60 \200\22390 m g, 2 \200\2234 times weekly, is used. Work to assess the role of bisphosphonates in other c ancers, such as prostatic carcinoma, is underway. Whilst intravenous pamidronate is success ful in some acute-pain situations, there is no way at present of predicting for whom it wil l be effective. Anesthetic techniques In a minority of patients, carefully managed drug treatment, with or without palliative radiation or chemotherapy or hormonal therapy, fails to provide acceptab le pain relief or does so only at the cost of intolerable side-effects. In these cases anes thetic techniques should OHO-14(227-248) 11/18/02 8:16 AM Page 234 PRINCIPLES OF PALLIATIVE CARE 234 be considered. Anesthetic techniques should also be considered in acute situations e.g. pat hological fracture awaiting internal \201xation. Consider the early use of anesthetic tec hniques if: (cid:2) Failure of pharmacological management due to side-effects in the presen ce of opioid-responsive pain; this may bene \201t from spinal opioids (cid:2) Pancreatic pain \200\224coeliac plexus block (cid:2) Nerve in \201ltration \200 \224brachial plexus block or epidural local anaes- thetic/steroids if lumbosacral nerve pain (cid:2) Un \201xed/un \201xable fractures or unstable bones Non-drug methods These should be used in conjunction with drug treatment and include: (cid: 2) Occupational therapy (cid:2) Physiotherapy (cid:2) Relaxation therapies (cid:2) Transcut aneous electrical nerve stimulation (TENS) (cid:2) Acupuncture OHO-14(227-248) 11/18/02 8:16 AM Page 235 CONTROL OF OTHER SYMPTOMS 235 Control of other symptoms Introduction Symptom control requires accurate assessment and history taking, with individu alized treatment and a holistic approach. Good symp- tom control enhances quality of life a nd trust in the carers. The aim should be to integrate active symptom control with anti-tum or therapy through the whole course of the patient \200\231s illness. Nausea and vomiting Nausea occurs in 40 \200\22370% of patients with advanced cancer. Its a ppro- priate management is dependent on establishing the probable cause and mechanism. (cid :2) Raised intra-cranial pressure (cid:2) Acute abdominal pathology (cid:2) Constipation (c id:2) Renal failure (cid:2) Hypercalcaemia (cid:2) Drugs A \201rst-line anti-emetic is se lected according to the most likely cause and administered via a suitable route. If vomitin g prevents oral administration, other options include sublingual and rectal routes, as well as IV/IM/SC. If symptoms persist after 24 hours, second-line or combination therapy should be introduced. Breathlessness Breathlessness is commonly multifactorial in origin. Simple reversible cause s (pleural or pericardial effusion, anemia, \202uid overload, asthma) must be corrected. A multidisciplinary approach is helpful, with consideration given to non-pharmacological st rategies such as breathing exercises, relaxation therapy, massages, and other comple- menta ry therapies. Patients should be helped to adjust their lifestyle and expectations. The following treatments may be used singly or in combination: (cid:2) Nebulized saline for tenacious secretions. (cid:2) Morphine eases the sensation of breathlessness \200\224current evidence of nebulized morphine does not support its use. (cid:2) Benzodiazepines \200\224bring relief through anxiolytic and sedative effects and, p ossibly, muscle relaxation. Concerns about respiratory depression are usually unfounded. O H 2 3 6 O 1 4 ( 2 2 7 2 4 8 ) 1 Table 14.4 Selection of antiemetics 1 / 1 Cause of nausea/vomiting Antiemetic Dose schedule Class of drug 8 / Metoclopramide Gastric stasis Prokinetic 20 \200\22330 mg qid 0 2 Gastric irritation (drugs, abdominal radiotherapy) Metoclopramide; ondansetron; granisetron 20 \200\22330 mg qid, 8 mg bd, 1 mg bd Prokinetic and dopamine antagonist; 5HT3 antagonist 8 : Cyclizine; haloperidol, dexamethasone Bowel obstruction 50 mg tds, 2 \200\2235 mg bd, 2 \200\2234 mg bd Antihistaminic and 1 6 anticholinergic; dopamine antagonist; corticosteroid Dopamine antagonist; 5HT3 antagonist; corticosteroid A M Chemical (chemotherapy, radiotherapy) Haloperidol; ondansetron; granisetron; 2 \200\2235 mg bd, 8 mg bd, 1 mg bd, P 2 \200\2234 mg bd dexamethasone a g e 2 3 6 O H O 1 Hypercalcaemia/ uraemia 4 ( Abdominal radiotherapy Intestinal distension Morphine/ digoxin 2 Hyponatraemia Movement/vertigo 2 Gastric irritants 7 Fear/ anxiety Raised intra- cranial pressure Clonidine Cytotoxic chemotherapy 2 4 8 2 Vestibular nuclei Cerebral cortex 5HT3 D2 ? 5HT3 ) AChm Area postrema Hl GABA 5HT Gut wall 1 1 / 1 Vagal/splanchnic afferents 8 / 0 2 8 : Emetic pattern generator (Vomiting center) 1 6 C O N T R O L O F O T H E R S Y M P T O M S A M -opioid 5HT2 AChm Hl P a g e 2 3 Gastric atony Retroperistalsis Thoracic and abdominal muscle contractions 7 Diagram of the neural mechanisms controlling vomiting. Modified from Twycross et al., 1997. Abbreviations refer to receptor types: ACHm = muscarinic cholinergic; (cid:2)2 = alpha-adr energic type 2; D2 = dopamine type 2; GABA = gamma-aminobutyric acid; 5HT, 5HT2, 5HT3 = 5-h ydroxytriptamine (serotonin) type undefined, type 2, type 3; H1 = histamine type 1. 2 3 7 OHO-14(227-248) 11/18/02 8:16 AM Page 238 PRINCIPLES OF PALLIATIVE CARE 238 (cid:2) Oxygen therapy should be considered on an individual basis. A trial of continuous o r intermittent oxygen accompanied by some form of subjective assessment by the patient and oximetry may be helpful. Constipation The aim should be to anticipate and prevent this ubiquitous problem. Constipat ion may result in nausea, colic, over \202ow diarrhea, urinary retention, or an acute conf usional state. Common causes in malig- nancy are: (cid:2) Drugs (particularly analgesics) Immobility (cid:2) Dehydration (cid:2) Hypercalcaemia (cid:2) Spinal cord compression (cid: 2) Pelvic or abdominal tumor If well enough, patients should be encouraged to increase \202uid and \201bre intake and mobilize. When opiate analgesics are prescribed, a laxativ e (usually a softener and a stimulant) should routinely be added. (cid:2) Drug therapy is straightforward. A softener laxative such as sodium docusate is prescribed if the stool is hard; a stimulant laxative (e.g. senna), if unable to expel stool; and a co mbination preparation (e.g. codanthramer/codanthrusate) for a mixed picture. Lactulose can cause troublesome wind. Rectal examination is required to identify fecal impaction and this may require suppositories, enemas, or digital evacuation. Lymphoedema Failure of lymph drainage is commonly due to tumor in \201ltration of lymphati cs and/or compromise of these channels by surgery, radio- therapy, or both. It is important to exclude venous occlusion as a cause of limb swelling and oedema. Prevention is the best strategy, with attention to massage and exercise, and avoidance of, and vigorous therapy f or, cutaneous infection, in patients at risk e.g. following axillary lymph node clearance f or breast cancer. Treatment of established lymph oedema requires daily skin care, self-massage, exercise, and the use of \201tted compression garments. Refractory oedema may require pressure bandagi ng before compres- sion garments can be \201tted. The value of mechanical devices such as the \202owtron pump is uncertain. In selected patients, a therapeutic trial of corticost eroids or diuretics may be appropriate. OHO-14(227-248) 11/18/02 8:16 AM Page 239 CONTROL OF OTHER SYMPTOMS 239 Anorexia/cachexia The precise mechanisms by which cancer causes anorexia and weight loss ar e still poorly understood, although circulating cytokines such as tumor necrosis factor cle arly play a role. This may be compounded by physical obstruction of the GI tract by tumor, therapeutic interv entions, and depressed mood. Control of nausea should be optimized and attention paid to pa in control, mouth care, and constipation. Simple dietary advice and the use of alcohol can help. While enteral/parenteral feeding may be appropriate during active anti-cancer therapy, it i s less appropriate as the disease progresses. Judicious prescription of progestagens or cor ticosteroids can aid appetite but will not usually in \202uence cachexia. Psychological distress Assessment of psychological problems and the provision of psycho- lo gical support must be an integral part of the package of care for patients with malignant d isease. Presentation may be in the form of denial, anger, anxiety, or depression. All healt h care professionals should be aware of the frequency with which psychological problems are overlooked and all patients should be given time and space to voice their distress. Patien ts should be given control over their management and helped to set realistic goals and deve lop coping strategies. Medical staff should recognize when drug therapy (antidepressant or anxio- lytic) or referral to a psychologist/liaison psychiatrist and/or specialist palliati ve care team is required. OHO-14(227-248) 11/18/02 8:16 AM Page 240 PRINCIPLES OF PALLIATIVE CARE 240 Supporting cancer patients Introduction For cancer patients, the trauma of diagnosis, protracted and some- times toxic curative treatments, possible disease relapse, with progres- sion to incurable and increas ingly disabling or terminal disease, provokes intense, often distressing emotional and psyc hological reactions. These may include: (cid:2) Fear (cid:2) Anxiety (cid:2) Anger (cid:2) Confusion (cid:2) Sense of loss (cid:2) Alienation (cid:2) Sadness/depression The cancer no t only impacts on the patient personally, but also on family, friends, their work, and \201nances. Up to one-third of cancer patients suffer signi \201cant psychological morbidi ty. Appropriate support interventions can help alleviate much of their distress. Palliative care is synonymous with good supportive care, at every stage of a cancer illness . Palliative care ameliorates all distressing symptoms, whether physical, psychological, so cial, or spiritual in an integrated approach, as essential in achieving the best of quality of life for patients and families. For patients with a terminal diagnosis, it strives to e nable them to live as actively as possible until death, while offering support of the famil y during the patient \200\231s illness and in their own bereavement. Detecting patients in need of support All patients bene \201t from support but assessment of the following can identify patients at particular risk: (cid:2) Degree of physical disab ility Internal resources of the patient (cid:2) (cid:2) Past history of functioning (cid:2) Social supports \200\224family (marital status, living arrangements, number of family members in the immediate geographical area and their capacity and willingness to provide support), friends, community/church links (cid:2) Hist ory of substance abuse OHO-14(227-248) 11/18/02 8:16 AM Page 241 SUPPORTING CANCER PATIENTS 241 Use a standardized measure of psychological morbidity and quality of life such as: (cid:2) Hospital Anxiety and Depression Scale (HADS) (cid:2) Functional Assessment of Cancer Therap y (FACT) (cid:2) Functional Living Index \200\223Cancer (FLIC) (cid:2) Cancer Rehabilitatio n Evaluation Systems (CARES) (cid:2) European Organization for Research and Treatment Quali ty of Life Questionnaire (EORTC QLQ-C30) (cid:2) The Schedule for Evaluation of Individualized Quality of Life (SEIQoL) \200\224allo ws patients to nominate the aspects of life they consider important in the evaluation of Qo L, and they are scored on these Providing support We can all offer support to cancer patients. Cancer patients tell us that they need to \201nd meaning and hope in the midst of deterioration, dis- tress, and desp air. Our challenge is to \201nd the balance in providing hope and alleviating fears throu ghout the cancer journey. Communication Effective communication is the cornerstone of good supportive care. Patients should be able to participate in decisions about their care, allowing them to retain some c ontrol over their lives. Doctors are not legally or ethically obliged to provide treatments that are futile or pro- long life (and sometimes the distress of dying) at all costs. Comp etent patients are entitled to refuse life-prolonging or life-sustaining treat- ments. Pote ntial con \202ict about such decisions can be avoided by good communication. Patients need honest, compassionately delivered information. Poor communication and breaking of bad news are consistently mentioned by patients and fami lies as a cause of stress and dissatisfac- tion. Good communication builds trust, reduces u ncertainty, and allows appropriate adjustment (practical and emotional) by patient and fami ly, thus reducing psychological morbidity. Breaking bad news is not a single, isolated even t. The process is ongoing and recurring, involving telling the diagnosis, updating the pati ent and family on changes and, possibly, preparing them for death. Breaking bad news \200\224a ten-step approach This approach can be used as a general framew ork and adapted for speci \201c situations. Remember, a patient has a right but not a duty to hear bad news. 1. Preparation: (know the facts; arrange the meeting; \201nd out who the patient wants present). OHO-14(227-248) 11/18/02 8:16 AM Page 242 PRINCIPLES OF PALLIATIVE CARE 242 2. Establish what the patient already knows (both doctors and family generally underestimat e the level of patient \200\231s knowledge). 3. Establish whether the patient wants more information. 4. Allow denial (denial is a defen se and a way of coping). Allow the patient to control the amount of information. 5. Give a warning shot (allows patient time to consider their own reactions and whether the y feel able to ask for more information). 6. Explain (if requested \200\224be clear and sim ple; avoid harsh state- ments; avoid medical jargon; check understanding; be as opti- misti c as possible). 7. Listen to concerns (avoid premature reassurance or excessive explanations). 8. Encourage ventilation of feelings (the key phases, as it conveys empathy). 9. Summarize and make a plan (reduces confusion and uncertainty; fosters hope). 10 Offer availability (communicating bad news is an ongoing process). Formal counseling/psychological therapies Some patients will need more formalized support \200\224trained counsel- lors, social workers, hospital chaplains may provide this. Cogniti ve \200\223 behavioral and brief psychotherapeutic interventions are effective for more sig ni \201cant levels of anxiety or depression e.g. adjuvant psy- chological therapy. Psychiatric interventions When psychological interventions are inadequate, psychotropic med ication may help. Drug therapy bene \201t 20 \200\22325% of cancer patients suffering sign i \201cant anxiety and depression. Support groups and information services These can help to reduce the sense of alienation an d isolation some- times associated with cancer. They facilitate the sharing of experi- ence s, the ventilation of feelings in a supportive environment, and the exchange of information about the physical, psychological, and social consequences of cancer and its treatment (e. g. Bristol Cancer Help Center, Cancer BACUP, Cancerlink). Support in death Often it is the actual mode of death that patients fear rather than the fa ct of dying e.g. \200\230What will it be like? \200\231 or \200\230I \200\231m afraid of dying in agony \200\231. Patients need reassurance that any physical distress can be allevi ated and that death is normally peaceful. Issues of spirituality may be important for indiv idual patients and religious ritual should be facili- tated where possible. Doctors need to be sensitive to psychological dis- tress (a sense of hopelessness, despair, meaninglessnes s; questions OHO-14(227-248) 11/18/02 8:16 AM Page 243 SUPPORTING CANCER PATIENTS 243 such as \200\230why me? \200\231) as it often masks intractable, distressing, physical sym ptoms (e.g. pain). During \201nal hours, patients should never be left alone to feel isolated or abandoned. Families need to be involved, and this includes children; they need to be kept updated on c hanges and encouraged to be present. Good care of a patient \200\231s family will reduce th e likelihood of complicated bereavement. If the family can \200\231t be there, a member of staff should sit with the patient. Staff stress Supporting cancer patients is stressful to the health professionals involved. Staff also need support structures (including training in communication skills, as well as direct supportive measures such as counseling and relaxation therapies). OHO-14(227-248) 11/18/02 8:16 AM Page 244 PRINCIPLES OF PALLIATIVE CARE 244 The \200\230holistic \200\231 approach to cancer