Jennifer A. M. Philip
Comprehensive care of a woman with gynecologic cancer involves anticancer treatment (directed at either cure or control of the cancer), good symptom relief, and personal and family support. In the setting of progressive disease, the priorities for care, from the patient's perspective, must be clarified. Such priorities may reflect the preferred place of care when dependency increases, the use of time for important tasks, and the personal issues involved in preparation for death. These matters should not be suddenly raised at time of crisis. Rather, discussion, elucidation, and realization of such priorities should occur over time and multiple clinical encounters. There is no dichotomy between care concerned with cure or control of cancer and care when disease is irreversibly progressive; all is concerned with enhancement of life (1).
The concept of “mixed management” or what may be better called “parallel care,” implies attention to the principles of palliative care (personal and family support, symptom relief, and care planning/death preparation) from the time of diagnosis of a disease that is likely to prove to be an eventually fatal illness, e.g., advanced ovarian cancer. The deficiencies associated with introducing palliative care and symptom relief only when anticancer treatments have failed have been well documented. Instead, the provision of palliative care concurrent with anticancer treatment is widely advocated (2,3).
The goals of palliative care should be to facilitate comfort, autonomy, dignity, as well as personal rehabilitation and development, especially in the face of an incurable illness.Efforts must be directed at assisting the patient to have realistic expectations and well-grounded hope in what will not fail her, notably in the fidelity of her caregivers, and a recognition of her own unique value as a person, come what may. The patient's quality of life will be determined by many aspects of her life including her values, her relationships, her sense of selfworth as well as health related matters. A woman can achieve much and indeed may report “quality” in a number of areas, even in the face of progressive illness. The challenge for health caregivers is to create a climate in which such achievements may emerge.
The last phase of life is crucial to the completion of a human life. Patients report that important issues at the conclusion of a fulfilled life include relief of pain and other symptoms, clear decision making by professionals, preparation for death, being able to contribute to others, and being affirmed as a whole person (4,5). During this final phase, whether it be months, weeks, or days, it is the responsibility of the medical and nursing professions, through careful symptom relief, good communication, and a supportive relationship, to facilitate maximum autonomy and dignity. The attitude of the physician to this last phase of life and to death itself may color clinical judgment. In general, it is crucial for the bond between the patient and her primary care physician to be strengthened at this time, and a continuity of professional relationships is desirable (6).
Practical Aspects of Palliative Care
The palliative care of a woman with advanced gynecologic malignancy involves several components: assessment, clarification and delineation of therapeutic options, implementation of treatment, evaluation of outcome, continuing review and reassessment, and prognostication. Attention to each of these clinical tasks is necessary for a woman to maximize her possibilities in the final part of life.
It is essential to make a comprehensive assessment, which includes listening to the patient's experience with her cancer, from the prediagnostic phase to the current time. There should be detailing of responses to treatments, side effects experienced, hopes realized and conversely, disappointments encountered. The narrative of the illness experience will give information on not only the patient's responses, but also her vulnerabilities and her supports. It also establishes a shared understanding of what has gone before, and as such is a much more useful therapeutic tool than a checklist approach.
A comprehensive assessment involves at least:
An adequate assessment may involve interaction not only with the patient, but also with family members and friends, though the extent of this interaction will be subject to the woman's wishes. The assessment should be regarded as a continuous process, as both the circumstances of the illness and the woman's priorities are constantly changing.
Clinical Decision Making
On the basis of a comprehensive assessment, with or without further investigations to elucidate the mechanism of troublesome symptoms, it is normally possible to delineate the reasonable therapeutic possibilities.
The choice between therapeutic options should reflect the patient's priorities. In general, alternatives involving the least dependence on medical facilities and the least use of the patient's time, resources, and personal energy should be recommended. For example, it is inappropriate to resort to intravenous (or spinal) techniques for pain relief if oral, transcutaneous, or subcutaneous techniques have not been adequately explored. When shared decision making serves to realize a woman's nominated priorities, quality of life is often improved. For example, the realization of a goal to return home may be more important to some than a minor extension of life from a further course of antibiotics.
Careful consideration of relevant antitumor measures (surgery, radiation therapy, or chemotherapy) is always mandatory because control of the neoplastic process usually offers the best chance of alleviating symptoms. Factors that should be considered when evaluating therapy include (7):
Figure 24.1 Factors to be taken into account when considering further anticancer therapy: benefit vs. cost.
If cost-benefit issues are considered, it is essential to avoid “flat of the curve” medicine. Good symptom relief is almost always high in benefit in relation to cost (broadly considered), whereas anticancer measures may vary in benefit. These matters, represented simply in Fig. 24.1, justify reflection by clinicians as well as administrators.
Clinical decision making is always undertaken in a context of prevailing values, much influenced by culture, social circumstances, and facts (legal, medical, and resource limitations). This is portrayed schematically in Fig. 24.2. Ethical principles such as autonomy, beneficence, non-malfeasance, and justice must be kept in mind. They need to be appropriately understood: a balance between sometimes competing principles may need to be struck after careful consideration of each. The discussion will usually involve input not only from the patient and her significant other, but also from the professional team involved in her care. However, if clinical wisdom is brought to bear, an appropriate recommendation will emerge to a conscientious clinician.
Decisions concerning treatment should usually involve the patient, who should be adequately informed about the advantages and disadvantages of the various options. Such involvement may help the patient to regain control at a potentially chaotic time in her life. Although the patient should share in decision making, her attending clinician should indicate the course of action he or she favors, and ultimately take the responsibility for any intervention, so that a distressing outcome does not engender guilt in the patient and her family. This being said, the physician should not compromise his or her better judgment or conscience in the face of patient or family pressure.
The burden of decision making is considerable, and ways of reaching decisions vary according to social, cultural, economic, and medical contexts. When disagreements arise between patients (or their families) and clinicians regarding clinical decisions, it is often useful to consult within the treating team to determine if a range of views exists among clinicians. A negotiated position between patient and clinician can almost always be reached. If not, a second opinion or a perceived “independent broker” may be useful (8).
Figure 24.2 The context of clinical decision-making.
There are no circumstances that justify a physician's declaring that “there is nothing more that can be done.” A decision not to pursue anticancer treatments, but to focus solely on symptomatic measures, does not indicate nihilism or inactivity. It may reflect authentic clinical wisdom with clear goals of comfort and dignity.
Evaluation of Outcomes
Evaluation of palliative interventions is best performed by the informed patient, although the observations of the medical and nursing staff are also important. Evaluations should be performed regularly, at intervals consistent with the clinical goal. Pain measurements may, for example, be appropriately performed each time observations such as blood pressure and temperature are undertaken. For patients with advanced disease when the goals of care are centered on comfort and dignity, monitoring only of those parameters that serve these goals is justified. Formal outcome measures based on subjective criteria, of which there are many examples (9,10,11,12), should ideally be introduced into routine clinical practice, with outcomes to be measured commensurate with the patient's priorities for comfort and for personal objectives.
Mention should be made of the art of prognostication, because estimates of survival underlie much of the clinical decision making. There is a considerable body of literature to guide the clinician when formulating a prognosis (13,14,15). Factors to be considered in such a formulation for patients with advanced cancer include: performance status, symptoms of the cancer cachexia syndrome, and patient-rated quality of life, while the presence of a leukocytosis or lymphopenia also appear to be important. Notably, these factors differ from those considered in a newly diagnosed cancer, such as tumor size and grade (15).
While it may be possible to determine a probability of survival for a particular patient, the communication of this information to the patient and her family requires thought and care. Such a discussion should occur in the context of a supportive relationship, and when the clinician has sufficient time to devote to the task. If the discussion has been prompted by a question, it is important to clarify what the patient has asked, and what has motivated her to ask it. The patient's understanding of her current situation should be ascertained. It is often helpful to ask the patient what she believes her prognosis to be. The uncertainty of prognostic elements must be explained, and information should be given slowly, at a pace dictated by the patient (16).
A reasonable approach for many patients in the face of a question concerning prognosis, is to offer some time boundaries within which death is likely to occur. Such boundaries are useful for determining priorities and for planning medical care to best serve those priorities. Time boundaries do not give a patient or her family an agonizing date around which to focus, nor do they suggest that what is still somewhat uncertain can be predicted precisely (17).
Symptoms and Their Relief
In general, effective anti-disease therapy offers the best chance of good symptom relief if the patient is a “responder,” but the quality of life of a “non-responder” to chemotherapy may be worse than that of an untreated patient. Expertise in palliative therapeutics should be made available alongside surgery, chemotherapy, and radiation therapy, and delivered according to clinical needs, not prognosis (3).
Symptoms are subjective, and their presence and severity is not necessarily apparent to the observer. A patient in severe pain may show no signs of distress, yet she may admit upon careful questioning that the pain is almost unbearable. Her expressions of pain will be influenced by cultural and environmental factors, as well as by personal and interpersonal relationships. Accurate assessment of symptoms requires skill, patience, and active, supportive listening. Symptoms vary in their significance for the patient, and anxiety or distress associated with the development of a particular symptom will inevitably have a psychological impact. It is important to give the patient a chance to express her fears and to offer some simple explanation for the symptom, because this will at least reduce uncertainty.
Symptoms may arise from the tumor itself, from the treatment, and/or from unrelated causes. Symptoms may precede signs or objective evidence (x-ray or scans) of disease. An example is the development of leg pain from lumbosacral plexus infiltration, which may herald recurrent cervical cancer. Imaging may fail to demonstrate a lesion suspected on the basis of symptoms, but the pain needs treatment even while awaiting a definitive diagnosis. Waiting for objective signs may be disastrous in certain circumstances, such as in the early diagnosis of remediable spinal cord compression.
There is now considerable literature concerning the understanding and therapy of major symptoms in cancer, and attention is given here to those seen more commonly, with emphasis on practical considerations.
Pain has been defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” Thus pain is subjective: All pain is “in the mind.” Psychological factors influence the perception of pain in all women: Pain is the experience of a person, not a part of the body, and changing the experience of a person is a major challenge. Effective pain management is dependent upon understanding and delineating the pain mechanisms involved, and prescribing medication based upon these mechanisms. Controversies relevant to gynecological practice remain, not least being the global inequity in access to pain relief for women with gynecological cancer (18).
Figure 24.3 Schema for the approach to pain management. NSAIDs, non-steroidal antiinflammatory drugs
Pain in gynecological cancer presents in many forms and may occur at any stage in the illness. It may be caused by both the disease and its treatment. Pain caused by treatment (e.g., radiation therapy) requires as close attention as that caused by tumor. Many guidelines for the assessment and treatment of cancer pain have been published, including those by the American Society of Clinical Oncology (19,20,21). The following simple steps provide a practical approach in the face of the complexity of recent research and practice (22).
Pain management may be considered to have four steps (Fig. 24.3):
Such steps should be considered in order, but measures relating to all four steps may be instituted simultaneously if the clinical circumstances dictate.
Step One: Reduce the Noxious Stimulus at the Periphery
This step demands an adequate understanding of the mechanism of the pain stimulus in the individual patient. Pain in patients with gynecologic cancer is most commonly due to soft tissue infiltration, bone involvement, neural involvement, muscle spasm (e.g., psoas spasm), infection within or near tumor masses, or intestinal colic. Pain felt in the back needs particularly careful consideration, because the causes are many and the treatments are diverse.
The mechanism of pain can usually be diagnosed clinically. The history should include the mode of onset, characteristics, distribution, aggravating factors, trends over time, and response to therapeutic endeavors thus far. Therapeutic approaches vary according to the mechanism that is operative. Peripherally acting drugs should be used irrespective of specific therapeutic measures (e.g., radiation therapy, chemotherapy, antibiotics, or surgery), which may be required.
Bone metastases frequently cause inflammatory changes with release of inflammatory mediators, including prostaglandins. When the pain is clearly arising from bone metastases, the use of drugs that interfere with prostaglandin synthesis (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]) is logical. These drugs should be avoided or used with caution in patients who have a history of peptic ulceration, excessive alcohol consumption, bleeding diathesis, renal impairment, or known allergies to aspirin or related drugs. Where the use of NSAIDs is precluded, acetaminophen (paracetamol) is a useful alternative. While its mechanism of action is yet to be fully elucidated, clinical utility suggests some peripheral action, although not a direct anti-inflammatory effect. Acetaminophen is fairly well tolerated and safe, but it should be used in reduced dosage in patients with impaired liver function.
Peripherally acting drugs such as acetaminophen and NSAIDs are also useful for pain arising in non-osseous sites and for postoperative pain. They should rarely be omitted from analgesic regimens, even in moribund patients. Rectal preparations may prove useful in patients who are unable to take oral drugs.
Muscle spasm requires muscle relaxants, as well as gentle massage. Psoas muscle spasm, usually resulting from direct tumor infiltration, is not infrequent in gynecologic cancer (23). Psoas muscle infiltration should be suspected if there is pain in a lumbosacral plexus distribution associated with difficulty achieving full extension of the hip. While radiation therapy is being considered or applied, relief can usually be achieved by careful adherence to the outlined principles, but will not be adequately managed by opioids alone.Acetaminophen and/or NSAIDs, an oral opioid (such as oxycodone), and a laxative must be supplemented by a drug that is active against spasm in skeletal muscle, such as diazepam.Steroids should also be given (e.g., dexamethone 2-4 mg daily). Polypharmacy is justified to relieve pain in the malignant psoas syndrome. If the pain does not respond to these measures, specialist help must be sought (24). No patient should die with intractable pain.
Experience at the Royal Hospital for Women in Sydney would suggest that pain associated with subacute and chronic radiation toxicity (e.g., vulvovaginal ulceration) may benefit from hyperbaric oxygen treatment.
Regional blockade with a local anesthetic and neurolytic techniques may be worthy of consideration if the area of pain is circumscribed and attributable to an accessible peripheral nerve, such as pain in the intercostal region.
Step Two: Raise the Pain Threshold
All persons should be considered to have a threshold above which they will be troubled by pain. It is useful to consider the threshold as “one's sense of mastery of a situation.” Such a threshold is dynamic, and may be influenced by many factors. The threshold for pain may be raised by explanation, comfort, care, concern, diversion, and various forms of relaxation. Similarly, the threshold will be lowered, or a patient's sense of mastery will be affected negatively by depression, anxiety, uncertainty, loneliness, and isolation.Threshold issues in general require a nonpharmacological approach.
A wide range of strategies exist to facilitate coping with pain, and simple measures, such as explanation of, for example, the likely cause of pain, should be tried initially. The diagnosis of a disturbed threshold in an individual patient is difficult, but the narrative approach to assessment of the patient gives clues. As the patient tells the story of her diagnosis, treatment, and the pattern of her pain, she imparts information not only about the cancer but also about herself, and excessive distress can be readily perceived. Many complementary therapies, such as massage and meditation, assist in the relief of pain, and it is likely that their benefits stem from enhancing a patient's sense of mastery.
Occasionally, anxiety and depression are so marked that the patient is impeded in her attempts to relate to her loved ones and to come to terms with her disease. In such circumstances, a formal psychiatric consultation may be of assistance and anxiolytics or antidepressants may prove helpful. In general, threshold issues, including extreme anguish, feelings of futility, loss of sense of meaning, personal guilt, and other forms of spiritual pain, require a different approach, with help from skilled counselors, pastors, and, above all, those people who are close to the patient.
Pain and suffering are related but distinct (25). Suffering has been described as a sense of impending personal disintegration (26). In common parlance, there may be a sense of being about to “go to pieces.” Suffering may be triggered by poorly controlled symptoms, perceived loss of dignity, loss of a sense of control or autonomy, fear for the future, and loss of a future. Pain may be the main cause of suffering, or a manifestation (through threshold shifts) of suffering, with the language of suffering expressed through pain. A conscientious clinical oncologist needs to be aware of suffering in a patient and should seek to provide comfort while seeking ways to relieve distress, (which may progress to suffering), by understanding and alleviating the causes (such as pain) and seeking the help of colleagues (27).
If suffering is defined as a sense of impending “personal disintegration,” then the response to suffering should be “reintegration.” Such reintegration may be most assisted by others who have skills in that dimension of care focused on existential issues that may or may not relate to religious matters. But every doctor has the responsibility and privilege to be aware of such dimensions of care, to provide the “space” for patients to consider their existential concerns (notably ensure that symptoms are well controlled), and to take time to be informed about current reflections on this area (28).
Step Three: Precise and Appropriate Use of Opioid Drugs
There is abundant literature on opioid use to supplement peripherally acting analgesics, with a range of opioids available (29,30). Despite the initiatives of the World Health Organization, there are still difficulties obtaining opioids for medical use in some countries. A variety of opioids is available, and the principles of choice need to be understood (Table 24.1) (31). In practice, low-potency opioids such as codeine or dextropropoxyphene, or high-potency opioids such as morphine, are combined with peripherally acting drugs such as acetaminophen or aspirin. Low- and high-potency opioids should not be given concurrently, but a change from one opioid to another may be justified (32,33). While at a global level morphine remains the preferred initial opioid of high potency, consideration is increasingly given to alternative high-potency opioids if available, such as, oxycodone, methadone, fentanyl, and hydromorphone (31). It is critical that local availability and affordability inform the choice of opioids: no woman should be deprived of pain relief because expensive, unaffordable drugs have been prescribed if cheaper drugs would have given significant benefit.
Regardless of the choice, opioids should be given at regular intervals in accordance with the half-life of the drug concerned, rather than haphazardly in response to a severe pain stimulus. Doses of opioid drugs should be carefully titrated against response and side effects.
Oral morphine and oxycodone are available in two forms: an immediate-release preparation that reaches a peak within 30 minutes of ingestion, and a sustained release preparation that for morphine takes several hours to reach peak concentrations, while for oxycodone peak levels are reached within 40 minutes (34). As a general rule, for a patient not previously taking opioids, initial prescribing should involve regular dosing with an immediate-release preparation as a “dose finding” exercise. This allows rapid escalation or reduction of dose according to clinical response.
Some types of pain are only partially responsive to opioids (30,35), including pain caused by nerve irritation, extreme muscle spasm, incident pain (i.e., pain exacerbated by a particular activity such as movement), or pain that is heightened by unaddressed anguish. Even in these circumstances opioids remain “partially effective” and should be introduced and carefully calibrated to ensure that optimum benefit is achieved while minimizing side effects (36).
Immediate-release morphine is best given every 4 hours, with a double dose (or 1.5 times the standard dose in the frail) at bedtime and a break of approximately 8 hours overnight to permit sleep for both patient and caregivers. A reasonable starting dose of oral morphine in a patient with severe pain not already on an opioid drug would be 10 mg in a patient of average size, or 3 to 5 mg in the frail or very elderly patient. The original dose should be repeated in 1 to 2 hours if there has been inadequate relief of pain. Over the next 24 to 48 hours, dose finding is undertaken by prescribing regular doses every 4 hours, together with one or two “breakthrough” doses, equal to the standard dose. The correct dose may range from 2 mg to more than 100 mg every 4 hours, but most patients need less than 50 mg every 4 hours.
Once the daily dose requirement is established, this can be converted to a sustainedrelease formulation, once again maintaining supplemental breakthrough doses of the immediate release preparation. For example, a patient taking 20 mg oral morphine sulfate mixture every 4 hours can be converted to 60 mg sustained-release morphine each 12 hours, with additional breakthrough doses of 20 mg of morphine sulfate mixture if required.
Sustained-release morphine (or other sustained release opioids) should not be used (i) in patients with uncontrolled or unstable pain; (ii) in patients with extensive upper abdominal or retroperitoneal disease that is likely to interfere with gastrointestinal motility; or (iii) when there is fecal loading or impaction. Subcutaneous morphine is a better choice in such circumstances.
If parenteral morphine is essential, the subcutaneous route is appropriate, either with intermittent injections through an indwelling butterfly needle every 4 hours or with a continuous infusion through a battery-driven syringe driver. When a patient is constipated or has a bowel obstruction, and pain is not well controlled with simple analgesics such asacetaminophen (paracetamol), 4-hourly morphine by the subcutaneous route is a useful maneuver to achieve pain relief and to calibrate the required morphine dose. Once her constipation is relieved, the subcutaneous 24-hourly dose may be easily converted to oral morphine. The intramuscular route is rarely advantageous. In general, a parenteral dose of one-half or one-third of the oral dose appears equianalgesic (37). If oral or subcutaneous morphine is efficacious but the side effects are troublesome, the epidural route is occasionally necessary, but a change to another oral or parenteral opioid should normally be tried first.
Table 24.1 Opioid Analgesics Used for the Treatment of Chronic Pain
Intravenous morphine infusions, although sometimes useful (e.g., in a patient with peripheral circulatory failure), do not offer significant advantage over the subcutaneous route for most patients and, because of the need to maintain intravenous access, generally ensure greater complexity and disruption for the patient. In addition, there are anecdotal reports of the development of tolerance associated with the intravenous route, which may not always be overcome by the addition of further morphine (38). In the setting of rapid dose escalation of intravenous morphine, cessation of the infusion and resumption of appropriate subcutaneous doses every 4 hours may be helpful. Simultaneously, it is important to review other aspects of management, such as the possible need for NSAIDs or drugs relevant to neuropathic pain, and to pay appropriate attention to psychological factors.
The efficacy of the regular dosing approach to morphine administration may depend on the contribution of an active metabolite (morphine 6-glucuronide), which, like morphine, is a powerful mu receptor agonist. Hepatic impairment, if severe, interferes with morphine metabolism to glucuronides. Renal impairment, even if only moderate, interferes with excretion of the active metabolites. In both of these circumstances, dose reduction is essential. In a patient with renal impairment, it may be necessary to extend the dose interval from 4-8 or even 12 hours. The use of morphine in a patient with marked renal impairment is very complex, and an alternative opioid that does not have active metabolites may be a better choice (39).
Some physicians and nurses, as well as patients, continue to harbor misconceptions about the use of morphine. When morphine is to be commenced, counseling should address three issues to counteract widely held fears:
Use of Alternative Opioids
Other potent opioids should be considered when: (i) pain persists despite careful drug calibration; (ii) unacceptable side effects persist (e.g., cognitive impairment, nausea) despite careful drug calibration; or (iii) drowsiness or toxicity occurs at levels of the drug required to control the pain. In these circumstances, after reconsideration of the pain mechanism and the other analgesic steps, an alternative opioid should be considered. Availability varies from country to country, but gynecologic oncologists should become familiar with a narrow range of opioids (see Table 24.1). In countries where there is wide availability and affordability of opioids, the choice may depend upon preferred route of administration (oral versus transdermal).
Oxycodone (available as immediate-release tablets, suspension, sustained-release preparations, parenteral and suppositories) is somewhat more potent (20% to 50%) than morphine: Oxycodone is being most often used in a dose of 5 mg to 20 mg every 4 to 6 hours. Some patients tolerate oxycodone better than morphine at the same dose, and vice versa. In general terms however, the side-effect profile is similar (40). Anecdotal reports suggest that oxycodone may be more effective in neurogenic pain, so may be helpful to relieve leg pain in patients with recurrent cancer of the cervix (41).
Meperidine (pethidine) is of very little value in palliative care. It has poor oral bioavailability and a short half-life, requiring frequent administration, approximately every 2 hours. At high doses (>1 g/day) or when renal failure is present, the metabolites lead to neurotoxicity, including delirium, agitation, and seizures. It is also addictive. If a patient is already receiving meperidine subcutaneously or intramuscularly, conversion to morphine can be achieved with approximately 10% of the meperidine dose given as subcutaneous morphine,or 30% of the meperidine dose given as oral morphine every 4 hours.
Methadone is occasionally useful, particularly for those who appear to have pain that is more difficult to control. Its long half-life is sometimes disadvantageous, particularly in the elderly, and its sedative action may outlast its analgesic activity. It has mechanisms of action that differ slightly from those of morphine, being reported to have both opioid receptor activity as well as activity on the N-methyl-D-aspartate (NMDA) receptor pathways (42). Therefore, methadone is occasionally useful when higher doses of other opioids are reached with only partial or inadequate response. Conversion from morphine to methadone may be difficult, with subsequent dose reduction frequently required (43,44).Methadone has a similar sideeffect profile to morphine.
Hydromorphone: Like morphine, hydromorphone is a mu agonist but with far greater solubility. It can be administered orally, intravenously, and subcutaneously with a duration of action and half-life similar to morphine. Its high potency allows smaller volume injections (45).
Fentanyl offers a transdermal route of administration, enabling continuous administration of a short-acting opioid (46). Dose calibration should usually occur with morphine, oxycodone, or subcutaneous or intravenous fentanyl before transdermal therapeutic system (TTS) fentanyl is applied. The patch forms a depot of drug in the dermis, resulting in a 12-to 48-hour delay before maximum plasma concentration is reached. After TTS removal, the terminal half-life is approximately 13 to 25 hours (47). In practice, this means that when the patch is applied, the immediate-release drug should be continued for at least 12 hours. If adverse effects develop, they will continue after TTS fentanyl removal, and the patient should be monitored closely. When a patient who is using TTS fentanyl experiences an increase of pain, a short-acting opioid should be given concurrently and the dose used to calculate the extra opioid requirement, which can then be incorporated into the TTS fentanyl dose.
TTS fentanyl is an attractive option for many patients because of the convenience of the delivery system and the slightly less troublesome constipation compared with morphine(46). Dose escalation is commonly observed, possibly related to the short half-life of the drug. If very rapid dose escalation occurs (without evidence of rapid tumor progression), a change to another opioid may be wise and less expensive. Fentanyl may be particularly useful in patients close to death.
The development of transmucosal fentanyl citrate provides an immediate-release fentanyl formulation for breakthrough pain that offers rapid onset of analgesia and similar or improved response compared with immediate release morphine (48,49). Expense may dictate that traditional preparations are still chosen.
When using TTS fentanyl, it must be remembered that:
Side Effects of Opioids
Side effects can be avoided in large part by precise prescribing. Although there are some side effects that are almost invariable, such as constipation, individual variation in side-effect profile may be used to advantage by substituting an alternative opioid.
Constipation occurs in most patients, and prophylactic laxatives should be prescribed. A reasonable laxative prescription would be senna and sodium docusate tablets twice daily. Fecal impaction, much more likely if opioids are given without a laxative, may cause a variety of distressing symptoms, such as nausea, vomiting, pelvic pain, or confusion. TTSfentanyl is slightly less constipating than slow-release morphine (46).
Nausea and vomiting may occur in association with opioid therapy as a result of gastric stasis, stimulation of the chemoreceptor trigger zone, or constipation. Nausea is particularly common when opioids are commenced or when the dose is changing, but a tolerance to this side effect develops in most patients within 48 hours. Suitable antinauseants such asmetoclopramide, 10 mg four times daily (oral/subcutaneous injection [SQ]), or haloperidol, 0.5 to 1.5 mg twice daily (oral/SQ), should be available if required. Regular prophylactic antiemetics should be prescribed for at least the first 48 hours if the patient is very anxious or if there is a history of opioid-induced nausea or vomiting. If vomiting persists, an alternative opioid should be substituted. All opioids may cause nausea, but there appears to be individual but unpredictable variability in response between the drugs. The evolving field of pharmacogenetics may in the future provide some ability to predict an individual's response.
The prescription of opioids should be individualized. As with a number of other medications (e.g., digoxin), if the dose prescribed is inadequate, there will be no clinical response. If however, the dose is too high, the patient will enter a toxic range and will develop dose-related side effects. The dose-related side effects of opioids include drowsiness and delirium. At the extreme end of the toxic range is respiratory depression, with reduced respiratory rate, which is rarely seen in chronic opioid prescribing, and not before the patient has exhibited earlier signs of toxicity such as drowsiness and delirium.
If drowsiness develops and persists for more than 24 hours, the opioid level is probably above the therapeutic range for that patient. Other causes of drowsiness should be excluded, such as sedating drugs or hypercalcemia, and a dose reduction of opioids should be considered.
The development of confusion or hallucinations indicates either excessive dosage or very occasionally, an idiosyncratic reaction. Hydration—either orally, subcutaneously, or intravenously—may assist in eliminating troublesome metabolites while dose reduction is undertaken. If the pain is not well controlled in the presence of drowsiness or confusion, another approach is usually required, such as an alternative opioid or an alternative route of administration (e.g., spinal).
Pruritus is troublesome for a small number of patients taking morphine because of its histaminogenic properties. It usually settles within 48 hours and can be managed with judicious use of promethazine. Pruritus is rarely reported for other opioids. Anticholinergic side effects of opioids are usually not troublesome.
Tolerance to opioids may be a significant clinical problem if the drug is not introduced and calibrated correctly. When opioids are used correctly, increased requirements during the course of an illness usually signify an increase in the noxious stimulus because of disease progression, rather than a reduction in the effectiveness of the analgesic. Ketamine, a drug used traditionally in anesthesia, has been found to reverse opioid tolerance for some patients with pain (50).
Step Four: Recognize Neuropathic Pain and Treat Correctly
Neuropathic pain is a term used to describe those pain syndromes in which the pathophysiology is related to aberrant somatosensory processes that originate with a lesion in the peripheral or central nervous system. Neuropathic pain is a frequent complication in gynecologic cancer, especially in advanced cancer of the cervix. It may be due to tumor infiltration (notably lumbar plexopathy) or occasionally may result from therapeutic interventions. It may be flashing or burning in nature, but is often an unpleasant ache in an area of altered sensation corresponding to a peripheral dermatome.
When pain is neuropathic in origin, an opioid and a peripherally acting drug should usually be supplemented by tricyclic antidepressants, anticonvulsants, and/or corticosteroids(51). In general, medications should be started at low doses and gradually increased as tolerated, but treatment of severe neuropathic pain is a challenge (52).
Other Dimensions of Pain
Ketamine, a drug used in anesthesia, has been found in lower doses to be useful in the management of very complex pain, both somatic and neuropathic in origin. Ketamine acts as an antagonist to the N-methyl-D-aspartate (NMDA) receptor system, a system frequently activated in refractory pain states when high doses of opioids appear ineffective. Low doses of infusional subcutaneous ketamine can reduce opioid tolerance and improve analgesia (50). It should be used in consultation with palliative medicine or pain specialists because of side effects such as hallucinations. However, it has an emerging role in refractory pain states (53).
Spinal analgesia may benefit a carefully selected small group of patients. Anesthetic opinion should be considered for patients who continue to have pain despite an adequate trial of analgesia according to steps one to four, or for those who have very severe incident pain, i.e., pain with a particular activity, such as weight bearing (54). The ongoing capacity of the care system to support the spinal analgesic delivery devices (implantable pumps, intrathecally inserted Port-o-cath devices, or other systems) must be considered prior to implementation. For some, the delivery of spinal analgesia requires ongoing hospitalization because community supports are unavailable. Expense may be very significant.
Table 24.2 Edmonton Classification System for Cancer Pain
Pain Prognostic Score
The recognition that patients with cancer-related pain vary considerably in their responses to standard analgesic regimes has led to the development of a classification system for pain. Based on the TNM classification system for cancer, this represents an attempt to group pain such that appropriate comparisons and predictions of outcome can be made (Table 24.2) (55). According to this classification, the presence of particular pain mechanisms, incident pain (pain during an activity), psychological distress, addictive behavior, anddisturbed cognitive function are all associated with increasing complexity of pain management.
Special Considerations in Pain Management
The Patient with Renal Failure
In patients with renal impairment, NSAIDs should be avoided, as they will frequently worsen renal function, and the use of morphine will result in the accumulation of activemorphine metabolites. Therefore, if prescribing morphine, a dose reduction may be necessary, and, more importantly, the interval between doses should be extended. Use of an alternative opioid such as fentanyl or methadone, which are reported not to have active metabolites, may be preferable (39).
Allergy to Opioids
Many patients will report they are allergic to opioids, or have such an allergy recorded on their medical record. A detailed exploration should be undertaken of the event when an allergy was first cited. Frequently, the original event was the development of nausea and vomiting when opioids were administered. Sometimes it is the report of confusional states, particularly in the setting of post-operative analgesia administration. Neither of these constitute a true allergic reaction. True allergy to opioids is extremely rare. If it is suspected, palliative care expertise should be sought.
The Patient with Reduced Motility of the Gastrointestinal Tract
The patient who has a hypomotile gastrointestinal tract, most commonly seen in patients with disseminated ovarian cancer, may have not only impaired peristalsis, but also impaired absorption of oral medication.
Motility may be further impaired by drugs such as 5HT3 blockers (e.g., ondansetron), which, although very effective antinauseants for patients undergoing chemotherapy, may induce constipation. Consideration should be given to delivering analgesics via an alternative route, such as transdermally (fentanyl) or, for the very ill, subcutaneously. Similarly, alternative routes of analgesic administration should be sought for the patient with established fecal loading.
The Patient with Cognitive Impairment
The cognitively impaired patient may not complain of pain, but if she does, she should be believed. If the location of the cancer is likely to cause pain, then pain should be assumed to be present. Facial expression may assist in the diagnosis (unless the pain is chronic), as may the presence of any physiological indicators such as tachycardia (56). Other clues may include restlessness and agitation. The family should be questioned about any behavioral changes they have observed. The possibility of painful fecal loading should be considered. Ultimately, diagnosis may require a therapeutic trial of analgesia and observation of the response.
Particular note should be made of the interaction of the two symptom complexes of pain and delirium, both of which are common in the very ill. Patients with delirium have global cognitive dysfunction, including problems with memory, concentration, alertness, and frequently hallucinations and delusions. It is postulated that usual inhibitory processes are also affected with consequent “unmasking” and heightened pain complaints. When the response to such complaints is to unquestioningly escalate opioid doses, this can further exacerbate the situation, since opioids at high doses (beyond the therapeutic range) may be implicated in causing delirium (57,58).
When a patient develops this complex set of clinical problems, the following approach is recommended:
Difficult-to-Manage Postoperative Pain
Occasionally, the management of pain in the postoperative setting is difficult. Possible reasons could include the following:
o open discussion of the concerns with the patient and with other physicians involved in her care. Many former opioid addicts will fear the prescription of opioids for their pain.
o be prepared to use higher doses of opioids.
o ensure a single point of prescription.
o prescribe precise amounts of opioids for relatively short periods of time, such as 1 week.
On the other hand, patients who are taking preoperative opioids as part of their current treatment need to continue equivalent opioid doses, with an additional moiety to cover the operative trauma.
Chronic Nonmalignant Pain
While not the focus of this chapter, a word of caution should be made about the management of the patient with chronic non-malignant pain. In general, the pain management approach for these patients has a rehabilitative focus. In common with cancer pain management is the need for diagnosis, repeated assessment, and use of pharmacological agents and interventions according to the pain mechanism involved. The difference between the management of cancer pain management and nonmalignant pain lies in the cautious use of opioids and the focus upon functional improvement outcomes in chronic nonmalignant pain (61). There is an extensive body of literature examining this particular clinical challenge (62,63).
Gastrointestinal symptoms are common in gynecological cancer, both because of the cancer and because of various aspects of treatment (64).
Anorexia is a common and significant symptom with a multitude of causes and serious nutritional consequences. The best initial approach to management includes careful preparation of small meals, elimination of reversible gastric stasis or constipation, emotional support, and direct nutritional supplements. It is helpful to educate both the patient and her family about the importance of these measures. Extensive research has isolated a number of potential therapies, but these remain in trial and developmental phase (65). Until such agents enter clinical practice, the pharmacological responses available to clinicians include the use of prokinetics, progestational agents, and cautious use of corticosteroids (65). Prokinetic agents will be useful when the symptom of early satiety is present indicating gastric stasis. Progestational agents have been demonstrated in randomized, double-blinded, placebocontrolled trials to increase appetite and food intake and to lead to weight gain in a number of patients, without undue side effects (66), but the expense is considerable. Corticosteroids have also been shown to improve appetite and daily activity of patients with cancer, but this effect is short lived, usually with a return to baseline responses by 28 days. Because patients must then undergo the problems of corticosteroid withdrawal, patient selection is critical.
Mouth symptoms, including xerostomia, pain, and altered taste, can be most distressing.
A dry mouth can result from many factors in the critically ill patient: oral candidiasis, previous radiation therapy, mouth breathing, nasal oxygen, and drugs, particularly those with anticholinergic effects. Management of xerostomia may include minimization of contributory nonessential medications, frequent small drinks with a small amount of lemon/orange to stimulate saliva production, use of artificial saliva or glycerin preparations, and pilocarpine drops to stimulate saliva locally with minimal systemic effects.
Frank pain can occur from treatment-related mucositis and infected ulcers, so mouth care is crucial in very ill patients. Oral candidiasis is often overlooked. It responds to antifungal agents such as nystatin mouthwashes (every 2 to 3 hours), amphotericin lozenges, and, if necessary, a systemic triazole derivative such as fluconazole. Pain from mucositis may be relieved by sucralfate suspension and by acetaminophen with morphine (orally or subcutaneously).
Altered taste, a not uncommon symptom in patients with cancer, is hard to relieve. Once all of the above causes of mouth pathology have been excluded, a dietitian may be able to assist in food choice and encouragement.
Nausea and Vomiting
Nausea and vomiting are common in advanced gynecologic cancer, and each symptom requires precise diagnosis so that rational therapy may be applied. Mechanisms of nausea and vomiting are complex (67). Nausea, with or without vomiting, is mediated finally by the vomiting center situated in the reticular formation of the medulla oblongata, an area rich in histaminic and muscarinic receptors. The vomiting center is influenced by several connections, each of which can be the causal pathway for nausea (Fig. 24.4 and Table 24.2). The search continues for better understanding and consequently, for better therapeutic approaches.
Figure 24.4 Factors that influence nausea and vomiting in the central nervous system and the gastrointestinal tract. Nausea, with or without vomiting, is mediated by the vomiting center. D, dopaminergic; H, histaminic; MCh, muscarinic; 5HT3, hydroxytryptophan.
Causal pathways include:
Once the likely mechanism has been identified by means of a careful history, physical examination, and investigations if indicated, the appropriate antinauseant may be prescribed (Tables 24.3 and 24.4). While the evidence base proving the efficacy of this approach remains scant, it continues to be useful in practice and is recommended as an appropriate approach (68).
When anxiety dominates the scene, anxiolytics may be crucial in reducing the nausea. When vestibular mechanisms are suspected or when no specific pathway can be identified, relatively less sedating antihistamines (e.g., cyclizine) that act directly on the vomiting and vestibular centers may be useful. Prochlorperazine has some affinity for dopaminergic, muscarinic, and histaminic receptors and is moderately useful, although less specific. Levomepromazine (methotrimeprazine) is a phenothiazine with potent D2- and α1-receptor antagonist and some 5HT2-receptor antagonist action. This means it is a broad-spectrum antiemetic, which is most commonly used as a second- or third-line drug when more specific drugs seem ineffective. It is significantly sedating, so is often reserved for patients in the final phase of their life (69).
Table 24.3 Commonly Used Antinauseant Drugs
Nausea clearly related to the chemoreceptor trigger zone requires a drug with high affinity for dopaminergic receptors, such as haloperidol. A dose of 1.5 to 3 mg or less at night (orally or subcutaneously) may be sufficient. Nausea related to chemotherapy or abdominal radiotherapy is usually well controlled with serotonin antagonists such as ondansetron ortropisetron. If delayed emesis resulting from chemotherapy is present, the introduction of haloperidol can be a useful adjunct. Constipation is a potentially distressing side effect ofondansetron, particularly in patients who are prone to bowel obstruction.
Nausea arising from stimuli in the gastrointestinal tract associated with slowing of the gut should respond to gastrokinetic antinauseants such as metoclopramide or domperidone,which promote gastric emptying and increase gut motility. These actions are counterproductive in a patient with a very high gastrointestinal obstruction, when vomiting will be aggravated.
Drugs available by more than one route are advantageous. Metoclopramide, haloperidol, and cyclizine may be used subcutaneously as well as orally.
In addition to the established antinauseant drugs, corticosteroids, which act by an unknown mechanism, are also useful in suppressing nausea, and are frequently used in premedication programs before chemotherapy. Caution must be exercised if the patient has a history of active peptic ulceration, tuberculosis, diabetes mellitus, psychosis, or severe emotional instability.
A number of women with extensive intraabdominal disease, usually as a result of ovarian cancer, will present with symptoms of gastrointestinal hypomotility. Typically the initial complaints will be of marked constipation requiring increasing doses of laxatives, followed by early satiety, and nausea. Eventually some will progress to develop symptoms of gastrointestinal obstruction. Examination reveals few or absent bowel sounds, and plain abdominal radiographs are frequently normal or may show fecal loading without air-fluid levels. The pathophysiology of this syndrome is not well understood, but probably includes tumor infiltration of the myenteric plexus.
Medication is aimed at increasing bowel peristalsis using infusional metoclopramide, 60-90 mg subcutaneously over 24 hours. Our own experience suggests corticosteroids(dexamethasone 4-8 mg daily) may also be useful to improve symptoms of obstruction in this group (70). The clinician should be mindful that gastrointestinal hypomotility will result in reduced absorption of oral medications including analgesics.
Hypomotility or dysmotility of the bowel sometimes follows apparently successful surgery for bowel obstruction. The condition may be temporary and related to the surgery, or it may be longer lasting and related to the underlying malignant infiltration. The difficulty facing the clinician is how best to support such patients nutritionally postoperatively. There is little literature to inform such a decision, and as always, it should be based on the patient's disease status, her performance status, the anticancer options still available, and her personal goals.
Constipation, a common symptom, may be due to changing diet, inactivity, opioid use without laxatives, or varying degrees of tumor-induced intestinal obstruction. Constipation can be largely avoided through anticipation and careful prescribing of laxatives. Recent reviews highlight the diversity both of mechanisms leading to constipation and of classes of laxatives (see Table 24.4) (70). Any prescription of opioids should be accompanied by a laxative as constipation is an inevitable side effect. In most instances, a combination of a fecal softener and a peristaltic agent such as sodium docusate and senna will be adequate to prevent opioid-induced constipation. Care should be taken in the use of bulking agents, because those patients with significant frailty may be unable to ingest the volume of water required for their adequate function.
Table 24.4 Classification of Laxatives
Severe constipation is a common cause of major symptoms, including nausea, vomiting, spurious diarrhea, pain, and even confusion, especially in the elderly. If unrecognized or untreated, it may result in inadequate absorption of oral medications including analgesics and even, rarely, perforation. Opioid-induced fecal impaction is usually avoidable, but if present, vigorous local treatment is required. This includes fecal softeners (e.g., docusate sodium), large bowel stimulants (e.g., senna), stimulant suppositories, or careful enemas.Osmotic laxatives (e.g., lactulose) may be helpful. Fecal impaction caused by a holdup at the sigmoid colon (with an empty, dilated rectum) sometimes requires high docusate sodium enemas if oral laxatives fail to provide relief.
Drugs other than opioids may also cause constipation. Drugs commonly implicated in this population would include 5HT3 antagonists (e.g., ondansetron) and tricyclic antidepressants. Constipation that is due to mechanical obstruction requires either surgical intervention or acceptance of the problem as an end-stage event.
Medical Management of Intestinal Obstruction
Obstruction may occur at any level of the gastrointestinal tract in patients with gynecologic cancer and frequently involves several different levels. It is a common late-stage problem, particularly in patients with ovarian cancer. Since the ground-breaking work at St. Christopher's Hospice, London (72), there have been several studies, reviews, and recommendations (73,74). The following represents a practical approach for the gynecologist (Table 24.5).
Patients presenting with an acute bowel obstruction should initially be placed on nil by mouth and given intravenous fluids. If there is copious vomiting, nasogastric suction is helpful. If the obstruction is not relieved within 72-96 hours, a choice needs to be made between surgical intervention and medical management.
In general, surgery provides the best palliative relief of symptoms, if successful. This is particularly true for the few patients who have a nonmalignant cause for the obstruction, such as adhesions from radiation therapy or previous surgery. Similarly, bowel obstruction in a patient for whom chemotherapeutic options have not been exhausted justifies active surgical intervention. Stents offer a useful means of bypassing obstruction that is due to a defined tumor mass and are associated with low morbidity and mortality. Stents have little role, however, in the patient with more than one level of obstruction (75). In patients whose life expectancy is limited to less than 2 months, a noninterventional approach is usually preferable.
One option for conservative management of obstruction at high or low levels is a trial of corticosteroids (e.g., dexamethasone, 4-8 mg parenterally daily for 3-5 days) (70,76). This presumably works by decreasing inflammatory edema, thereby improving luminal diameter. It may be repeated in the future. There is need for caution when using corticosteroids in patients with a history of diabetes mellitus, peptic ulceration, recent infection, impending bowel perforation, significant psychiatric disorder, or tuberculosis. Corticosteroids are best used in patients considered unsuitable for surgical intervention.
In a patient with high end-stage obstruction, when the aforementioned measures have failed to relieve the problem, a conservative medical approach may be helpful. In brief, this approach avoids the use of full intravenous fluid replacement. It relies on careful mouth care, with a little food and drink as desired. The patient remains mildly dehydrated, but this is beneficial and decreases the amount of vomiting. Centrally acting antinauseants (e.g., cyclizine) are used, if necessary, in combination with low doses of opioid analgesics. Gastrokinetic antinauseants (e.g., metoclopramide or domperidone) are contraindicated. For many, gastric drainage via a nasogastric tube or a venting gastrostomy will still be required to ensure comfort.
Hyoscine butyl bromide may serve several purposes in patients with bowel obstruction, reducing gastrointestinal secretions and also reducing intestinal tone, effectively increasing bowel capacity. This alleviates nausea for the patient with complete obstruction and avoids multiple small vomits, although infrequent large-volume vomits continue.
A subcutaneous butterfly needle with or without a battery-driven syringe driver can be used to deliver appropriate doses of antinauseants, such as cyclizine 25-150 mg/day, as well as hyoscine butyl bromide 10-20 mg every 6 hours. With careful calibration of dose, the patient need not be drowsy. Morphine may be given in the same syringe as hyoscine if pain is present. If colic is not controlled with morphine, additional hyoscine may be useful. Rectal prochlorperazine, 50-100 mg/day, may be tried instead of cyclizine. Octreotide,starting at a dose of 50 µg subcutaneously every 8 hours, can provide additional relief of symptoms by further reducing secretions and colic, and has been demonstrated to be superior to hyoscine hydrobromide, though it is also more expensive (73). Doses greater than 600 µg per day probably do not afford additional benefit.
Table 24.5 Management of Gastrointestinal Obstruction in Patients With Gynecological Cancer
Some patients prefer occasional bouts of vomiting to a continuous nasogastric tube. Under all these circumstances, electrolytes should neither be monitored nor corrected. Electrolyte imbalance becomes inevitable and should be allowed to take its course.
Low-bowel obstruction commences with reduced then absent defecation, followed by severe abdominal distention, pain, and later nausea and vomiting. If colostomy or stenting is not to be undertaken, the focus is on relief of discomfort with low-dose opioids. Subcutaneous morphine or transdermal fentanyl may be the drugs of choice. If nausea occurs, antinauseants are useful. Metoclopramide subcutaneously may help keep the stomach empty and may be combined with a centrally acting antinauseant (such as cyclizine). A very light diet may be tolerated if the patient wishes to try to eat.
Diarrhea and Tenesmus
Diarrhea in a patient with advanced gynecologic cancer is probably best considered as a sign of fecal impaction until proven otherwise. True irritative diarrhea can occur by tumor involvement of the bowel wall or after radiation therapy. Loperamide may be useful in the management of such patients.
When fecal soiling is associated with an enterovaginal or rectovaginal fistula, surgical diversion should be considered if at all possible. If such surgery is not possible, the emphasis is on nursing procedures calculated to keep the vagina and perineum as clean and comfortable as possible, and to support the patient in her distress. Antibiotics, especiallymetronidazole, locally as well as systemically, may reduce some of the distressing odor when necrosis has occurred. A urinary catheter may assist in restoring urinary continence. Cases have been reported of the successful use of octreotide to reduce small bowel fistula drainage (77). The use of stool bulking agents (e.g., cellulose) may reduce the amount of fecal ooze if the fistula is colonic.
Tenesmus usually responds to anticholinergic agents, corticosteroids, and opioids, often in combination. Anecdotal experience has shown that low-dose ketamine, followed by very low dose methadone may be effective for more refractory cases. Occasionally, resection of tumor as a palliative procedure may be justified. In severe cases, spinal local anesthetics or sacral nerve blocks may be necessary.
Many of the gastrointestinal symptoms (which are such a feature of gynecologic cancer) are disturbances of gastrointestinal motility. This subject is a focus of current research, and the mechanisms involved are being elucidated (78). The gynecologic oncologist needs to recognize the following:
Abdominal distention that is due to intractable ascites can be a major cause of distress. Despite being a common complication of advanced cancer, the optimal approach to management is far from clear. Paracentesis has an important role in diagnosis and for the immediate relief of symptoms. It should be performed when there is significant abdominal discomfort and patients should be warned that in the absence of systemic control of the malignancy, ascites will generally reaccumulate. Attempts to reduce the rate of reacumulation include the institution of diuretics, particularly spironolactone, 50-150 mg/day, if necessary coupled with a loop diuretic such as frusemide. These may prove helpful initially. If ascites is reaccumulating rapidly, the clinician should anticipate the need for recurrent paracenteses and book clinical reviews accordingly. Shunting procedures are not reliable and have been associated with significant morbidity and mortality. Systemic cytotoxic agents should be considered, though for the heavily pre-treated patient with advanced disease, their potential is limited. Discomfort is usually controlled with a combination of a drug such as acetaminophen and a low dose of an opioid.
A clinical history, physical examination, and a chest radiograph should differentiate between dyspnea caused by a pleural effusion, bronchial obstruction, diffuse lung involvement, reduced excursion that is due to massive ascites, bronchial asthma, chronic obstructive airway disease, cardiac failure, and respiratory infection. However, in advanced cancer, dyspnea may be multifactorial, with anemia, advanced cachexia and resultant muscle asthenia contributing to the situation. Treatment of contributing comorbidities, such as cardiac failure, should be considered in all patients. Drainage of a pleural effusion, with early consideration of a pleurodesis, may afford prompt relief of dyspnea, cough, and chest wall discomfort. Radiation therapy to a bronchial lesion causing hemoptysis, cough, or obstruction may produce prolonged palliation of symptoms.
When the cause of dyspnea is not reversible, the careful use of morphine may improve the situation significantly (79). Oral morphine should be commenced at doses of 2-5 mg every 4 hours and increased until drowsiness develops or until no further benefit is gained. In practice, this usually means doses of approximately 5-10 mg every 4 hours. The mechanism by which morphine reduces dyspnea is poorly understood, but includes both central and peripheral actions. If a patient is already receiving morphine calibrated correctly for pain relief but becomes dyspneic because of tumor progression, morphine may be increased by a further 30% to 50% to give relief.
For the patient with an obstructing bronchial lesion or with carcinomatous lymphangitis, corticosteroids may afford some relief by reducing peritumor edema. This can be achieved with daily doses equivalent to 8-16 mg dexamethasone, with reduction to the lowest possible dose when an effect has been achieved. For those with bronchial obstruction, this should be followed by immediate review by a radiation oncologist.
The role of oxygen in dyspneic patients with advanced cancer who are not seriously hypoxic is controversial (80). Some patients find that oxygen masks or even nasal prongs inhibit communication, restrict their movements, and induce claustrophobia. These patients may find an open window or a fan to be effective. Other patients appear to obtain benefit from oxygen and feel unable to manage without it. The use of oxygen should depend upon the patient's report of improvement of dyspnea and not according to measures of oxygenation. Some patients who have been previously oxygen dependent because of dyspnea can become less so with careful use of morphine.
Anxiolytics may be valuable in modest doses. Benzodiazepines (e.g., 2 mg diazepam orally or 0.5 mg lorazepam sublingually) may have significant benefit for the anxious patient. For the patient who is in the last few days of life, an infusion of subcutaneous midazolam at low doses (e.g., 5-15 mg over 24 hours in the patient who is benzodiazepine naive) can afford significant relief of dyspnea.
Urinary Tract Symptoms
Urinary tract symptoms are common in women with far-advanced gynecologic cancer. Bilateral ureteric obstruction, with subsequent infection, pain, and acute renal failure, may justify mechanical measures such as nephrostomy or ureteric stent insertion if the prognosis on other grounds is for at least several good-quality months of life. Although some patients clearly benefit, fine judgment is required in the individual case, and such patients should be managed in consultation with a gynecologic oncologist. For patients with no reasonable treatment options and problematic symptoms, it is prudent to refrain from mechanical intervention.
Improved patency of ureters may be achieved by short courses of corticosteroids (e.g., oral dexamethasone, 4 mg/day for 3-5 days), but should only be considered if goals are short term, for example, to prolong life for a few weeks (82).
Bladder symptoms may benefit from the use of NSAIDs to reduce detrusor irritability or drugs with an anticholinergic action to reduce bladder contractility. Catheterization may be unavoidable in some circumstances. Urinary incontinence resulting from fistulae to the vagina or rectum is usually best managed by urinary diversion if feasible. If not, urinary catheterization may assist in keeping the perineum dry.
Deep venous thrombosis should be excluded, particularly if other signs such as pain, increased temperature of the affected limb, or superficial venous dilatation are present. Anticoagulation in patients who have a deep venous thrombosis may lead to a reduction of symptoms, but the decision to anticoagulate a patient with advanced cancer must be made in the context of the patient's prognosis and goals.
If the swelling is due to lymphatic obstruction, the management must be individualized. Physical therapies, in experienced hands, are most helpful for moderate to severe lymphedema. Massage, bandaging, and fitting of support garments may add much to a patient's comfort (83). Care should be taken when applying compression bandages to grossly edematous legs to ensure venous circulation is not compromised.
Rarely, a patient who has serious nutritional deficiency (for example, associated with several months of nausea and anorexia) may exhibit severe edema that is due to thiamine deficiency. This is classically associated with an increase in jugular venous pressure and a bounding pulse. If recognized, improvement may be dramatic, occurring within 24 to 48 hours of giving thiamine.
Weakness or fatigue can be profound when there is a large tumor burden, but there are many reversible causes of this symptom (84). These include nutritional deficiencies, hypotension, hypokalemia, hypoglycemia or hyperglycemia, hypoadrenalism, hypercalcemia, renal failure, infection, and anemia. At least some of these may be readily treated in appropriate circumstances. Anemia per se does not require correction in every patient because the benefit may be short lived and not proportionate to the expenditure of resources. A patient who is confined to bed because of advanced disease often tolerates a hemoglobin of 7.0 g/dL or less. However, if the hemoglobin is low and weakness is a dominant symptom, transfusion may be justified.
For a number of patients, fatigue remains a dominant symptom without readily correctible contributory factors. For those women who are maintaining some independence,preliminary evidence suggests that a program which seeks to maintain and increase gentle physical activity improves both fatigue and quality of life (85).
Hypercalcemia (raised ionized plasma calcium level) is a recognized complication of malignancy and a potent cause of symptoms, ranging from lethargy; weakness; and constipation to severe nausea; vomiting; confusion; psychotic symptoms (notably paranoia); and exacerbation of bone pain. In general, treatment of hypercalcemia should be coupled with anticancer therapy directed at removing the cause of the hypercalcemia if still feasible.
Hypercalcemia usually heralds a poor prognosis, and for the relatively asymptomatic or already obtunded patient, aggressive treatment may not be warranted. However, the presence of troublesome symptoms often makes palliative antihypercalcemic therapy worthwhile (86).
Treatment of hypercalcemia depends on its severity. The following measures are necessary in moderate or severe cases:
Improvement of symptoms with these measures can be expected within a few days, as calcium uptake in bone increases. When calcium is extremely high and intravenous bisphosphonate therapy is not causing a rapid reduction, subcutaneous calcitonin administration combined with bisphosphonate therapy may provide a more rapid reduction of calcium levels, but administration of calcitonin always warrants specialist assistance.
Should hypercalcemia recur, the bisphosphonate dose may be repeated. The rate of relapse depends in part on the availability of effective therapy for the underlying tumor, as well as on the biologic characteristics and tempo of the neoplastic process. Therefore the decision to repeat doses of bisphosphonate must take into account these factors, the likely prognosis and the symptoms implicated.
Care of the Patient Close to Death
Good palliative care is concerned with the enrichment of life, even when facing the human task common to all, that of dying (88). It is important to recognize that a woman is actually dying; this is an important diagnosis with clinical as well as social implications. What is medically possible at this stage, such as treatment of renal failure, septicemia, or hypercalcemia, may not necessarily be medically wise.
There are many physical indicators that a patient is actually dying, and these are well known to clinicians, although not necessarily to family members. There may be a change in the tempo of the disease, a manifest change in the function of critical organs, or a rapid deterioration in strength or physical performance in the absence of reversible factors, such as gross anemia, septicemia, hypercalcemia, or drug interactions.
There are also psychological signs that a patient is dying. An experienced clinician may note the gradual withdrawal of the patient from interest in the wider world, from interest in personal friends, and even the gradual loosening of bonds with those very close. In some patients, this “cutting of the moorings” is very obvious: intrapersonal activity may be very intense and expressed only to a trusted few. The patient herself may clearly articulate her awareness that she is now close to death, or she may choose not to speak of it. The essence of clinical response is to respect the mystery of the individual.
The process of dying is fraught with uncertainties. When it is clear that the patient is dying, the goal is dignity, privacy, peace, and space for the woman to complete those remaining tasks important to “a life well-lived.”
Once recognized that the woman is dying, care should encompass the following domains:
Sometimes it is justifiable to offer direct sedation when, in spite of adequate symptom control, distress is extreme and opportunities for verbal communication no longer exist. There are circumstances in which a patient should be able to sleep peacefully as she dies. This is particularly the case if an agitated delirium is present after treating any remediable factors such as fecal impaction, urinary retention, or unrelieved pain. If hallucinations are prominent, an antipsychotic may be most useful, whereas if agitation and distress are present, a benzodiazepine should be used, either alone or in combination with an antipsychotic. Suitable benzodiazepines include midazolam (2-5 mg subcutaneously, intramuscularly, or intravenously stat and 10-50 mg over 24 hours by subcutaneous infusion if distress is protracted) or sublingual lorazepam (0.5-2.5 mg every 4-6 hours).Antipsychotics used commonly would include haloperidol (0.5-5 mg twice daily orally or subcutaneously), risperidone (0.5-1 mg twice daily orally), or olanzapine (2.5-10 mg daily orally or buccal wafer). Some of the older sedating antipsychotic agents (such as chlorpromazine) remain useful in this setting.
On rare occasions, distress and agitation may not be relieved with the combination of a benzodiazepine and an antipsychotic. In such circumstances, careful dosing of phenobarbital(50-100 mg given 8 hourly orally or subcutaneously) may allow calm in the final part of life. Large doses of opioids are not appropriate for sedation of the dying. Ensuring that a patient sleeps most of the time during the last hours (or few days) of her life is not euthanasia.
The development of “rattling” respirations indicating pooling of secretions is common in the patient close to death. Management should include repositioning of the patient, and possibly the judicious use of anticholinergic agents (hyoscine hydrobromide 0.2-0.4 mg subcutaneously up to 4 hourly) to reduce the production of secretions. The latter must be coupled with measures to keep the mouth moist. Reassurance should be given to families that this is usually not distressing to the patient.
Complex equipment should be avoided if possible, as should tubes of all sorts, to facilitate maximum physical contact with loved ones. Nursing care must remain excellent, with particular emphasis on pressure care, mouth care, and “grooming.” Teaching family members to assist with the care of their loved one can do much to enhance intimacy and diminish the sense of helplessness many families feel. In the face of imminent death, respect for individual religious and cultural customs is mandatory.
It is essential that medical and nursing staff accept and understand the personal significance of the final phase of life. It is a crucial period of personal development and a time for clarifying, reconciling, healing and/or affirming personal relationships—always a complex task at the close of life.
Death serves as the master-test of our journeyman years. It tests the height we have reached, the value of our inner metaphysics; it examines its strength, its utility, durability, and suitability in mobilization and in the most terrible reality: it introduces a factor alien to the subject and thus summons us directly from the subjectively ideal sphere, from the freely suspended realm of ideal self-definitions, to the “cosmic” realm of danger and diffusion, and of the gathering from the bustle of this world of death in which the self finally proves itself after all (89).
It is worthwhile reflecting once again on the issues which patients view as significant in the final part of life, for these must inform all care provided. These are: (i) receiving adequate pain and symptom management; (ii) avoiding inappropriate prolongation of dying; (iii) achieving a sense of control; (iv) relieving the burden on caregivers; and (v) strengthening relationships with loved ones (5,90).
Good care of patients with incurable, progressive disease is concerned with enrichment of remaining life, reduction of relievable distress, and support for personal growth and development, even when facing the human task common to all, that of dying. The inherent dignity of the dying woman can be maintained and enhanced by the care she receives and the respect afforded to her continued relationships with those she loves (91).
A Final Note
Mention has been made of the suffering of patients, yet nothing has been said of the distress of the health professionals who care for and journey with these patients. Such distress is often not articulated or shared. The sensitive clinician may take comfort from the words of a French oncologist:
Suffering is something like crossing a sea, traversing a mountain or a desert; it is an experience, painful indeed, in which the person will become more oneself and will discover oneself; it is an experience in which a person will experience evil, and yet, at the same time, will be led to discover and express the deepest meaning of one's life. This is true also for the suffering of the doctor. (92)
However, the burden of distress remains with women with gynecologic cancer, especially in situations of oppression, poverty, and exploitation. Competent as well as compassionate palliative care may salvage dignity and meaning for the individual who is suffering, and in some small way, for the doctor himself. Few doctors have such an opportunity.