523
were no differences in survival and interferon treatment was associated with troublesome side-effects, predominantly influenza-like symptoms and tiredness. Use of interleukin-2 (IL-2, initially administered together with lymphokine activated killer [LAK] cells) was first reported in a wave of excitement in 1985.6 In the initial series’ 11 % of patients with metastatic renal cell cancer showed a complete response and 22% a partial response. Nevertheless, toxicity was profound, necessitating intensive supportive care largely because of a capillary leak syndrome. In a subsequent multicentre trial of this therapy the overall response rate was 16%. The severe side-effects associated with IL-2 (with or without LAK cells) are now well recognised.9 To reduce toxicity and to simplify treatment, IL-2 has been given by infusion with LAK cells," or alone by bolus administration or infusion.7,11 These regimens are associated with fewer side-effects, but response rates have likewise been reduced. More recently, IL-2 has been given subcutaneously, often together with interferon, in another attempt to reduce toxicity and simultaneously increase efficacy. In two such studies,12,13 total response rates of 31 % and 36% were
acetate; there
recorded. In no trial has IL-2 therapy been compared with standard, symptomatic care. The criteria for identifying patients who are likely to respond to biological therapy are similar to those for predicting a good outcome. The toxicity associated with such treatment has precluded the use of this approach in most patients with metastatic renal cell cancer. Phase II studies in the past two years12,13 have excluded patients with low performance status, and also those with any evidence of renal dysfunction or coexisting cardiac or pulmonary disease. Clinicians should be cautious about interpreting the response rates reported in relation to their own patients. Biological therapy seems to result in response in metastatic renal cell cancer, but does the patient benefit? The answer has to be perhaps. In an analogous disease-advanced non-small-cell lung cancer-similar response rates have been reported for toxic treatments (in this case chemotherapy). However, randomised trials with palliative care as a control 1116 showed little or no benefit, and consequently cytotoxic agents are not usually prescribed in this condition. Both interferon and IL-2 have now been licensed for therapeutic use in several European countries but not in the USA. Some observers find it strange that agents such as these can be licensed and marketed without trials to determine their efficacy in relation to toxicity and cost. If biological therapies are to have a therapeutic role we need to know not only the likely rates of radiological or clinical regression but also the size of effect (if any) on symptom relief and survival. These effects must be balanced against the often severe impairment of quality of life in patients who
respond and in the much larger number who do not. Only multicentre trials with a palliative treatment control group
can
settle these issues.
1. Oliver RTD, Nethersell ABW, Bottomley JM. Unexplained spontaneous
regression and alpha-interferon as treatment for metastatic renal carcinoma. Br J Urol 1989; 63: 128-31. 2. Dekernion JB, Ramming KP, Smith RB. The natural history of metastatic renal cell carcinoma: a computer analysis. J Urol 1978; 78: 148-53.
Maldazys JD, Derkernion JB. Prognostic factors in metastatic renal carcinoma. J Urol 1986; 136: 376-79. 4. Horoszewicz JS, Murphy GP. An assessment of the current use of human interferons in therapy of urological cancers. J Urol 1989; 142: 1173-80. 5. Steineck G, Strander H, Carbin BE, et al. Recombinant leukocyte interferon alpha-2A and medroxyprogesterone in advanced renal cell carcinoma. Acta Oncol 1990; 29: 155-62. 6. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J 3.
Med 1985; 313: 1485-92. Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 8. Fisher RI, Coltman CA, Doroshow JH, et al. Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1988; 108: 518-23. 9. Margolin KA, Rayner AA, Hawkins MJ, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol 1989; 7: 486-98. 10. Parkinson DR, Fisher RI, Rayner AA, et al. Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen. J Clin Oncol 1990; 8: 1630-36. 11. West WH, Kurt MD, Tauer W, et al. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987; 316: 898-905. 12. Atzpodien J, Korfer A, Franks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-&agr;2b in advanced human malignancies. Lancet 1990; 335: 1509-12. 13. Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 1989; 7: 1863-74. 14. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer: report of Canadian multicenter randomised trial. J Clin Oncol 1988; 6: 633-41. 15. Ganz PA, Figlin RA, Haskell CM, et al. Supportive care versus supportive care and combination chemotherapy in metastatic nonsmall cell lung cancer. Cancer 1989; 63: 1271-78. 16. Woods RL, Williams CJ, Levi J, et al. A randomised trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 1990; 61: 608-11. 7.
Rosenberg SA,
Alarm bells for enuresis Childhood nocturnal enuresis can be defined as involuntary discharge of urine during sleep in the absence of a urological or a neurological disorder. The condition afflicts 10% of 5-year olds and 5% of 10-year oldsl,2 and the frequency shows no signs of diminishing.That there are wide variations in reported prevalence rates (1-32% in 5-12-year olds) can be explained by the characteristics of the particular study population and by the way in which researchers define enuresis.4 Management of enuresis is dominated by pharmacotherapy and by conditioning techniques such as enuresis alarms. Long-term efficacy of tricyclic antidepressants is poor,5while antidiuretic agents such as desmopressin are rapidly effective but relapse is common after treatment is stopped.6 Forsythe and Butler, 7 in a comprehensive review of
524
the efficacy of enuresis alarms, reported an overall initial success rate of 68%. However, the range in cures varied from 15 to 100%. Part of this wide variation might be due to difficulties with definition and the lack of universally acceptable criteria of efficacy. These factors hinder comparison of results, so the newly published working definitions for alarm therapy8 are especially welcome. Before a trial of alarm therapy is initiated, baseline data must be recorded-eg, age and sex of the child, severity of the bed-wetting, and presence of other factors that might influence outcome including daytime wetting and organic disease. A 1-month baseline observation period will confirm enuresis severity. Moreover, with supervision, many children achieve continence during this time.9 Initial success should be measured in terms of 14 consecutive dry nights. Alarm treatment usually works in 5-8 weeks; there is little advantage in continuing therapy for more than 2 weeks after initial success. Persistence with an alarm after 16 weeks is unlikely to be beneficial. Drop-outs should be monitored closely and reasons for cessation of therapy noted. Most cases of failure to attend are probably due to treatment failure, although some parents do not keep follow-up appointments because the child has become dry .10 It is harder to define relapse; Butler, in his review of sixteen centres, noted ten definitions. Relapse depends on quantification of three factors: (a) duration of monitoring (most relapses occur within 6 months of treatment); (b) duration over which wet nights are observed; and (c) number of wet nights. By use of these criteria, relapse is defmed as 2 or more wet nights over 2 weeks, and continued success as no relapse in 6 months after initial success. Complete success means that the child is dry 2 years after the initial arrest of
wetting. What factors influence outcome? There are equal for the commonly used pad and bell and body worn alarms, so alarm type is not a factor.An enthusiastic clinic with close monitoring of therapy is important;1112 failures are common if supervision is poor. 13 Failure to respond to the alarm has been explained by domestic difficulties such as sharing a bed, inadequate parental supervision, the child’s lack of interest, and failing to wake to the alarm. These problems should be explored by the therapist because some can be solved-eg, an alarm booster will make the alarm more audible. Adverse environmental success rates
factors, including unsatisfactory housing and family stress, militate against a successful outcome; in the child, behavioural deviance, developmental delay, urological disorder, and daytime wetting are other unfavourable variables.9,14 A child without adverse factors has an excellent chance of achieving dryness. There are few complications of alarm treatment; modem reliable alarms seldom induce buzzer ulcers. Even though relapse after use of an alarm is less
frequent than after pharmacotherapy, careful supervision is necessary for 6 months after treatment. If relapse occurs, treatment may be repeated and the likelihood of success is similar
to
the initial
course
of
therapy. J, Peckham C. Nocturnal enuresis in childhood. Dev Med Child Neurol 1976; 18: 577-89. Douglas JWB. Early disturbing events and later enuresis. In: Kolvin I, Mac Keith RC, Meadow SR, eds. Bladder control and enuresis. Clinics in developmental medicine no 48/49. Philadelphia: Lippincott, 1973. 109-17. Foxman B, Valdez RB, Brook RH. Childhood enuresis: prevalence, perceived impact and prescribed treatments. Pediatrics 1986; 77: 482-87. de Jonge GA. Epidemiology of enuresis: a survey of the literature. In: Kolvin I, Mac Keith RC, Meadow SR, eds. Bladder control and enuresis. Clinics in developmental medicine no. 48/49. Philadelphia Lippincott, 1973: 39-46. Kolvin I, Taunch J, Currah J, et al. Enuresis: a descriptive analysis and a controlled trial. Dev Med Child Neural 1972; 14: 715-26. Wille S. Comparison of desmopressin and enuresis alarm for enuresis. Arch Dis Child 1986; 61: 30-33. Forsythe WI, Butler RJ. Fifty years of enuretic alarms. Arch Dis Child 1989; 64: 879-85. Butler RJ. Establishment of working definitions in nocturnal enuresis. Arch Dis Child 1991; 66: 267-71. Devlin JB, O’ Cathain C. Predicting treatment outcome in nocturnal enuresis. Arch Dis Child 1990; 65: 1158-61. Young GC, Morgan RTT. Reasons for appointment failure among enuretic patients. Common Med 1972; 129: 23-25. Meadow R. How to use buzzer alarms to cure bed-wetting. Br MedJ 1977; ii: 1073-75. Butler RJ. Nocturnal enuresis: psychological perspectives. Bristol: John Wright. 1987. Close GC. Nocturnal enuresis and the buzzer alarm: role of the general practitioner. Br Med J 1980; 281: 483-84. Dische S, Yule W, Corbett J, Hand D. Childhood nocturnal enuresis: factors associated with outcome of treatment with an enuresis alarm. Dev Med Child Neurol 1983; 25: 67-80.
1. Essen
2.
3.
4.
5. 6. 7.
8. 9. 10. 11. 12. 13.
14.
Postoperative pain relief and non-opioid analgesics Routine management of pain after surgery is unsatisfactory and has not advanced substantially for many years.1 Studies published in the past 2 years have shown that about 40% of patients who receive conventional treatment complain of insufficient analgesia and moderate or severe pain. 2,3 After major surgery, an opioid is usually administered "as intramuscularly required". In practice, because of fears among nursing and medical staff about the potential for addiction and depression of ventilation, and because administration of a controlled drug may be inconvenient, opioids are often withheld until the patient is in great discomfort. Moreover, an intramuscular injection given at this time will not bring rapid relief.1 Epidural or intravenous opioids give more continuous analgesia, but at greater risk of ventilatory depression because of the wide variation in individual dose requirements. Patient-controlled analgesia is effective but requires expensive
equipment. Opioids are generally unsuitable for acute pain after day-case surgery because of their sedative action, and may
cause
unnecessary
side-effects when
were no differences in survival and interferon treatment was associated with troublesome side-effects, predominantly influenza-like symptoms and tiredness. Use of interleukin-2 (IL-2, initially administered together with lymphokine activated killer [LAK] cells) was first reported in a wave of excitement in 1985.6 In the initial series’ 11 % of patients with metastatic renal cell cancer showed a complete response and 22% a partial response. Nevertheless, toxicity was profound, necessitating intensive supportive care largely because of a capillary leak syndrome. In a subsequent multicentre trial of this therapy the overall response rate was 16%. The severe side-effects associated with IL-2 (with or without LAK cells) are now well recognised.9 To reduce toxicity and to simplify treatment, IL-2 has been given by infusion with LAK cells," or alone by bolus administration or infusion.7,11 These regimens are associated with fewer side-effects, but response rates have likewise been reduced. More recently, IL-2 has been given subcutaneously, often together with interferon, in another attempt to reduce toxicity and simultaneously increase efficacy. In two such studies,12,13 total response rates of 31 % and 36% were
acetate; there
recorded. In no trial has IL-2 therapy been compared with standard, symptomatic care. The criteria for identifying patients who are likely to respond to biological therapy are similar to those for predicting a good outcome. The toxicity associated with such treatment has precluded the use of this approach in most patients with metastatic renal cell cancer. Phase II studies in the past two years12,13 have excluded patients with low performance status, and also those with any evidence of renal dysfunction or coexisting cardiac or pulmonary disease. Clinicians should be cautious about interpreting the response rates reported in relation to their own patients. Biological therapy seems to result in response in metastatic renal cell cancer, but does the patient benefit? The answer has to be perhaps. In an analogous disease-advanced non-small-cell lung cancer-similar response rates have been reported for toxic treatments (in this case chemotherapy). However, randomised trials with palliative care as a control 1116 showed little or no benefit, and consequently cytotoxic agents are not usually prescribed in this condition. Both interferon and IL-2 have now been licensed for therapeutic use in several European countries but not in the USA. Some observers find it strange that agents such as these can be licensed and marketed without trials to determine their efficacy in relation to toxicity and cost. If biological therapies are to have a therapeutic role we need to know not only the likely rates of radiological or clinical regression but also the size of effect (if any) on symptom relief and survival. These effects must be balanced against the often severe impairment of quality of life in patients who
respond and in the much larger number who do not. Only multicentre trials with a palliative treatment control group
can
settle these issues.
1. Oliver RTD, Nethersell ABW, Bottomley JM. Unexplained spontaneous
regression and alpha-interferon as treatment for metastatic renal carcinoma. Br J Urol 1989; 63: 128-31. 2. Dekernion JB, Ramming KP, Smith RB. The natural history of metastatic renal cell carcinoma: a computer analysis. J Urol 1978; 78: 148-53.
Maldazys JD, Derkernion JB. Prognostic factors in metastatic renal carcinoma. J Urol 1986; 136: 376-79. 4. Horoszewicz JS, Murphy GP. An assessment of the current use of human interferons in therapy of urological cancers. J Urol 1989; 142: 1173-80. 5. Steineck G, Strander H, Carbin BE, et al. Recombinant leukocyte interferon alpha-2A and medroxyprogesterone in advanced renal cell carcinoma. Acta Oncol 1990; 29: 155-62. 6. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J 3.
Med 1985; 313: 1485-92. Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 8. Fisher RI, Coltman CA, Doroshow JH, et al. Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1988; 108: 518-23. 9. Margolin KA, Rayner AA, Hawkins MJ, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol 1989; 7: 486-98. 10. Parkinson DR, Fisher RI, Rayner AA, et al. Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen. J Clin Oncol 1990; 8: 1630-36. 11. West WH, Kurt MD, Tauer W, et al. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987; 316: 898-905. 12. Atzpodien J, Korfer A, Franks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-&agr;2b in advanced human malignancies. Lancet 1990; 335: 1509-12. 13. Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 1989; 7: 1863-74. 14. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer: report of Canadian multicenter randomised trial. J Clin Oncol 1988; 6: 633-41. 15. Ganz PA, Figlin RA, Haskell CM, et al. Supportive care versus supportive care and combination chemotherapy in metastatic nonsmall cell lung cancer. Cancer 1989; 63: 1271-78. 16. Woods RL, Williams CJ, Levi J, et al. A randomised trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 1990; 61: 608-11. 7.
Rosenberg SA,
Alarm bells for enuresis Childhood nocturnal enuresis can be defined as involuntary discharge of urine during sleep in the absence of a urological or a neurological disorder. The condition afflicts 10% of 5-year olds and 5% of 10-year oldsl,2 and the frequency shows no signs of diminishing.That there are wide variations in reported prevalence rates (1-32% in 5-12-year olds) can be explained by the characteristics of the particular study population and by the way in which researchers define enuresis.4 Management of enuresis is dominated by pharmacotherapy and by conditioning techniques such as enuresis alarms. Long-term efficacy of tricyclic antidepressants is poor,5while antidiuretic agents such as desmopressin are rapidly effective but relapse is common after treatment is stopped.6 Forsythe and Butler, 7 in a comprehensive review of
524
the efficacy of enuresis alarms, reported an overall initial success rate of 68%. However, the range in cures varied from 15 to 100%. Part of this wide variation might be due to difficulties with definition and the lack of universally acceptable criteria of efficacy. These factors hinder comparison of results, so the newly published working definitions for alarm therapy8 are especially welcome. Before a trial of alarm therapy is initiated, baseline data must be recorded-eg, age and sex of the child, severity of the bed-wetting, and presence of other factors that might influence outcome including daytime wetting and organic disease. A 1-month baseline observation period will confirm enuresis severity. Moreover, with supervision, many children achieve continence during this time.9 Initial success should be measured in terms of 14 consecutive dry nights. Alarm treatment usually works in 5-8 weeks; there is little advantage in continuing therapy for more than 2 weeks after initial success. Persistence with an alarm after 16 weeks is unlikely to be beneficial. Drop-outs should be monitored closely and reasons for cessation of therapy noted. Most cases of failure to attend are probably due to treatment failure, although some parents do not keep follow-up appointments because the child has become dry .10 It is harder to define relapse; Butler, in his review of sixteen centres, noted ten definitions. Relapse depends on quantification of three factors: (a) duration of monitoring (most relapses occur within 6 months of treatment); (b) duration over which wet nights are observed; and (c) number of wet nights. By use of these criteria, relapse is defmed as 2 or more wet nights over 2 weeks, and continued success as no relapse in 6 months after initial success. Complete success means that the child is dry 2 years after the initial arrest of
wetting. What factors influence outcome? There are equal for the commonly used pad and bell and body worn alarms, so alarm type is not a factor.An enthusiastic clinic with close monitoring of therapy is important;1112 failures are common if supervision is poor. 13 Failure to respond to the alarm has been explained by domestic difficulties such as sharing a bed, inadequate parental supervision, the child’s lack of interest, and failing to wake to the alarm. These problems should be explored by the therapist because some can be solved-eg, an alarm booster will make the alarm more audible. Adverse environmental success rates
factors, including unsatisfactory housing and family stress, militate against a successful outcome; in the child, behavioural deviance, developmental delay, urological disorder, and daytime wetting are other unfavourable variables.9,14 A child without adverse factors has an excellent chance of achieving dryness. There are few complications of alarm treatment; modem reliable alarms seldom induce buzzer ulcers. Even though relapse after use of an alarm is less
frequent than after pharmacotherapy, careful supervision is necessary for 6 months after treatment. If relapse occurs, treatment may be repeated and the likelihood of success is similar
to
the initial
course
of
therapy. J, Peckham C. Nocturnal enuresis in childhood. Dev Med Child Neurol 1976; 18: 577-89. Douglas JWB. Early disturbing events and later enuresis. In: Kolvin I, Mac Keith RC, Meadow SR, eds. Bladder control and enuresis. Clinics in developmental medicine no 48/49. Philadelphia: Lippincott, 1973. 109-17. Foxman B, Valdez RB, Brook RH. Childhood enuresis: prevalence, perceived impact and prescribed treatments. Pediatrics 1986; 77: 482-87. de Jonge GA. Epidemiology of enuresis: a survey of the literature. In: Kolvin I, Mac Keith RC, Meadow SR, eds. Bladder control and enuresis. Clinics in developmental medicine no. 48/49. Philadelphia Lippincott, 1973: 39-46. Kolvin I, Taunch J, Currah J, et al. Enuresis: a descriptive analysis and a controlled trial. Dev Med Child Neural 1972; 14: 715-26. Wille S. Comparison of desmopressin and enuresis alarm for enuresis. Arch Dis Child 1986; 61: 30-33. Forsythe WI, Butler RJ. Fifty years of enuretic alarms. Arch Dis Child 1989; 64: 879-85. Butler RJ. Establishment of working definitions in nocturnal enuresis. Arch Dis Child 1991; 66: 267-71. Devlin JB, O’ Cathain C. Predicting treatment outcome in nocturnal enuresis. Arch Dis Child 1990; 65: 1158-61. Young GC, Morgan RTT. Reasons for appointment failure among enuretic patients. Common Med 1972; 129: 23-25. Meadow R. How to use buzzer alarms to cure bed-wetting. Br MedJ 1977; ii: 1073-75. Butler RJ. Nocturnal enuresis: psychological perspectives. Bristol: John Wright. 1987. Close GC. Nocturnal enuresis and the buzzer alarm: role of the general practitioner. Br Med J 1980; 281: 483-84. Dische S, Yule W, Corbett J, Hand D. Childhood nocturnal enuresis: factors associated with outcome of treatment with an enuresis alarm. Dev Med Child Neurol 1983; 25: 67-80.
1. Essen
2.
3.
4.
5. 6. 7.
8. 9. 10. 11. 12. 13.
14.
Postoperative pain relief and non-opioid analgesics Routine management of pain after surgery is unsatisfactory and has not advanced substantially for many years.1 Studies published in the past 2 years have shown that about 40% of patients who receive conventional treatment complain of insufficient analgesia and moderate or severe pain. 2,3 After major surgery, an opioid is usually administered "as intramuscularly required". In practice, because of fears among nursing and medical staff about the potential for addiction and depression of ventilation, and because administration of a controlled drug may be inconvenient, opioids are often withheld until the patient is in great discomfort. Moreover, an intramuscular injection given at this time will not bring rapid relief.1 Epidural or intravenous opioids give more continuous analgesia, but at greater risk of ventilatory depression because of the wide variation in individual dose requirements. Patient-controlled analgesia is effective but requires expensive
equipment. Opioids are generally unsuitable for acute pain after day-case surgery because of their sedative action, and may
cause
unnecessary
side-effects when
