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QUALITY OF LIFE IN EARLY PROSTATE CANCER
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QUALITY OF LIFE IN EARLY PROSTATE CANCER Do We Know Enough to Treat? James A. Talcott, MD, SM
WHY SHOULD QUALITY OF LIFE AFFECT TREATMENT DECISIONS?
For patients with many cancers, the issue of quality of life is a minor subtext in discussions of treatment choice. For patients with rapidly lethal diseases,
particularly those for which cure is possible, the goal of both physician and patient is to use as aggressive a treatment as necessary to achieve remission, the necessary milestone on the way to long-term survival. Under the immediate threat of death from cancer, the primary goal of treatment is the patient’s 5-year survival) which signifies decisive control of the cancer, and any toxicity during and complications after treatment are considered necessary evils. Of course, potential complications must be accurately enough described to obtain the patients’ informed consent for treatment, but the required litany of potential side effects of combination chemotherapy usually does not affect the decision to begin treatment, but rather simply raises fears, often unfounded, in a patient who feels, accurately, to be without significant alternatives. For the patient with early (nonmetastatic) prostate cancer, the situation is quite different. Patients may choose from at least two well-established altemative treatments, radical prostatectomy and radical external beam radiotherapy, with two further alternatives added in the last decade: (1) radiation implants
This work was supported by the Agency for Health Care Policy and Research Grant HS06824
From the Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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(”seeds”), or brachytherapy, and (2) cryotherapy, or freezing of the prostate. Furthermore, recent evidence has made a final option, initial observation with delayed hormonal therapy-sometimes called “watchful waiting” and long a common approach for old patients with other serious illnesses+onsidered in wider contexts: reports of favorable outcomes for observed patients8,l6 and a decision analytic model that found little average survival benefit of active treatment for older patients and those with well-differentiated tumors.’oEach of these treatment alternatives has a distinctive pattern of potential complications, some of which may be long-lasting. For watchful waiting, the potential complications come, of course, not from treatment but from future progression of untreated cancer. For all patients, accurate information about the likely complications of treatment is required to provide the ethical and legal basis for patient informed consent. But knowledge about potential complications may be beneficial in itself Patients with accurate information about likely complications can anticipate, prepare for, and, when they occur, adapt to them more easily. A patient warned before treatment that a complication may occur feels unlucky when the complication occurs. The patient who has not been warned or has been given inaccurately low estimates of its likelihood feels injured and misused. The problem of toxicity from cancer treatment is certainly not confined to surgical and radiation treatment of prostate cancer. Many of the side effects of cancer chemotherapy are extraordinarily unpleasant, and some are potentially life-threatening. Yet patients rarely blame their medical oncologists for the complications they experience if they have been told to expect them. Although it may be tempting for a treatment provider to minimize potential complications to spare patients unnecessary anxiety about their cancer therapy, particularly when they lack realistic alternatives, accurate information, even the worst, is what they need, and usually know they need, to get through it. Because of the long natural history of prostate cancer, accurate information about complications of treatment is even more important than for other cancers. Prostate cancer is characterized by a very slow progression as compared with quick killers such as lung cancer, acute leukemia, and lymphoma. For prostate cancer to kill within 5 years is distinctly unusual; for too many other cancers, 5year survival is an uncommon signal of cure. Furthermore, prostate cancer occurs in older men, during the stage in their lives when other potentially lethal illnesses are increasingly likely to arise. Presumably because of screening with the prostate-specific antigen (PSA) test,’5, 26 the average age at diagnosis has fallen rapidly, and the number of patients diagnosed has spectacularly increased. There is no reason to think that the natural history of prostate cancer disease, which most men die with, not of. has changed since screening emerged. Rather, cancers are simply being discovered sooner, possibly allowing more patients to receive curative therapy, but certainly forcing many more men to choose therapy for cancer several years earlier. Thus, a man destined to die of prostate cancer at age 80 may now be diagnosed at age 65 through PSA screening, rather than at age 70 through clinical indicators, such as progressive urinary obstructive symptoms o f an abnormal digital rectal examination (DRE). The hypothetic 5year interval between diagnosis from screening and that from symptoms or DRE is not chosen arbitrarily: Retrospective analysis of blood specimens taken from physicians enrolled in a randomized cancer and coronary artery disease prevention trial found an average ”lead time” of over 5 years between an abnormal PSA and the later diagnosis of prostate cancer.I3This lead time bias, or apparently prolonged cancer survival because of earlier diagnosis, is one
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of two "biases" that make patients diagnosed by screening appear to have prolonged survival as compared with men diagnosed from symptoms. The other-length bias-may have as large an effect but is much harder to estimate. It arises because slow-growing tumors spend more time at the stage when they can be detected by screening but do not yet cause symptoms. These more indolent tumors are more likely to be diagnosed by screening than are rapidly progressing tumors and less likely to metastasize and kill. Because of both effects of screening, most of the men diagnosed with prostate cancer now are likely to live significantly longer after diagnosis without being harmed by their cancers than were men diagnosed in previous generations. As a result, the time between diagnosis of prostate cancer (and the consequent need to make a decision about treatment) and when symptoms of metastatic cancer are likely to arise is almost certainly greater now than in the past. The goal of treating prostate cancer is to prevent the first metastasis, because only metastatic disease, not local disease, causes death. Therefore, local therapy will provide no benefit at all for the patient who has already had metastatic spread, even if the metastases are microscopic and undetectable. Because metastatic seeds have already been planted in the patient's bones, only the race between his cancer and any other potentially lethal diseases he might develop will determine whether he will die of prostate cancer. The patient without micrometastasis will not necessarily benefit from therapy, either: If the prostate cancer progresses more slowly than competing comorbid diseases, treatment would be unneeded and again without benefit. Thus, for many, if not (more likely) for most, therapy provides no benefit in terms of prolonged life. For those patients whose metastatic disease is prevented by local therapy, the benefit of treatment is not realized until micrometastases grow to a size that causes symptoms, a period likely to be a decade or more for most patients. As a result, even successful treatment of prostate cancer can be expected to provide no tangible benefits for years, if at all; however, although the intended consequences of treatment are in the future, the complications of treatment may be immediate and enduring. Permanent effects of prostate cancer therapy on sexual potency, urinary incontinence, and bowel function may begin immediately after radical prostatectomy, and within the first year or two after radiation therapy. Because of early prostate cancer's long natural history, men with complications will survive to experience them for years. Thus, paradoxically, the issue of treatment complications matters particularly to prostate cancer patients because, whether or not treatment is successful, their prognosis is so good, relative to other cancer patients. The publicity given recently to studies documenting good results for some men after observations, lo, l6 has not apparently led large numbers of men to reject local therapy. For most patients in the United States, to knowingly allow a cancer to go untreated is intuitively wrong, even if some evidence suggests that, on average, it may be better. But it has made men increasingly aware that their treatment choices may well contribute importantly to the quality of their lives during the final decade or more of their lives. To a young person, the attempt to prolong life may mean the opportunity to accomplish significant life goals, such as starting and raising a family, building a career, and cultivating avocations and friendships. For an older man, many of those goals have been accomplished, and most men have seen in the lives of their friends, family, and acquaintances that death cannot be postponed indefinitely. In this latter setting, in which other infirmities of advancing age have manifest themselves, men may be more cautious about accepting the chance of significant new iatrogenic ones.
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POOR EVIDENCE FOR THE EFFICACY AND COMPLICATIONS OF TREATMENT The available data provide a shaky foundation upon which to choose a treatment strategy based on the tradeoff between distant potential benefits and potential complications much sooner. Despite the extraordinary frequency of prostate cancer and its unprecedented rate of increase, the quality of the data documenting the efficacy of the most widely used treatments, radical prostatectomy and radical external beam radiotherapy, and their likely frequency of complications is very poor. Even less is known about alternative approaches, including brachytherapy and cryotherapy. Single small randomized trials exist comparing radical prostatectomy with radiotherapy and with 0bservation.2~Neither study found a statistically significant survival difference. Recent attempts to complete randomized trials have been largely unavailing, although early reports indicate that the current Prostate Intervention versus Observation Trial (PIVOT) is accruing significantly.faster than any other randomized trial of therapy for early prostate The much more commonly published singlemodality treatment case series are subject to selection bias and are untrustworthy for comparing therapies. The absence of the primary scientific advantage of randomized trials-that because chance alone determines treatment, patients in the treatment groups have on average the same prognosis-deeply flaws nonrandomized series of patients receiving treatment for early prostate cancer. Patients who receive radical prostatectomy differ systematically and importantly from those who receive external beam radiotherapy. Urologists prefer radical prostatectomy for early prostate cancer, just as radiotherapists prefer radiothera ~ y *however, ~; because urologists perform the biopsies that diagnose prostate cancer, they are in the influential position of offering the first treatment recommendations to the newly diagnosed patient. They usually favor radical prostatectomy, largely because of its possibly greater efficacy. But because of both the increasing risk general anesthesia poses to older patients and the shorter expected life expectancy of older men in which any survival advantage from surgery might play out, radical prostatectomy is preferentially offered to younger patients and denied to older men, particularly over 70 years of age. In addition, men with serious cardiac and pulmonary comorbid disease, for whom prolonged general anesthesia would be particularly hazardous, and men with evidence of spread of the tumor beyond the prostate capsule, making complete surgical resection unlikely, are also referred for radiotherapy. Thus, younger, healthier patients and those with smaller tumors are preferentially selected for radical prostatectomy, making a better outcome for them, compared with the remainder who receive radiation therapy, predictable and not very informative about the efficacy of treatment. Many older, sicker patients receive watchful waiting by default, because their physicians, perhaps with the informed agreement of their patients, do not work them up for, or offer them, potentially curative local treatment at all? The unequal prognoses for radiotherapy, surgery, and bservation patients is not the only reason case series are often unhelpful. h& t treatment series reports do not provide adequate information on prognostically important clinical variables, an omission preventing even rough comparisons of the treated populations, according to a large structured analysis of the published Despite the poor quality of available data on the efficacy of treatment and the natural history of untreated disease, attempts have been made to construct decision-analytic models to estimate treatment outcomes and the variables that most influence them. The first and most influential of these, published by the
s"
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Prostate Patient Outcomes Research Team (Prostate PORT), concluded that men who were older (in their seventies) or had well-differentiated tumors would benefit little from treatment, particularly when the expected gain in length of life was adjusted for reduced quality due to common complications.'nAlthough this study has been criticized based on some of the numeric values used in the analysis, their conclusion that many men might not benefit very much from treatment has not been persuasively refuted. Another model, developed to assess screening for prostate cancer, came to a similar conclusion, that screening and subsequent therapy might have limited ~sefulness.'~ But because in the screening model any benefit of treating those men found with cancer is diluted by the large group of screened men found not to have cancer, the maximum expected benefits of screening in the most favorable groups were only a few days, compared with months or years in the Fleming model. Furthermore, the study concluded that quality-adjusting survival for complications of therapy eliminated the expected benefit of screening completely. Although both studies concluded that the quality of data on which they based their models was poor, they confirm the belief that adjusting outcomes for reduced quality of life substantially influences the overall judgment about the value of treatment.
PROBLEMS WITH MEASUREMENT OF QUALITY OF LIFE Assessing quality of life in patients with prostate cancer has two main tasks: identifying what is to be measured, and measuring it accurately. Quality of life is a complex concept, comprising many areas, or domains, whose relative and absolute values may differ from person to person. A person's health status certainly contributes to his or her quality of life, and for seriously ill patients, it comprises the greatest part. But many other factors, such as personal relationships, economic circumstances, vocational satisfactions, and artistic and musical experiences, determine most persons' quality of life to an important degree. The aspect of quality of life most likely to be influenced by medical conditions is health-related quality of life (HRQoL), which itself is conceptually heterogeneous. The best known instrument measuring generic or global HRQoL, the Medical Outcomes Study Short Form Health Survey (SF-36),2ncomprises eight distinct domains pertaining to mental and physical health. Because even a life-threatening disease such as cancer does not solely determine a patient's sense of health, most investigators of quality of life distinguish between global HRQoL and disease-specific aspects of quality of life.', 6, Other diseases than the most prominent may contribute importantly to health status. Therefore, a complete health assessment includes a measurement of other comorbid diseases, such as the Index of Co-existent Diseases (ICED) developed by Greenfield and colleag~es.'~ The disease-specific aspect of HRQoL often focuses on symptoms prominent in a particular disease, such as coronary artery disease or cancer. Some instruments developed to measure cancer-specific health status include the Functional Assessment of Cancer Therapy scale (FACT): the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30,2 and the CAncer Rehabilitation Evaluation System (CARES).27Further specificity in the target disease may be necessary. Particular cancers have some aspects in common with many others, particularly in the advanced stages, such as pain, weight loss, and fatigue. Particular symptoms, however, may be unique to a particular cancer, or even the stage of that cancer. The FACT has been adapted to a number of cancers by adding a few symptom-specific questions, or items, to the core instrument. When the instrument was adapted to prostate cancer,
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however, the additional items in the resultant FACT-P focus on symptoms of patients with metastatic prostate cancer, such as bone pain, which are rare and largely irrelevant to a patient's first years following treatment for early disease. Therefore, an instrument measuring HRQoL for early prostate cancer must include items that address the specific areas in which treated patients experience problems, specifically related to bowel, bladder, and sexual function. One further dimension arises because the same symptom may affect two men differently. For one man, for example, an occasional large leakage of urine may be more a minor annoyance, whereas for another the experience may be a devastating humiliation. This variation in patient values requires measuring not only the degree or frequency of symptoms but also how much the symptoms bother the patients, the so-called "bother" questions developed by Fowler et allz The measurement of symptoms in these organ-specific areas is not uniformly well-developed. The complications from prostate cancer and from the alternative therapies to treat it overlap but differ importantly. Prostate cancer itself may obstruct urine flow and may be a factor in impotence. Radical prostatectomy may cause obstruction (due to bladder neck or urethral strictures), but it is more likely to cause incontinence, whereas radiotherapy may exacerbate obstruction and cause irritative bladder symptoms subacutely, and only uncommonly result in incontinence. Surgery rarely causes bowel symptoms, whereas radiation therapy frequently causes symptoms due to rectal injury, including diarrhea, rectal urgency, and bleeding. Even impotence may be expressed differently; although surgery patients report immediate and complete postoperative impotence followed by gradual recovery of function, radiotherapy patients report gradually increasing difficulties in getting erections and decreasing erectile firmness in the months and years following treatment. Because of important work by Fowler and colleagues'* in evaluating complications of transurethral resection of the prostate (TLJRP) for benign prostatic hyperplasia (BPH), later modified for radical prostatectomy,ll excellent items for assessing incontinence and impotence are available. Items to assess the complications of radiotherapy, however, particularly those of radiation proctitis, are less well developed. The attempt by Litwin et all9to develop scales of sexual, urinary, and bowel function to compare outcomes of patients previously treated by radical prostatectomy, radiotherapy, and observation were least successful for bowel function. A final problem is that the average contribution of each dimension contributing to overall HRQoL for a population does not apply to each individual. What is most crucial to overall HRQoL may differ from person to person. Therefore, any attempt to "add up" assessments of various domains of HRQoL to get an overall summary measure may work well for some persons but not others. As a result of these interpersonal differences, the component parts of a summary score may be of significantly greater interest than the whole and individual items or subscales, paradoxically, may provide more information than a global measure. Assessing the distinct contributions of prostate cancer itself and of its treatment to HRQoL is more important than for many other cancers, because the cancer itself, apart from the far from negligible psychological effects of the cancer diagnosis, has few physical consequences in the first years after diagnosis. Many patients have symptoms of obstructive uropathy, but their relationship to the cancer itself, rather than its very common companion BPH, is uncertain. Treatment-related complications are far more likely than cancer to affect a man's quality of life early in the disease course. Furthermore, even when complications due to treatment do occur, patients may consider them irrelevant to their healthrelated quality of life, because they are perceived as due to something other than their cancer. A patient may have substantial symptoms of impotence or
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incontinence and be bothered by them, but he may not feel that his overall health status has changed at all. Thus, the likelihood that he will develop treatment-related complications may be very relevant to his treatment choice, but still considered distinct from his primary health problem, prostate cancer. As a result, the relationship between treatment-related symptoms and HRQoL must be shown empirically. In fact, early investigations have found little correlation between global measures of HRQoL, such as the SF-36, and treatment-related symptoms?, Therefore, it is not only extraordinarily difficult, but conceptually suspect, to believe that one could identify a single symptom numeric scale that would summarize usefully and accurately changes in HRQoL for a patient who has received treatment for early prostate cancer. We have used global measures of HRQoL, in our case the SF-36 and the Profile of Mood States but we have found them in general to show little change even when patients develop substantial new treatment-related symptoms. The poor correlation between these global health status measurements and the symptoms arising from prostate cancer treatment may have two explanations: (1)either the instruments we tested are insensitive to changes of the magnitude caused by, for example, new impotence or radiation proctitis, or (2) the patients experience the changes as being distinct from their overall HRQoL. Therefore, we have concluded that, for now, the most useful information for patients is accurate information about the frequency of treatment-related disease-specific symptoms. For early prostate cancer, these include measures of sexual function, urinary symptoms, particularly irritative bladder symptoms and incontinence, and bowel symptoms. The carefully developed scales for bowel, bladder, and sexual function by Litwin et al, and others developed for the American Urologic Association by Barry and colleagues> 24 are useful for comparing groups, but they may provide an unreliable guide for a patient attempting to choose the treatment option most likely to meet his needs and values. Information about particular symptoms and the ”bother” they cause may need to be further broken down by other characteristics of the population. The relative importance of sexual dysfunction, urinary incontinence, and rectal symptoms varies substantially within a single population because of age, marital status and other factors. For example, we have observed that loss of erections is more important on average for younger men than for older men, both absolutely and compared with urinary incontinence. A summary scale that does not include stratification for patient age may not generalize to a younger or older population. Once investigators have decided which complications of treatment they wish to investigate, survey technique is important. Individual questions or items must be asked in clear, easily understood language, and the responses to each question must be equally clear, unambiguous, and relevant to patient experience. Confusing questions generate meaningless variability in patient responses, or “noise.” If the questions are open-ended or the answers not specific enough, interviewer subjectivity and thus possible bias may distort the results. Such ambiguity may contribute to minimization of complications in physician interviews of their patients. Physicians in general would prefer to believe, and record, that their patients are doing better rather than worse. A second, probably equally important bias comes from the relationship between patient and treating physician. Patients are often reluctant to tell their doctors the full extent of their treatment-related problems, perhaps for fear of seeming an ungrateful, ”bad patient.” These subconscious biases, if given free play by imprecise questions or incompletely specific answers, probably result in published reports that minimize the extent of complications. That this may occur can be seen in Table 1. The impotence and incontinence rates reported by leading academic urologists
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Table 1. REPORTED COMPLICATIONS AFTER RADICAL PROSTATECTOMY Percent of Patients with Complication Study Walsh, et al, 198730 Walsh, et al, 199lZ8 Catalona and Basler, 19905 Fowler, et al, 1993” Litwin, et al, 199519 Talcott, et al, 1994=
Study Design Surgical case series Surgical case series Surgical case series Retrospective survey Retrospective survey Prospective survey
Impotence
Incontinence
Pads
28
-
-
47
8 2
-
-
89 71 77
6
47
-
31 40
13
40
WalshZ8, 30 and Catalona5for their patients who have received radical prostatectomy are low: One half or more are reported as being fully potent; that is, able to have sexual intercourse after their surgery. Further, incontinence is reported in fewer than 10% of men. Complication rates obtained using standard methodology, however, are substantially higher. These include two retrospective ~ some of reports”, l9 and our own preliminary prospective r e ~ u l t s ?Although this difference between the surgical series and the direct patient surveys may be due to other factors such as the definition of the complication, the age of patient population, and the time between treatment and the symptom assessment, probably most important is that complication rates were higher when patients were surveyed more scientifically and by other than treating physicians. Although improper survey technique is the most important problem with much published data, other factors may alter results. The definition of the complication varies from study to study. Sexual potency could be defined as differently as ”the occurrence of any noticeable erection at any time after treatment” or ”reliable, hard, and durable erections in most sexual encounters.” We have used two different definitions of potency in our own studies: “the occurrence of any erection in the past 4 weeks” and “erections usually adequate for sexual intercourse in the past 4 weeks,” to identify both evidence for the physiologic ability to support erections and, more stringently, their utility. The definition of erections used in most surgical reports is even more strict than the latter: ”erections adequate for intercourse.” Nevertheless, despite this strict definition, surgical series tend to report lower rates of impotence than our own. The age of the study population may influence outcomes. Both sexual impotence and urinary incontinence are increasingly prevalent with increasing age. Therefore, symptoms in substantially older populations may be due to other age-related comorbid illness, rather than the effects of treatment. The cross-sectional patients assessed by the surveys of both Fowler and Litwin were substantially older than most recent surgical case series, in part because patients were surveyed several years after they had undergone surgery. The interval after treatment may also affect the frequency of complications. Men are most symptomatic immediately after surgery, when nearly all are impotent and most have some degree of incontinence; however, many patients improve during the first year or two after surgery. An assessment of impotence or incontinence 3 months after surgery would have very different (and much worse) results than assessments taken 12 or 24 months after surgery, when recovery is likely to be nearly complete. For radiotherapy, the relationship between the time elapsed since treatment and functional status is reversed: Erectile dysfunction tends to progress for several years after radiotherapy. Therefore, an assessment of erectile
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function at 6 months after radiotherapy would provide a misleadingly low estimate of post-treatment impotence, which would almost certainly be substantially greater a year or two later. Thus, interpreting complication rates requires close attention to what is measured, in whom, and when. A final problem with available data on treatment-related complications is due to the lack of methodologically rigorous prospective information. Ideally, comparative data on treatment complications, just as for the efficacy of therapy, would come from randomized trials. Randomized trials of treatments for early prostate have been very difficult to complete, however. Because such studies have accrued poorly, the few patients enrolled in trial may be unrepresentative of the average patient. Nearly all reported case series have been seriously marred by poor data collection techniques. The two best published surveys were performed by researchers who did not provide the cancer treatment. Although these surveys were likely to assess patient symptoms accurately, they were unable to assign treatment as their cause. The effects of other comorbid disease or the pretreatment effects of cancer itself prior to therapy may have caused impotence or incontinence, apart from therapy. Only prospective data unambiguously identify complications that have developed since therapy, and are thus plausibly due to therapy. Our own studies are an attempt to accomplish this.
A FINAL WORD
Although much of the data available in the literature is uninterpretable owing to poorly defined populations or inadequate data collection techniques, reliable methods for obtaining accurate information about complications are now available. Careful attention to modern survey techniques can eliminate ambiguity due to poorly defined items and underestimates of complications due to subconscious biases arising when treating physicians interview their own patients. Prospective cohort studies such as our own should clarify the frequency of complications following treatment. As a result of this research, patients and physicians will increasingly have at their disposal accurate information about patient complications; however, this information alone will not be enough to identify a particular therapy for early prostate cancer that is best for all patients. Patients will always differ by which complications they fear the most and how much they fear them. Some men may find it impossible to face the possibility of significant urinary incontinence or radiation proctitis, whereas others may find it unacceptable not to have had the most aggressive treatment available. Therefore, careful and sympathetic discussions between the patient and his physician will always be necessary to identify the optimal choice. But even perfectly accurate and fully detailed information about complications, as important as it may be to a man’s quality of life the decade after treatment, is inadequate. Without an accurate estimate of the effect of treatment on prolonging life, the other side of the treatment equation, the benefit of treatment, remains blank. Useful information about efficacy can come only from randomized clinical trials. Although such studies have unfortunately been difficult to complete in the past, preliminary information indicates that the PIVOT trial is accruing patients at a rate far higher than any prior randomized trial of early prostate cancer treatment in the United States. Although definitive results from this trial will not be known for 10 years or more, the early success of the trial may indicate a fundamental change in the research climate, raising hopes that other randomized trials will be spawned and completed. Only when patients
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have accurate information about both efficacy and treatment-related complications will they be able to choose their treatment with confidence.
References 1. Aaronson NK. Quality of life research in cancer clinical trials: A need for common rules and language. Oncology (Williston Park) 4:59, 1990 2. Aaronson NK, Ahmedzai S, Bergman B, et al: "he European Organization for Research and Treatment of Cancer QLQ-C30 A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365, 1993 3. Barry MJ, Fowler FJ Jr, O'Leary MP, et a1 The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 148:1549, 1992 4. Bennett CL, Greenfield S, Aronow H, et al: Patterns of care related to age of men with prostate cancer. Cancer 672633, 1991 Return of erections and urinary continence following nerve 5. Catalona WJ, Basler JW: sparing radical retropubic prostatectomy. J Urol 150905, 1993 6. Cella DF, Tulsky D S Measuring quality of life today: Methodological aspects. Oncology (Williston Park) 429, 1990 7. Cella DF, Tulsky DS, Gray G, et a1 The Functional Assessment of Cancer Therapy scale: Development and validation of the general measure. J Clin Oncol 11:570, 1993 8. Chodak GW, Thisted RA, Gerber GS, et al: Results of conservative management of clinically localized prostate cancer. N Engl J Med 330:242, 1994 9. Clark J, Rieker P, Kalish L, et al: Evaluation of the SF-36 measures of health related quality of life (HRQoL) in prostate cancer [abstract]. Proc Annu Meet Am SOCCIin Oncol 12:A1508, 1993 10. Fleming C, Wasson JH, Albertsen PC, et al: A.decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 2692650, 1993 11. Fowler F, Jr, Barry MJ, Lu-Yao G, et a 1 Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988-1990 (updated June 1993). Urology 42622, 1993 12. Fowler FJJ, Wennberg JE, Timothy RP, et al: Symptom status and quality of life following prostatectomy. JAMA 259:3018, 1988 13. Gann PH, Hennekens CH, Stampfer MJ: A prospective evaluation of plasma prostatespecific antigen for detection of prostatic cancer. JAMA 273:289, 1995 14. Greenfield S, Aronow HU, Elashoff RM, Watanabe D Flaws in mortality data. The hazards of ignoring comorbid disease. JAMA 260:2253, 1988 15. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al: Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 274:1445, 1995 16. Johansson JE, Adami HO, Andersson SO, et al: Natural history of localised prostatic cancer. A population-based study in 223 untreated patients. Lancet 1:799, 1989 17. Krahn MD, Mahoney JE, Eckman MH, et al: Screening for prostate cancer. A decision analytic view. JAMA 272:773, 1994 18. Litwin M Health-related quality of life after treatment for localized prostate cancer. Cancer 75:2000, 1995 19. Litwin MS, Hays RD, Fink A, et al: Quality-of-life outcomes in men treated for early prostate cancer. JAMA 273:129, 1995 20. McHomey CA, Ware JEJ, Rogers W, et a1 The validity and relative precision of MOS short- and long-fonn health status scales and Dartmouth COOP charts. Results from the Medical Outcomes Study. Med Care 3O(suppl5):MS253, 1992 21. McNair DM, Lorr M, Droppleman L F Profile of Mood States, ed 2. San Diego, Educational and Industrial Testing Service. 1981 22. Moinpour CM, Hayden KA, Thompson IM, et al: Quality of life assessment in Southwest Oncology Group trials. Oncology (Williston Park) 479, 1990 23. Moore MJ, OSullivan B, Tannock I F How expert physicians would wish to be treated if they had genitourinary cancer. J Clin Oncol 6:1736, 1988
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24. OLeary MP, Fowler FJ, Lenderking WR, et al: A brief male sexual function inventory for urology. Urology 46:697, 1995 25. Paulson DF, Lin GH, Hinshaw W, Stephani S: Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J Urol 128:502, 1982 26. Potosky AL, Miller BA, Albertsen PC, Kramer BS The role of increasing detection in the rising incidence of prostate cancer. JAMA 273:548, 1995 27. Schag CA, Ganz PA, Heinrich RL: CAncer Rehabilitation Evaluation System-short form (CARES-SF). A cancer specific rehabilitation and quality of life instrument. Cancer 68:1406, 1991 28. Steiner MS, Morton RA, Walsh PC: Impact of anatomical radical prostatectomy on urinary continence. J Urol 145:512, 1991 29. Talcott JA, Rieker P, Propert K, et al: Complications of treatment for early prostate cancer: A prospective, multi-institutional outcomes study [abstract]. Proc Annu Meet Am SOCClin Oncol 13:A711, 1994 30. Walsh PC, Epstein JI, Lowe FC: Potency following radical prostatectomy with wide unilateral excision of the neurovascular bundle. J Urol 1382323, 1987 31. Wasson JH, Cushman CC, Bruskewitz RC, et al: A structured literature review of treatment for localized prostate cancer. Prostate Disease Patient Outcome Research Team. Arch Fam Med 2487, 1993 32. Wilt TJ, Brawer M K The Prostate Cancer Intervention Versus Observation Trial: A randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer. J Urol 152:1910, 1994
Address reprint requests to James A. Talcott, MD, SM Dana-Farber Cancer Institute, D 1118 44 Binney Street Boston, MA 02115
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QUALITY OF LIFE IN EARLY PROSTATE CANCER Do We Know Enough to Treat? James A. Talcott, MD, SM
WHY SHOULD QUALITY OF LIFE AFFECT TREATMENT DECISIONS?
For patients with many cancers, the issue of quality of life is a minor subtext in discussions of treatment choice. For patients with rapidly lethal diseases,
particularly those for which cure is possible, the goal of both physician and patient is to use as aggressive a treatment as necessary to achieve remission, the necessary milestone on the way to long-term survival. Under the immediate threat of death from cancer, the primary goal of treatment is the patient’s 5-year survival) which signifies decisive control of the cancer, and any toxicity during and complications after treatment are considered necessary evils. Of course, potential complications must be accurately enough described to obtain the patients’ informed consent for treatment, but the required litany of potential side effects of combination chemotherapy usually does not affect the decision to begin treatment, but rather simply raises fears, often unfounded, in a patient who feels, accurately, to be without significant alternatives. For the patient with early (nonmetastatic) prostate cancer, the situation is quite different. Patients may choose from at least two well-established altemative treatments, radical prostatectomy and radical external beam radiotherapy, with two further alternatives added in the last decade: (1) radiation implants
This work was supported by the Agency for Health Care Policy and Research Grant HS06824
From the Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 10 NUMBER 3 * JUNE 1996
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(”seeds”), or brachytherapy, and (2) cryotherapy, or freezing of the prostate. Furthermore, recent evidence has made a final option, initial observation with delayed hormonal therapy-sometimes called “watchful waiting” and long a common approach for old patients with other serious illnesses+onsidered in wider contexts: reports of favorable outcomes for observed patients8,l6 and a decision analytic model that found little average survival benefit of active treatment for older patients and those with well-differentiated tumors.’oEach of these treatment alternatives has a distinctive pattern of potential complications, some of which may be long-lasting. For watchful waiting, the potential complications come, of course, not from treatment but from future progression of untreated cancer. For all patients, accurate information about the likely complications of treatment is required to provide the ethical and legal basis for patient informed consent. But knowledge about potential complications may be beneficial in itself Patients with accurate information about likely complications can anticipate, prepare for, and, when they occur, adapt to them more easily. A patient warned before treatment that a complication may occur feels unlucky when the complication occurs. The patient who has not been warned or has been given inaccurately low estimates of its likelihood feels injured and misused. The problem of toxicity from cancer treatment is certainly not confined to surgical and radiation treatment of prostate cancer. Many of the side effects of cancer chemotherapy are extraordinarily unpleasant, and some are potentially life-threatening. Yet patients rarely blame their medical oncologists for the complications they experience if they have been told to expect them. Although it may be tempting for a treatment provider to minimize potential complications to spare patients unnecessary anxiety about their cancer therapy, particularly when they lack realistic alternatives, accurate information, even the worst, is what they need, and usually know they need, to get through it. Because of the long natural history of prostate cancer, accurate information about complications of treatment is even more important than for other cancers. Prostate cancer is characterized by a very slow progression as compared with quick killers such as lung cancer, acute leukemia, and lymphoma. For prostate cancer to kill within 5 years is distinctly unusual; for too many other cancers, 5year survival is an uncommon signal of cure. Furthermore, prostate cancer occurs in older men, during the stage in their lives when other potentially lethal illnesses are increasingly likely to arise. Presumably because of screening with the prostate-specific antigen (PSA) test,’5, 26 the average age at diagnosis has fallen rapidly, and the number of patients diagnosed has spectacularly increased. There is no reason to think that the natural history of prostate cancer disease, which most men die with, not of. has changed since screening emerged. Rather, cancers are simply being discovered sooner, possibly allowing more patients to receive curative therapy, but certainly forcing many more men to choose therapy for cancer several years earlier. Thus, a man destined to die of prostate cancer at age 80 may now be diagnosed at age 65 through PSA screening, rather than at age 70 through clinical indicators, such as progressive urinary obstructive symptoms o f an abnormal digital rectal examination (DRE). The hypothetic 5year interval between diagnosis from screening and that from symptoms or DRE is not chosen arbitrarily: Retrospective analysis of blood specimens taken from physicians enrolled in a randomized cancer and coronary artery disease prevention trial found an average ”lead time” of over 5 years between an abnormal PSA and the later diagnosis of prostate cancer.I3This lead time bias, or apparently prolonged cancer survival because of earlier diagnosis, is one
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of two "biases" that make patients diagnosed by screening appear to have prolonged survival as compared with men diagnosed from symptoms. The other-length bias-may have as large an effect but is much harder to estimate. It arises because slow-growing tumors spend more time at the stage when they can be detected by screening but do not yet cause symptoms. These more indolent tumors are more likely to be diagnosed by screening than are rapidly progressing tumors and less likely to metastasize and kill. Because of both effects of screening, most of the men diagnosed with prostate cancer now are likely to live significantly longer after diagnosis without being harmed by their cancers than were men diagnosed in previous generations. As a result, the time between diagnosis of prostate cancer (and the consequent need to make a decision about treatment) and when symptoms of metastatic cancer are likely to arise is almost certainly greater now than in the past. The goal of treating prostate cancer is to prevent the first metastasis, because only metastatic disease, not local disease, causes death. Therefore, local therapy will provide no benefit at all for the patient who has already had metastatic spread, even if the metastases are microscopic and undetectable. Because metastatic seeds have already been planted in the patient's bones, only the race between his cancer and any other potentially lethal diseases he might develop will determine whether he will die of prostate cancer. The patient without micrometastasis will not necessarily benefit from therapy, either: If the prostate cancer progresses more slowly than competing comorbid diseases, treatment would be unneeded and again without benefit. Thus, for many, if not (more likely) for most, therapy provides no benefit in terms of prolonged life. For those patients whose metastatic disease is prevented by local therapy, the benefit of treatment is not realized until micrometastases grow to a size that causes symptoms, a period likely to be a decade or more for most patients. As a result, even successful treatment of prostate cancer can be expected to provide no tangible benefits for years, if at all; however, although the intended consequences of treatment are in the future, the complications of treatment may be immediate and enduring. Permanent effects of prostate cancer therapy on sexual potency, urinary incontinence, and bowel function may begin immediately after radical prostatectomy, and within the first year or two after radiation therapy. Because of early prostate cancer's long natural history, men with complications will survive to experience them for years. Thus, paradoxically, the issue of treatment complications matters particularly to prostate cancer patients because, whether or not treatment is successful, their prognosis is so good, relative to other cancer patients. The publicity given recently to studies documenting good results for some men after observations, lo, l6 has not apparently led large numbers of men to reject local therapy. For most patients in the United States, to knowingly allow a cancer to go untreated is intuitively wrong, even if some evidence suggests that, on average, it may be better. But it has made men increasingly aware that their treatment choices may well contribute importantly to the quality of their lives during the final decade or more of their lives. To a young person, the attempt to prolong life may mean the opportunity to accomplish significant life goals, such as starting and raising a family, building a career, and cultivating avocations and friendships. For an older man, many of those goals have been accomplished, and most men have seen in the lives of their friends, family, and acquaintances that death cannot be postponed indefinitely. In this latter setting, in which other infirmities of advancing age have manifest themselves, men may be more cautious about accepting the chance of significant new iatrogenic ones.
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POOR EVIDENCE FOR THE EFFICACY AND COMPLICATIONS OF TREATMENT The available data provide a shaky foundation upon which to choose a treatment strategy based on the tradeoff between distant potential benefits and potential complications much sooner. Despite the extraordinary frequency of prostate cancer and its unprecedented rate of increase, the quality of the data documenting the efficacy of the most widely used treatments, radical prostatectomy and radical external beam radiotherapy, and their likely frequency of complications is very poor. Even less is known about alternative approaches, including brachytherapy and cryotherapy. Single small randomized trials exist comparing radical prostatectomy with radiotherapy and with 0bservation.2~Neither study found a statistically significant survival difference. Recent attempts to complete randomized trials have been largely unavailing, although early reports indicate that the current Prostate Intervention versus Observation Trial (PIVOT) is accruing significantly.faster than any other randomized trial of therapy for early prostate The much more commonly published singlemodality treatment case series are subject to selection bias and are untrustworthy for comparing therapies. The absence of the primary scientific advantage of randomized trials-that because chance alone determines treatment, patients in the treatment groups have on average the same prognosis-deeply flaws nonrandomized series of patients receiving treatment for early prostate cancer. Patients who receive radical prostatectomy differ systematically and importantly from those who receive external beam radiotherapy. Urologists prefer radical prostatectomy for early prostate cancer, just as radiotherapists prefer radiothera ~ y *however, ~; because urologists perform the biopsies that diagnose prostate cancer, they are in the influential position of offering the first treatment recommendations to the newly diagnosed patient. They usually favor radical prostatectomy, largely because of its possibly greater efficacy. But because of both the increasing risk general anesthesia poses to older patients and the shorter expected life expectancy of older men in which any survival advantage from surgery might play out, radical prostatectomy is preferentially offered to younger patients and denied to older men, particularly over 70 years of age. In addition, men with serious cardiac and pulmonary comorbid disease, for whom prolonged general anesthesia would be particularly hazardous, and men with evidence of spread of the tumor beyond the prostate capsule, making complete surgical resection unlikely, are also referred for radiotherapy. Thus, younger, healthier patients and those with smaller tumors are preferentially selected for radical prostatectomy, making a better outcome for them, compared with the remainder who receive radiation therapy, predictable and not very informative about the efficacy of treatment. Many older, sicker patients receive watchful waiting by default, because their physicians, perhaps with the informed agreement of their patients, do not work them up for, or offer them, potentially curative local treatment at all? The unequal prognoses for radiotherapy, surgery, and bservation patients is not the only reason case series are often unhelpful. h& t treatment series reports do not provide adequate information on prognostically important clinical variables, an omission preventing even rough comparisons of the treated populations, according to a large structured analysis of the published Despite the poor quality of available data on the efficacy of treatment and the natural history of untreated disease, attempts have been made to construct decision-analytic models to estimate treatment outcomes and the variables that most influence them. The first and most influential of these, published by the
s"
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Prostate Patient Outcomes Research Team (Prostate PORT), concluded that men who were older (in their seventies) or had well-differentiated tumors would benefit little from treatment, particularly when the expected gain in length of life was adjusted for reduced quality due to common complications.'nAlthough this study has been criticized based on some of the numeric values used in the analysis, their conclusion that many men might not benefit very much from treatment has not been persuasively refuted. Another model, developed to assess screening for prostate cancer, came to a similar conclusion, that screening and subsequent therapy might have limited ~sefulness.'~ But because in the screening model any benefit of treating those men found with cancer is diluted by the large group of screened men found not to have cancer, the maximum expected benefits of screening in the most favorable groups were only a few days, compared with months or years in the Fleming model. Furthermore, the study concluded that quality-adjusting survival for complications of therapy eliminated the expected benefit of screening completely. Although both studies concluded that the quality of data on which they based their models was poor, they confirm the belief that adjusting outcomes for reduced quality of life substantially influences the overall judgment about the value of treatment.
PROBLEMS WITH MEASUREMENT OF QUALITY OF LIFE Assessing quality of life in patients with prostate cancer has two main tasks: identifying what is to be measured, and measuring it accurately. Quality of life is a complex concept, comprising many areas, or domains, whose relative and absolute values may differ from person to person. A person's health status certainly contributes to his or her quality of life, and for seriously ill patients, it comprises the greatest part. But many other factors, such as personal relationships, economic circumstances, vocational satisfactions, and artistic and musical experiences, determine most persons' quality of life to an important degree. The aspect of quality of life most likely to be influenced by medical conditions is health-related quality of life (HRQoL), which itself is conceptually heterogeneous. The best known instrument measuring generic or global HRQoL, the Medical Outcomes Study Short Form Health Survey (SF-36),2ncomprises eight distinct domains pertaining to mental and physical health. Because even a life-threatening disease such as cancer does not solely determine a patient's sense of health, most investigators of quality of life distinguish between global HRQoL and disease-specific aspects of quality of life.', 6, Other diseases than the most prominent may contribute importantly to health status. Therefore, a complete health assessment includes a measurement of other comorbid diseases, such as the Index of Co-existent Diseases (ICED) developed by Greenfield and colleag~es.'~ The disease-specific aspect of HRQoL often focuses on symptoms prominent in a particular disease, such as coronary artery disease or cancer. Some instruments developed to measure cancer-specific health status include the Functional Assessment of Cancer Therapy scale (FACT): the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30,2 and the CAncer Rehabilitation Evaluation System (CARES).27Further specificity in the target disease may be necessary. Particular cancers have some aspects in common with many others, particularly in the advanced stages, such as pain, weight loss, and fatigue. Particular symptoms, however, may be unique to a particular cancer, or even the stage of that cancer. The FACT has been adapted to a number of cancers by adding a few symptom-specific questions, or items, to the core instrument. When the instrument was adapted to prostate cancer,
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however, the additional items in the resultant FACT-P focus on symptoms of patients with metastatic prostate cancer, such as bone pain, which are rare and largely irrelevant to a patient's first years following treatment for early disease. Therefore, an instrument measuring HRQoL for early prostate cancer must include items that address the specific areas in which treated patients experience problems, specifically related to bowel, bladder, and sexual function. One further dimension arises because the same symptom may affect two men differently. For one man, for example, an occasional large leakage of urine may be more a minor annoyance, whereas for another the experience may be a devastating humiliation. This variation in patient values requires measuring not only the degree or frequency of symptoms but also how much the symptoms bother the patients, the so-called "bother" questions developed by Fowler et allz The measurement of symptoms in these organ-specific areas is not uniformly well-developed. The complications from prostate cancer and from the alternative therapies to treat it overlap but differ importantly. Prostate cancer itself may obstruct urine flow and may be a factor in impotence. Radical prostatectomy may cause obstruction (due to bladder neck or urethral strictures), but it is more likely to cause incontinence, whereas radiotherapy may exacerbate obstruction and cause irritative bladder symptoms subacutely, and only uncommonly result in incontinence. Surgery rarely causes bowel symptoms, whereas radiation therapy frequently causes symptoms due to rectal injury, including diarrhea, rectal urgency, and bleeding. Even impotence may be expressed differently; although surgery patients report immediate and complete postoperative impotence followed by gradual recovery of function, radiotherapy patients report gradually increasing difficulties in getting erections and decreasing erectile firmness in the months and years following treatment. Because of important work by Fowler and colleagues'* in evaluating complications of transurethral resection of the prostate (TLJRP) for benign prostatic hyperplasia (BPH), later modified for radical prostatectomy,ll excellent items for assessing incontinence and impotence are available. Items to assess the complications of radiotherapy, however, particularly those of radiation proctitis, are less well developed. The attempt by Litwin et all9to develop scales of sexual, urinary, and bowel function to compare outcomes of patients previously treated by radical prostatectomy, radiotherapy, and observation were least successful for bowel function. A final problem is that the average contribution of each dimension contributing to overall HRQoL for a population does not apply to each individual. What is most crucial to overall HRQoL may differ from person to person. Therefore, any attempt to "add up" assessments of various domains of HRQoL to get an overall summary measure may work well for some persons but not others. As a result of these interpersonal differences, the component parts of a summary score may be of significantly greater interest than the whole and individual items or subscales, paradoxically, may provide more information than a global measure. Assessing the distinct contributions of prostate cancer itself and of its treatment to HRQoL is more important than for many other cancers, because the cancer itself, apart from the far from negligible psychological effects of the cancer diagnosis, has few physical consequences in the first years after diagnosis. Many patients have symptoms of obstructive uropathy, but their relationship to the cancer itself, rather than its very common companion BPH, is uncertain. Treatment-related complications are far more likely than cancer to affect a man's quality of life early in the disease course. Furthermore, even when complications due to treatment do occur, patients may consider them irrelevant to their healthrelated quality of life, because they are perceived as due to something other than their cancer. A patient may have substantial symptoms of impotence or
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incontinence and be bothered by them, but he may not feel that his overall health status has changed at all. Thus, the likelihood that he will develop treatment-related complications may be very relevant to his treatment choice, but still considered distinct from his primary health problem, prostate cancer. As a result, the relationship between treatment-related symptoms and HRQoL must be shown empirically. In fact, early investigations have found little correlation between global measures of HRQoL, such as the SF-36, and treatment-related symptoms?, Therefore, it is not only extraordinarily difficult, but conceptually suspect, to believe that one could identify a single symptom numeric scale that would summarize usefully and accurately changes in HRQoL for a patient who has received treatment for early prostate cancer. We have used global measures of HRQoL, in our case the SF-36 and the Profile of Mood States but we have found them in general to show little change even when patients develop substantial new treatment-related symptoms. The poor correlation between these global health status measurements and the symptoms arising from prostate cancer treatment may have two explanations: (1)either the instruments we tested are insensitive to changes of the magnitude caused by, for example, new impotence or radiation proctitis, or (2) the patients experience the changes as being distinct from their overall HRQoL. Therefore, we have concluded that, for now, the most useful information for patients is accurate information about the frequency of treatment-related disease-specific symptoms. For early prostate cancer, these include measures of sexual function, urinary symptoms, particularly irritative bladder symptoms and incontinence, and bowel symptoms. The carefully developed scales for bowel, bladder, and sexual function by Litwin et al, and others developed for the American Urologic Association by Barry and colleagues> 24 are useful for comparing groups, but they may provide an unreliable guide for a patient attempting to choose the treatment option most likely to meet his needs and values. Information about particular symptoms and the ”bother” they cause may need to be further broken down by other characteristics of the population. The relative importance of sexual dysfunction, urinary incontinence, and rectal symptoms varies substantially within a single population because of age, marital status and other factors. For example, we have observed that loss of erections is more important on average for younger men than for older men, both absolutely and compared with urinary incontinence. A summary scale that does not include stratification for patient age may not generalize to a younger or older population. Once investigators have decided which complications of treatment they wish to investigate, survey technique is important. Individual questions or items must be asked in clear, easily understood language, and the responses to each question must be equally clear, unambiguous, and relevant to patient experience. Confusing questions generate meaningless variability in patient responses, or “noise.” If the questions are open-ended or the answers not specific enough, interviewer subjectivity and thus possible bias may distort the results. Such ambiguity may contribute to minimization of complications in physician interviews of their patients. Physicians in general would prefer to believe, and record, that their patients are doing better rather than worse. A second, probably equally important bias comes from the relationship between patient and treating physician. Patients are often reluctant to tell their doctors the full extent of their treatment-related problems, perhaps for fear of seeming an ungrateful, ”bad patient.” These subconscious biases, if given free play by imprecise questions or incompletely specific answers, probably result in published reports that minimize the extent of complications. That this may occur can be seen in Table 1. The impotence and incontinence rates reported by leading academic urologists
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Table 1. REPORTED COMPLICATIONS AFTER RADICAL PROSTATECTOMY Percent of Patients with Complication Study Walsh, et al, 198730 Walsh, et al, 199lZ8 Catalona and Basler, 19905 Fowler, et al, 1993” Litwin, et al, 199519 Talcott, et al, 1994=
Study Design Surgical case series Surgical case series Surgical case series Retrospective survey Retrospective survey Prospective survey
Impotence
Incontinence
Pads
28
-
-
47
8 2
-
-
89 71 77
6
47
-
31 40
13
40
WalshZ8, 30 and Catalona5for their patients who have received radical prostatectomy are low: One half or more are reported as being fully potent; that is, able to have sexual intercourse after their surgery. Further, incontinence is reported in fewer than 10% of men. Complication rates obtained using standard methodology, however, are substantially higher. These include two retrospective ~ some of reports”, l9 and our own preliminary prospective r e ~ u l t s ?Although this difference between the surgical series and the direct patient surveys may be due to other factors such as the definition of the complication, the age of patient population, and the time between treatment and the symptom assessment, probably most important is that complication rates were higher when patients were surveyed more scientifically and by other than treating physicians. Although improper survey technique is the most important problem with much published data, other factors may alter results. The definition of the complication varies from study to study. Sexual potency could be defined as differently as ”the occurrence of any noticeable erection at any time after treatment” or ”reliable, hard, and durable erections in most sexual encounters.” We have used two different definitions of potency in our own studies: “the occurrence of any erection in the past 4 weeks” and “erections usually adequate for sexual intercourse in the past 4 weeks,” to identify both evidence for the physiologic ability to support erections and, more stringently, their utility. The definition of erections used in most surgical reports is even more strict than the latter: ”erections adequate for intercourse.” Nevertheless, despite this strict definition, surgical series tend to report lower rates of impotence than our own. The age of the study population may influence outcomes. Both sexual impotence and urinary incontinence are increasingly prevalent with increasing age. Therefore, symptoms in substantially older populations may be due to other age-related comorbid illness, rather than the effects of treatment. The cross-sectional patients assessed by the surveys of both Fowler and Litwin were substantially older than most recent surgical case series, in part because patients were surveyed several years after they had undergone surgery. The interval after treatment may also affect the frequency of complications. Men are most symptomatic immediately after surgery, when nearly all are impotent and most have some degree of incontinence; however, many patients improve during the first year or two after surgery. An assessment of impotence or incontinence 3 months after surgery would have very different (and much worse) results than assessments taken 12 or 24 months after surgery, when recovery is likely to be nearly complete. For radiotherapy, the relationship between the time elapsed since treatment and functional status is reversed: Erectile dysfunction tends to progress for several years after radiotherapy. Therefore, an assessment of erectile
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function at 6 months after radiotherapy would provide a misleadingly low estimate of post-treatment impotence, which would almost certainly be substantially greater a year or two later. Thus, interpreting complication rates requires close attention to what is measured, in whom, and when. A final problem with available data on treatment-related complications is due to the lack of methodologically rigorous prospective information. Ideally, comparative data on treatment complications, just as for the efficacy of therapy, would come from randomized trials. Randomized trials of treatments for early prostate have been very difficult to complete, however. Because such studies have accrued poorly, the few patients enrolled in trial may be unrepresentative of the average patient. Nearly all reported case series have been seriously marred by poor data collection techniques. The two best published surveys were performed by researchers who did not provide the cancer treatment. Although these surveys were likely to assess patient symptoms accurately, they were unable to assign treatment as their cause. The effects of other comorbid disease or the pretreatment effects of cancer itself prior to therapy may have caused impotence or incontinence, apart from therapy. Only prospective data unambiguously identify complications that have developed since therapy, and are thus plausibly due to therapy. Our own studies are an attempt to accomplish this.
A FINAL WORD
Although much of the data available in the literature is uninterpretable owing to poorly defined populations or inadequate data collection techniques, reliable methods for obtaining accurate information about complications are now available. Careful attention to modern survey techniques can eliminate ambiguity due to poorly defined items and underestimates of complications due to subconscious biases arising when treating physicians interview their own patients. Prospective cohort studies such as our own should clarify the frequency of complications following treatment. As a result of this research, patients and physicians will increasingly have at their disposal accurate information about patient complications; however, this information alone will not be enough to identify a particular therapy for early prostate cancer that is best for all patients. Patients will always differ by which complications they fear the most and how much they fear them. Some men may find it impossible to face the possibility of significant urinary incontinence or radiation proctitis, whereas others may find it unacceptable not to have had the most aggressive treatment available. Therefore, careful and sympathetic discussions between the patient and his physician will always be necessary to identify the optimal choice. But even perfectly accurate and fully detailed information about complications, as important as it may be to a man’s quality of life the decade after treatment, is inadequate. Without an accurate estimate of the effect of treatment on prolonging life, the other side of the treatment equation, the benefit of treatment, remains blank. Useful information about efficacy can come only from randomized clinical trials. Although such studies have unfortunately been difficult to complete in the past, preliminary information indicates that the PIVOT trial is accruing patients at a rate far higher than any prior randomized trial of early prostate cancer treatment in the United States. Although definitive results from this trial will not be known for 10 years or more, the early success of the trial may indicate a fundamental change in the research climate, raising hopes that other randomized trials will be spawned and completed. Only when patients
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have accurate information about both efficacy and treatment-related complications will they be able to choose their treatment with confidence.
References 1. Aaronson NK. Quality of life research in cancer clinical trials: A need for common rules and language. Oncology (Williston Park) 4:59, 1990 2. Aaronson NK, Ahmedzai S, Bergman B, et al: "he European Organization for Research and Treatment of Cancer QLQ-C30 A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365, 1993 3. Barry MJ, Fowler FJ Jr, O'Leary MP, et a1 The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 148:1549, 1992 4. Bennett CL, Greenfield S, Aronow H, et al: Patterns of care related to age of men with prostate cancer. Cancer 672633, 1991 Return of erections and urinary continence following nerve 5. Catalona WJ, Basler JW: sparing radical retropubic prostatectomy. J Urol 150905, 1993 6. Cella DF, Tulsky D S Measuring quality of life today: Methodological aspects. Oncology (Williston Park) 429, 1990 7. Cella DF, Tulsky DS, Gray G, et a1 The Functional Assessment of Cancer Therapy scale: Development and validation of the general measure. J Clin Oncol 11:570, 1993 8. Chodak GW, Thisted RA, Gerber GS, et al: Results of conservative management of clinically localized prostate cancer. N Engl J Med 330:242, 1994 9. Clark J, Rieker P, Kalish L, et al: Evaluation of the SF-36 measures of health related quality of life (HRQoL) in prostate cancer [abstract]. Proc Annu Meet Am SOCCIin Oncol 12:A1508, 1993 10. Fleming C, Wasson JH, Albertsen PC, et al: A.decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 2692650, 1993 11. Fowler F, Jr, Barry MJ, Lu-Yao G, et a 1 Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988-1990 (updated June 1993). Urology 42622, 1993 12. Fowler FJJ, Wennberg JE, Timothy RP, et al: Symptom status and quality of life following prostatectomy. JAMA 259:3018, 1988 13. Gann PH, Hennekens CH, Stampfer MJ: A prospective evaluation of plasma prostatespecific antigen for detection of prostatic cancer. JAMA 273:289, 1995 14. Greenfield S, Aronow HU, Elashoff RM, Watanabe D Flaws in mortality data. The hazards of ignoring comorbid disease. JAMA 260:2253, 1988 15. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al: Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 274:1445, 1995 16. Johansson JE, Adami HO, Andersson SO, et al: Natural history of localised prostatic cancer. A population-based study in 223 untreated patients. Lancet 1:799, 1989 17. Krahn MD, Mahoney JE, Eckman MH, et al: Screening for prostate cancer. A decision analytic view. JAMA 272:773, 1994 18. Litwin M Health-related quality of life after treatment for localized prostate cancer. Cancer 75:2000, 1995 19. Litwin MS, Hays RD, Fink A, et al: Quality-of-life outcomes in men treated for early prostate cancer. JAMA 273:129, 1995 20. McHomey CA, Ware JEJ, Rogers W, et a1 The validity and relative precision of MOS short- and long-fonn health status scales and Dartmouth COOP charts. Results from the Medical Outcomes Study. Med Care 3O(suppl5):MS253, 1992 21. McNair DM, Lorr M, Droppleman L F Profile of Mood States, ed 2. San Diego, Educational and Industrial Testing Service. 1981 22. Moinpour CM, Hayden KA, Thompson IM, et al: Quality of life assessment in Southwest Oncology Group trials. Oncology (Williston Park) 479, 1990 23. Moore MJ, OSullivan B, Tannock I F How expert physicians would wish to be treated if they had genitourinary cancer. J Clin Oncol 6:1736, 1988
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24. OLeary MP, Fowler FJ, Lenderking WR, et al: A brief male sexual function inventory for urology. Urology 46:697, 1995 25. Paulson DF, Lin GH, Hinshaw W, Stephani S: Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J Urol 128:502, 1982 26. Potosky AL, Miller BA, Albertsen PC, Kramer BS The role of increasing detection in the rising incidence of prostate cancer. JAMA 273:548, 1995 27. Schag CA, Ganz PA, Heinrich RL: CAncer Rehabilitation Evaluation System-short form (CARES-SF). A cancer specific rehabilitation and quality of life instrument. Cancer 68:1406, 1991 28. Steiner MS, Morton RA, Walsh PC: Impact of anatomical radical prostatectomy on urinary continence. J Urol 145:512, 1991 29. Talcott JA, Rieker P, Propert K, et al: Complications of treatment for early prostate cancer: A prospective, multi-institutional outcomes study [abstract]. Proc Annu Meet Am SOCClin Oncol 13:A711, 1994 30. Walsh PC, Epstein JI, Lowe FC: Potency following radical prostatectomy with wide unilateral excision of the neurovascular bundle. J Urol 1382323, 1987 31. Wasson JH, Cushman CC, Bruskewitz RC, et al: A structured literature review of treatment for localized prostate cancer. Prostate Disease Patient Outcome Research Team. Arch Fam Med 2487, 1993 32. Wilt TJ, Brawer M K The Prostate Cancer Intervention Versus Observation Trial: A randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer. J Urol 152:1910, 1994
Address reprint requests to James A. Talcott, MD, SM Dana-Farber Cancer Institute, D 1118 44 Binney Street Boston, MA 02115