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Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Correspondence: James A. Talcott, M.D., S.M., Center for Outcomes Research, Massachusetts General Hospital, B75 230, 55 Fruit Street, Boston, Massachusetts 02114, USA. Telephone 617-724-5451; Fax: 617-724-5457; e-mail: talcott{at}dfci.harvard.edu
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ABSTRACT |
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Key Words. Fever • Neutropenia • Risk assessment • Practice guidelines • Outpatient care
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INTRODUCTION |
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Nonetheless, trying to identify and eliminate medical precautions we no longer need is worthwhile, for they may have associated costs. First, they constrain patients’ lives, taking away control of their decision and limiting their freedom of movement. Health care providers, in our often-narrow focus on medical problems, may forget that a life-threatening diagnosis such as cancer fundamentally changes a patient’s life. The patient is "medicalized," replacing a daily schedule determined by his or her own habits, needs, preferences and plans with a rigid and often confusing schedule of commitments—to physicians, medications, clinics, and hospitals—the purpose of which is often incompletely understood, yet all presented as potentially life-saving. Despite our best efforts to introduce these changes as humanely as possible, time spent in hospitals and clinics will always be a poor substitute for the comforts and activities of familiar home and work environments. The threat of death from cancer makes the burden of these changes heavier. The knowledge that death may be near makes the nourishment of home, family and friends even more sustaining.
A second cost of extra precautions is more obvious: they cost money. Whether additional tests, more frequent medical examinations, additional medications, or prolonged hospital stays, extra precautions entail more intensive, and thus more expensive, medical care. Perhaps never before have all the stakeholders in the medical care system been so aware of costs and the imperative to reduce them than now.
Finally, unneeded precautions invite others outside of medicine to eradicate them by directive, further eroding the control of medical care by physicians and other medical care providers. Given the current highly price-competitive medical environment with its powerful drive to reduce medical costs, others, often with more administrative than patient care experience, will propose scrapping care that lacks an obvious ongoing clinical rationale. Any medical practice or procedure about whose value physicians are uncertain is a candidate for administrative elimination. The more inessential medical practices we physicians identify and eliminate, the more authority we have to defend useful practices accountants and their minions may call into question. Put simply, thinking rationally about reducing costs is essential to retaining long-term control of our practices.
The Standard Approach to Treating Febrile Neutropenia
Febrile neutropenia is an iatrogenic, self-limited syndrome created by the cytotoxic therapy of cancer. Over time, care of fever and neutropenia has evolved. Initially, after the association between neutropenia, fever, and serious infection was recognized [1], neutropenic patients without fever were often hospitalized from fear that the medical response to fever might be dangerously delayed for an outpatient. This purely inpatient approach to neutropenia is still used for some patients receiving intensive chemotherapy, such as remission induction therapy for acute myelogenous leukemia. However, the current standard of care is to hospitalize neutropenic patients only when fever arises, and to administer i.v. broad-spectrum antibiotics in the hospital until both fever and neutropenia have resolved. Recently, this widely accepted approach has begun to erode. Many patients are now being sent home with a variety of improvised home care plans, some as part of planned therapeutic trials, and others developed ad hoc by individual physicians or groups who presume that early discharge will reduce costs safely. While early discharge is far from universal, it represents a growing challenge to the established standard of care, leading to the pointed question of whether the standard management practice should change [2]. While some believe that the increased recent exploration of alternatives to the status quo argues for a change in the standard of care, to others, including me, it indicates that the time for a definitive trial has come. The ongoing controversy, despite powerful economic incentives to accept an outpatient alternative presumed cheaper, provides evidence that such a trial has not yet been done.
A Brief History of Febrile Neutropenia
The syndrome of febrile neutropenia was first described over thirty years ago by Bodey and colleagues [1]. His seminal paper reviewed the course of 52 leukemic patients seen at the National Cancer Institute over four years and found that more and worse infections occurred when patients had fewer than 1,000 granulocytes per mm3. This association between fever, infection, and a fall in granulocytes below a threshold level is the paper’s best-remembered lesson. However, these investigators also noted that the patients’ prognosis depended on other factors. Patients with stable or falling granulocyte counts after seven days fared worse, as did patients whose leukemia was in relapse. Thus, along with the original description of fever and neutropenia, additional factors which modified patient risk were identified.
Taking advantage of the newly available antipseudomonal semisynthetic penicillin, carbenicillin, Schimpff and colleagues added the next major component to treatment of febrile neutropenia—empirical broad-spectrum antibiotic coverage. They observed that 75 febrile neutropenic patients with acute leukemia treated with empirical carbenicillin and gentamicin fared far better than patients in the previous year treated with gentamicin alone whose infection, Pseudomonas aeruginosa, the most serious pathogen, usually led to rapid death [3]. Further, they noted that unlike patients who received both antibiotics, patients treated with gentamicin alone occasionally had persistent bacteremia, despite apparent in vitro gentamicin sensitivity. This observation provided a scientific basis for the subsequent practice of two-antibiotic "double coverage" of Pseudomonas in empirical regimens for febrile neutropenia.
Pizzo and his colleagues at the National Cancer Institute further clarified empirical antibiotic management of febrile neutropenia. Like Bodey and colleagues, these investigators defined patients whose neutropenia resolved within seven days as being at low risk. To determine the optimal antibiotic management of the remaining high-risk patients with ongoing neutropenia after seven days, they divided them into two small but effective randomized trials based upon whether or not their fever resolved. Patients no longer febrile (but still neutorpenic) were randomized to either stopping or continuing their empirical antibiotics, which consisted of cephalothin (Keflin), carbenicillin, and gentamicin (KCG). When antibiotics were stopped, 7 of 17 patients rapidly developed infectious complications, compared to none if their antibiotics were continued. Among these patients without continued fever, no drug resistance or superinfection was found [4]. The remaining group of high-risk patients, who had persistent neutropenia and fever after seven days, was randomized to stopping antibacterials (a possible source of allergic fever), continuing them without changes, or adding the antifungal agent amphotericin empirically. Of the 16 patients whose antibiotics were discontinued, six developed septic shock, while 6 of 16 patients whose antibiotics were continued unchanged eventually developed fungal infections, nearly all Candida. However, the group given additional amphotericin experienced only two infectious complications, one viral [5]. These two studies produced a powerful algorithm for treating patients with ongoing neutropenia after seven days; if fever has resolved, continue antibacterials to protect against the ongoing risk of bacterial infection; but if not, continue antibacterials against the ongoing risk of bacterial infection, adding amphotericin against fungal superinfection which the ongoing fever may indicate. The remaining patients who resolved their neutropenia by seven days were felt to be at low risk, in need of no special management beyond prompt empirical antibacterials. With the publication of these studies, the main elements of the standard therapy for febrile neutropenia were in place.
Other refinements of the management of febrile neutropenia have been proposed and debated, most with little long-term effect. For example, granulocyte transfusions were recommended for patients with prolonged neutropenia. After a period of shrinking indications, they were abandoned [6, 7]. Prophylactic broad-spectrum antibiotics were proposed with an enthusiasm which waned as resistance emerged, first for trimethoprim/sulfamethoxazole [8–11] and later for the quinolones [12, 13], although the quinolones remain widely prescribed. Hematopoietic growth factors were shown to reduce the incidence and shorten the duration of febrile neutropenia in patients with very intensively treated tumors such as small-cell lung cancer [14], bladder cancer [15], leukemia [16], and lymphoma [17]. However, the high cost of these drugs, uncertainty about the long-term sequelae of pharmacological stimulation of hematopoietic stem cells [18, 19], and difficulty showing that the shortened neutropenia reduces serious infection [20–23], have led some to suggest more limited use [24, 25]. However, a recently published survey by a committee of the American Society of Clinical Oncology (ASCO) found that many oncologists use growth factors to treat (rather than prevent) febrile neutropenia, despite the lack of an FDA-approved indication for their use and the ASCO recommendation against it [26]. In short, physicians have enthusiastically embraced several technological fixes for febrile neutropenia, including novel blood component transfusions, extended empirical use of antibiotics, and pharmacological manipulations of granulocyte recovery, the extent of initial use in each case apparently exceeding the supporting data.
Identifying Low-Risk Febrile Neutropenia
Another approach to modifying risk assessment in treatment of febrile neutropenia emphasized another aspect of Bodey’s seminal description, the observation that risk varies among patients with febrile neutropenia [1]. In Bodey’s original description, febrile neutropenia had better outcomes during leukemia remissions and when granulocyte counts were stable or increased seven days after it occurred. These risk differences raised the possibility that some patient groups with fever and neutropenia might have such high or low risk that standard inpatient antibiotic therapy could be modified. This attempt at "risk stratification" of patient subgroups arose from a clinical paradox: despite the notoriety of febrile neutropenia as the paradigm medical oncology emergency, many so-called "hot and low" patients are treated with routine procedures and clinical nonchalance. For many severely ill, intensively treated cancer patients, such as those receiving bone marrow transplantation or remission induction chemotherapy for acute leukemia, developing fever while neutropenic is worrisome. Many other patients, however, respond promptly and completely to empirical broad-spectrum antibiotic treatments, becoming clinically stable and feeling well within hours. This apparent clinical heterogeneity could be exploited therapeutically. If patients at the beginning of a benign course of febrile neutropenia could be identified early on, a modified, less intensive treatment which takes into account their lower medical risk could be developed.
Early discharge may harm patients financially. The financial benefit to medical care payers may come at a cost to patients and perhaps to society. Denying a patient the room, board, nursing, and other services of inpatient treatment may require that substitutes be provided by the patient’s family. While some of those costs, such as meals or transportation to the clinic for physician examinations or transfusions, may be small, some services may come at substantial but hidden cost. If the home services provided by payers are inadequate, patients may need to enlist informal caregivers such as friends or family members for assistance, possibly diverting them from their usual employment and wages. These indirect costs are difficult to identify, and since payers have no economic incentive to identify costs shifted to others, they go unrecorded. When these unrecorded costs are included, home care may be more expensive than, for example, nursing home stays [27,28]. Despite the stunning speed with which inpatient acute care has been replaced by outpatient treatments, almost no data are available on nonmedical costs arising from home care previously delivered in acute care hospitals.
One immediately obvious possible change in therapy for low-risk patients would be to treat them at home. It has long been possible to administer at home i.v. antibiotics, the technical core of therapy for febrile neutropenia. Home i.v. treatment of deep-seated infections requiring prolonged antibiotics, such as endocarditis and osteomyelitis, was reported in the 1970s [29]. Given its logistical feasibility, treatment at home offers obvious potential benefits. Most patients feel more comfortable at home, absent a need for ongoing medical or nursing reassurance or a particularly unattractive home environment. This potential for better quality of life at home, which originally motivated this line of research, has been recently overshadowed by a second potential benefit, cost savings. Because of the capital costs embedded in hospital rooms and the expense of 24-h nursing staffs, the home therapy option is likely to be cheaper than inpatient care, to medical payers at least, providing a strong economic incentive for home therapy. The economic motive for discharging patients from hospitals earlier is so obvious and the stunning speed with which hospital length of stay has dropped under cost containment pressure is so abrupt that the sudden practice change throughout medicine to early discharge of patients worries some patient advocates. The willingness to substitute outpatient care for part of ever-shorter stays has spread too rapidly for careful assessment of its impact on patient interests. In reaction to shorter stays, some legislatures have limited early discharge by, for example, mandating that mothers be allowed to stay 48 h after childbirth. Outcomes researchers have found some evidence that short maternity stays have adverse clinical effects [30], and others have questioned whether the burden of proof should fall on those who suspect that shortening stays to save money harms patients, rather than on those wanting shorter stays to show that they do not [31].
Hospitals provide more than logistical convenience for delivering medical care. They also provide the ready opportunity for close medical surveillance. If the logistical requirement for broad-spectrum antibiotics no longer justifies hospitalizing febrile neutropenic patients, the opportunity it provides for close medical surveillance may. Before transferring care of febrile neutropenia from the inpatient to the outpatient setting, the patients’ level of medical risk must be considered, not just the risk of infection. Cancer patients with fever and neutropenia are certainly at risk for infection, but also from other treatments, other comorbid diseases, and the broad range of potential complications caused by the cancers the chemotherapy was instituted to combat. A physician’s decision to send any patient home implies the judgment that the patient’s risk of serious medical instability is acceptably low. While physicians do not formally and quantitatively assess their patients’ level of risk before discharge, informal risk assessment is embedded in the practice of medicine, and physicians learn it over time as they train and practice. However, their criteria are not usually stated, clarified, and assessed. We felt that we needed to assess the level of risk of patients with febrile neutropenia explicitly before we sent any home for treatment [32, 33].
We reasoned that the closer surveillance possible in the hospital would benefit only those patients needing urgent assessment and treatment. Our goal was to identify for potential outpatient therapy those patients at very low risk of new serious problems, such as hypotension, respiratory failure, or bleeding. For these stable patients, we assumed, home care would be safe. We could have attempted to assess the risk of outcome events other than serious medical complications, but for each alternative outcome we considered, the disadvantages outweighed the advantages. Death, for example, is an unambiguous outcome of unquestioned importance, and any patient at a significant risk of preventable death would certainly be an inappropriate candidate for home care. However, death occurs rarely in febrile neutropenia, thereby requiring huge studies to collect adequate information to detect mortality differences. When death occurs, it usually results from ineffective treatment for the underlying cancer rather than from inadequate supportive care of febrile neutropenia. Another outcome often used in studies of febrile neutropenia, particularly comparative antibiotic trials, is "response to [antibiotic] therapy," usually defined as "the resolution of all evidence of infection." Using an outcome which ignores noninfectious complications assesses risk incompletely, since cancer patients receiving chemotherapy have other medical problems than just infection, as our subsequent studies showed. To define risk only by the course of infection and ignore problems common to cancer patients such as bleeding, heart failure, or bowel obstruction is opening a rather small window on the medical stability of cancer patients receiving active therapy.
Using serious medical complications as our outcome, we performed a retrospective study of all 261 episodes of febrile neutropenia occurring within one year at the Dana-Farber Cancer Institute [32]. The initial results can be seen in Table 1
. Our study found that, on average, patients face a high risk, about one in five, of a serious complication occurring during an episode of febrile neutropenia. While infection may cause some of the common complications such as systemic hypotension, altered mental status, and respiratory failure, many different complications occurred, none of which appeared in as many as half the episodes with serious complications. The high frequency of major medical complications we found confirmed the implicit assumption underlying the standard inpatient approach to febrile neutropenia: on average, these patients are at too high a risk to be sent home for treatment.
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). The results were surprising. Three groups of patients seemed to be at high risk: those who were inpatients at presentation of febrile neutropenia (Group I), outpatients who presented with serious acute comorbidity (defined as another reason for hospitalization other than fever and neutropenia) (Group II), and outpatients without serious acute comorbidity, but who had "uncontrolled cancer" (Group III). Another, low-risk group (Group IV), was comprised of patients with acute leukemia not in complete remission and patients with other cancers which progressed during the patient’s last evaluable chemotherapy regimen. When these three risk factors were included in the model, other intuitively important factors were no longer statistically significant, including the presenting granulocyte count, the presence of renal failure (serum creatinine >2 mg/dl), a positive blood culture, older age, or the diagnosis of leukemia or lymphoma. The three major risk factors accounted for nearly all patients with complications, leaving relatively little to be accounted for by other clinical factors most clinicians associate with high risk. The complication rate for patients in any of the high-risk groups (Groups I-III) was greater than 30%, with only 2% for the remaining patients (Group IV). Further, the low-risk Group IV patients were numerous and accounted for 70% of those who developed febrile neutropenia as outpatients, enough to make developing an altered management strategy for low-risk patients worthwhile.
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While the first risk assessment study justified continued research, our observations required confirmation. After studying our "training" patient population, we had created data-derived high-risk factor categories chosen to contain the largest proportion of complications. Our data collection had been retrospective, which often results in incomplete or inaccurate findings. Our patients were treated only at a single clinical site, a National Cancer Institute-designated comprehensive cancer center, with an atypically young and healthy population seen at tertiary-care centers.
Pilot Studies: Treating Low-Risk Patients at Home
Therefore, we undertook a prospective, 444-patient validation study, working with Dr. Robert Siegel at the Miriam Hospital in Providence, RI [33]. To prevent bias, investigators were allowed to see only medical charts of the first 24 h to identify risk factors and only the records of the remainder of the hospital stay to identify complications. Our results supported the original model, although the risk differences between high- and low-risk patients were reduced. High-risk patient groups had higher than 20% complication rates compared to 5% among the 104 low-risk (Group IV) patients (two patients with transient hypotension, and the remaining three patients developed complications only after at least seven days of continuous clinical deterioration, long enough for detection of emerging problems and readmission if clinical follow-up was reasonably careful). We therefore proceeded to a pilot study of early discharge of low-risk patients identified as being at low risk to receive their antibiotic therapy at home, using our validated risk assessment model.
Our pilot study had been preceded by attempts by other investigators to treat patients with febrile neutropenia at home. Rubenstein and colleagues at the M.D. Anderson Cancer Center used their own criteria for identifying low-risk patients and applied them to patients still in the Emergency Department. Low-risk patients were sent home on either i.v. or oral antibiotic therapy. The study was stopped after half its planned accrual because of nephrotoxicity on the oral arm. Although no differences were seen in the assessed responses to antibiotic therapy, hospital readmission and renal toxicity were more common on the oral antibiotic arm. The authors concluded ambiguously that outpatient therapy "should not be considered the new standard of care," but that "outpatient i.v. antibiotic therapy with careful monitoring is an appropriate alternative to hospitalized care" [34].
Our own pilot study relied primarily on the risk assessment criteria from our studies to identify the low-risk patients appropriate for home therapy, although additional exclusions, such as positive cultures, pneumonia, and age over 65 years were added during the institutional review of the protocol. The primary goal of the study was to troubleshoot any unexpected medical problems of early discharge for receiving the standard inpatient i.v. antibiotic regimens at home, although we also pilot-tested measurement of quality of life and costs of care. While we could have used other, simpler antibiotic regimens for our outpatient therapy, we chose to manipulate only a single variable, the site of treatment, in our planned randomized trial. Our study using the criteria we had developed allowed us to enroll highly neutropenic patients (medium: 9 granulocytes/mm3) requiring prolonged treatment at home (up to 24 days). Nine patients were readmitted, five because of prolonged fevers (
5days) and four with serious medical complications; none died. The complications were diverse, and, surprisingly, in three of four cases involved significant rises in creatinine. This unexpectedly frequent evidence of renal failure echoed that seen by Rubenstein and colleagues among patients who received outpatient oral antibiotics, implying that some aspect of inpatient management, presumably i.v. fluids or promotion of oral fluids, was protecting patient renal functions [24]. Patients in our pilot study were generally happy with home care, even if they were readmitted with complications. While the study lacked a comparable control group, patients eligible for the study but remaining in the hospital had daily medical charges 50% greater than patients sent home. Two categories of medical charges contributed about equally to this difference: the daily room rate for inpatients and the charges for the additional diagnostic tests performed on patients who remained in the hospital [35].
Other investigators have performed additional pilot studies of outpatient therapy for low-risk patients [36–40]. While none of these investigators used empirical data to identify or assess risk factors, they generally specified their criteria for low-risk patients in advance, although one study simply relied on a clinician’s assessment without formal criteria [36]. Low-risk patients received a variety of outpatient treatments, including oral or long-acting i.v. antibiotics, early cessation of antibiotics, and early discharge. In none of these studies did patients receive conventional broad-spectrum i.v. antibiotic regimens in the outpatient or home setting. Most patients receiving outpatient treatment did well, although only two trials were randomized.
The most rigorous study was conducted by Malik et al. [41]. After they had found no difference between inpatients receiving conventional i.v. antibiotics and those randomly assigned to the single agent ofloxacin [42], they randomized 180 low-risk patients to receive oral ofloxacin alone as inpatients or at home. The study outcome, as in the earlier trial, was "response to therapy without modification of the initial treatment," and was achieved for 98% of inpatient and 96% of outpatient episodes. One-fifth of patients assigned to the outpatient arm were readmitted to the hospital, two patients on each arm died after prolonged neutropenia, and one outpatient returned to the hospital in septic shock and died. The statistically indistinguishable outcomes of the two arms led Anaissie and Vadhan-Raj of the M.D. Anderson group to ask rhetorically in the title of their accompanying editorial, "Is it time to redefine the management of febrile neutropenia in cancer patients?" although they concluded that "we believe that the burden of proof has not been met yet" [43].
Should the Standard of Care Change?
If not, then why not? In my mind, several important reasons for residual uncertainty remain. The fundamental one is that no comparative study sufficiently well designed to justify replacing a well-established standard of care has been done. Several key features of such a pivotal study are still missing from published trials. First, most reported studies have simply been uncontrolled pilot studies of outpatient care. While acceptable results in such studies support the continued investigation of the outpatient approach, they provide no direct comparison of care shifted from the inpatient to the outpatient setting. Secondly, no trials have studied the existing standard of care—inpatient treatment with standard broad-spectrum i.v. antibiotics, consisting of an antipseudomonal semisynthetic penicillin and an aminoglycoside (or for low-risk patients, ceftazidime alone) [44]. Rather, they have compared outpatient treatment with either inpatient treatment with an oral agent [41] or with another outpatient regimen [45]. Third, no study has used a safety outcome with adequate power to detect clinically important differences in outcomes, i.e., the risk of death or preventable complications. Rather, comparative trials have measured "response to therapy," whether infection resolves without changing antibiotics. While this outcome may be useful to compare empirical antibiotic regimens for febrile neutropenia, it is much less obviously relevant to the fundamental issue directly pertinent to early discharge: When patients are sent home where they can’t be watched as closely, do they do worse? Do outpatients more often develop serious medical problems which are potentially more easily detected and treated in the hospital? One outpatient in the study of Malik et al. appeared to have succumbed to sepsis, a preventable death [41]. Was this death simply a rare event equally likely in the hospital, or is it an indicator of less serious but more common mishaps resulting from outpatient treatment, the price to be paid for sending patients home? Death is too rare during low-risk episodes of fever and neutropenia for any but utterly immense studies to detect an absolute increase in mortality of 1%-2% (corresponding to an at least doubled risk of death). However, preventable deaths occurring on the outpatient arm may signal that we should be alert to other outpatients with still-significant but nonfatal complications.
The other potential benefits of outpatient care, improved quality of life and less expensive care, have largely been asserted, not demonstrated. If the benefits come at a cost in patient safety, we need to quantify them to assure ourselves that the trade we are making is a good one, for our patients and for society. If the costs were the same, would we be willing to declare a new treatment with an extra 1% mortality the new standard of care? If not, how much would we have to save to make the trade in good conscience? Such questions are especially compelling given the current intensive drive to reduce inpatient stays as a strategy of cost containment. Finally, we need to determine whether shifting to outpatient care will benefit all stakeholders in health care (payers, providers, patients, and their families) or just to payers (and risk-sharing providers).
A careful study designed to address all these issues was recently funded by the National Cancer Institute. This study of the Cancer and Leukemia Group B will assess nearly 900 episodes of febrile neutropenia complications giving it a 90% power to detect a 4% increase in the frequency of serious medical complications among outpatients. Health-related quality of life and perceived quality of medical care will be measured, and, perhaps most importantly, a large economics research component will carefully evaluate the direct and indirect medical costs, including out-of-pocket costs to outpatients and the time informal caregivers lose from their normal activities to care for patients at home.
To change a well-established standard of medical care requires caution under any circumstances. When the proposed change shortens hospital stays in a fiscal climate pressing strongly for early discharge, special care must be taken. A great deal of research has been performed over the last decade to prepare for a rational test of alternatives to inpatient management of fever and neutropenia. Those who adopt an outpatient standard early may be responding to subtle, nonscientific pressures. In Boston, Harvard Pilgrim Health Care, the largest managed care provider, has chosen to treat their febrile neutropenia patients with the outpatient treatment arm’s regimen rather than allowing them to enroll in the ongoing randomized trial. The treatment of patients with febrile neutropenia is an excellent paradigm for studying the substitution of outpatient for inpatient care. After all we have learned about febrile neutropenia, we face a choice: we may await the results of a well-designed clinical trial, or as others have done many times in the past, act as if we already know its result.
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ACKNOWLEDGMENT |
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This work was supported by National Cancer Institute Research Grant CA 71125.
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