Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in BRCA2-Associated Prostate Cancer Resulting From Biallelic BRCA2 Reversion Mutations Restores Both Germline and Somatic Loss-of-Function Mutations.

PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline BRCA2 mutation with acquired resistance to olaparib related to biallelic BRCA2 reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline BRCA2 mutations. Within the germline BRCA2-positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.

Interleukins in the treatment of mycosis fungoides.

Mycosis fungoides is typified by a cutaneous infiltrate of CD4+ lymphocytes with a Th2 phenotype. As the disease advances, there is increased expression of Th2 cytokines. This results in a subsequent suppression of Th1 cytokines and impaired cell mediated cytotoxic host response to the lymphoma cells. Disarming this cell mediate cytotoxic immune response creates a relentless cycle of disease progression. A cell mediated cytotoxic immune response can be stimulated with the use of Th1 cytokines such as IL-2 and IL-12. In this report, the Authors review the rational for the use of these particular cytokines in the treatment of mycosis fungoides. Further they comment on the experience and success regarding these two agents in phase I and II trials for the treatment of mycosis fungoides. Lastly, they discuss other potential cytokine therapies which could play a role in the future treatment of mycosis fungoides.

Cutaneous T-cell lymphoma: a paradigm for biological therapies.

Mycosis Fungoides and Sézary Syndrome are the most common types of cutaneous T-cell lymphomas. There is no current standard of care for Mycosis Fungoides/Sézary Syndrome, with a general tendency to rely on topical interventions for early disease delaying systemic, more toxic therapy until the development of extensive symptoms. Knowledge of the biological characteristics of this disease has allowed for the development of rational interventions and a significant advance in its treatment. Retinoids are active in Mycosis Fungoides/Sézary Syndrome with the newer rexinoids being available in topical and systemic forms. Interferon alpha remains one of the most active therapeutic agents for Mycosis Fungoides/Sézary Syndrome, especially in combination with other agents such as PUVA. The monoclonal antibody alemtuzumab leads to responses in at least half of patients with advanced disease with its side effect profile consisting mainly of immunosupression and infusion reactions. The recombinant IL2-diphteria toxin denileukin diftitox (Ontak) is active in this disease and appears to have a beneficial effect in symptoms relief and quality of life. Extracorporeal photochemotherapy as an immunostimulating intervention seems to be very effective in a subset of patients, but its availability is limited to less than a hundred centers worldwide. Experimental and less studied interventions include autologous and allogeneic peripheral stem cell transplantation, Interleukin-12, the histone-deacetylator depsipeptide and the synthetic deoxynucleotide CpG7909. Cutaneous T-cell lymphoma has served as a paradigm for the development of biological agents. Further knowledge of the signaling pathways in Mycosis Fungoides/Sézary Syndrome will allow for the development of more effective treatment strategies.

A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon alpha-2b in advanced renal cell carcinoma: major durable responses in a less highly selected patient population.

BACKGROUND: A prospective multi-institutional phase II trial was undertaken to define the activity and toxicity of a unique decrescendo infusion of interleukin-2 (IL-2) in combination with interferon (IFN) in patients with metastatic renal cell carcinoma. The identical regimen has shown promise in advanced melanoma. PATIENTS AND METHODS: Between February 1997 and March 1999, 47 patients with metastatic renal cell carcinoma, from five institutions, were treated with outpatient s.c. IFN (10 mU/m2/day) on days 1-5, followed by inpatient IL-2 via continuous i.v. decrescendo infusion [18 million International Units (MIU) (I mg)/m2/6 h, followed by 18 MIU/m2/12 h, then 18 MIU/m2/24 h and 4.5 MIU/m2/24 h for the following 3 days] on days 8-12, in a hospital ward without intensive care unit (ICU)-type monitoring. Treatment was repeated every 4 weeks. In contrast to high dose IL-2 protocols, patient eligibility did not require pulmonary function tests and allowed serum creatinine up to 2 mg/dl. RESULTS: Among 44 eligible patients, 57% (25) had their primary in place, 57% (25) had bone or visceral involvement, and only 4% (2) had lung as their only site of disease. The overall response rate in 43 response-evaluable patients was 16.3% [95% confidence interval (CI) 5.3 to 27.3], with three complete responses and four partial responses observed. The median survival was 13 months; nine patients remain alive at >23 months. The median duration of response is 36 months (range 11.5 to 48+ months). Toxicity was modest, consisting of typical cytokine-induced systemic symptoms and rare organ dysfunction. Severe grade 4 toxicity occurred in only 13% of the 130 cycles. CONCLUSIONS: This unique, reasonably well tolerated IL-2/IFN combination induced a modest response rate with a number of durable remissions. While the optimal IL-2-based regimen for the treatment of advanced renal cell carcinoma remains elusive, the present regimen should attract considerable interest. This is based on tumor activity very similar to high dose IL-2 in a patient population not as carefully selected for optimal organ function.

Health literacy and shared decision making for prostate cancer patients with low socioeconomic status.

Quality of life (QOL) considerations are important in the treatment decision making process for prostate cancer patients. Although patient involvement in the treatment decision process has been encouraged, low health literacy can limit patient understanding of the complex information about treatments and their probable QOL outcomes and is a barrier to patient participation in the decision-making process. The objectives of the study were to evaluate (i) knowledge, level of satisfaction, and treatment preferences and intentions of men newly diagnosed with prostate cancer after participation in a CD-ROM shared decision making program; and (ii) the relationship between prostate cancer knowledge and health literacy. Thirty newly diagnosed prostate cancer patients from two Veteran's Administration (VA) hospitals in Chicago completed a demographic questionnaire and participated in an interactive CD-ROM shared decision making program. Subsequently, knowledge of prostate cancer, satisfaction with the information in the computer CD-ROM program, treatment preferences, and likelihood of following treatment preferences were assessed using interviewer-administered questionnaires. Health literacy was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). The Pearson correlation test was used to assess the relationship between health literacy and prostate cancer knowledge. The chi2 test and the Fischer exact test were used to evaluate relationships between patient demographics and other variables. More than three-quarters of the patients rated the information in the CD-ROM as "very satisfactory" (highest possible rating). Two-thirds of the patients (21 of 30) selected a treatment after participation in the CD-ROM program and 90.5% of these patients stated that they were very or somewhat likely to adhere to their selection. However, prostate cancer knowledge was variable, with one-third of the patients scoring 69.9% or lower. Participants' health literacy was equivalent to a 7th-8th grade reading level (mean = 57.1+/-10.9), and more than one-third of participants (36.7%) had lower than 9th grade literacy levels. Participants' prostate cancer knowledge was correlated with health literacy (Pearson correlation rhor = 0.65, rhop = 0.0001). Patients were satisfied with the interactive shared decision making CD-ROM program, and two-thirds of patients were able to select a preferred treatment based on the information presented in the program that they intended to follow. However, prostate cancer knowledge scores varied among participants after participation in the CD-ROM program, raising doubts that patients were adequately informed to make appropriate choices regarding their treatment. Lower prostate cancer knowledge scores corresponded to lower literacy scores, indicating that low literacy may have hindered patient understanding of the shared decision making program. The development of shared decision making tools should include collaborative efforts with the target population to improve the success of shared decision making programs among patients with low health literacy.

The role for interleukin-12 therapy of cutaneous T cell lymphoma.

Recent phase I and phase II trials using recombinant human interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA-1+ T cells. These results suggest that rhIL-12 may induce lesion regression by augmenting antitumor cytotoxic T cell responses. Future trials will be focused on strategies for further immune enhancement by the concomitant use of additional immune augmenting cytokines with rhIL-12.

A phase III, randomized, double-blind, placebo-controlled study of peldesine (BCX-34) cream as topical therapy for cutaneous T-cell lymphoma.

BACKGROUND: The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor. OBJECTIVE: We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL). METHODS: Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (> or = 50%) clearing of patches and plaques. RESULTS: Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P =.677). CONCLUSION: Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL.

Human T-cell lymphotropic-I-associated leukemia/lymphoma.

Human T-cell lymphotropic virus-I (HTLV-I)-related adult T-cell leukemia/lymphoma (ATL) is a model disease for proof of viral oncogenesis. HTLV-I infection is endemic in southern Japan and the Caribbean basin, and occurs sporadically in Africa, Central and South America, the Middle East, and the southeastern United States. ATL occurs in only 2% to 4% of HTLV-I-infected people [1-3]. When it does occur, it is usually aggressive and difficult to treat; most people survive for less than 1 year [1-3]. Combination chemotherapy with cytotoxic agents has yielded complete response rates of 20% to 45%, but responses usually last only a few months [3]. Recently, novel treatments, such as monoclonal antibodies directed at the interleukin-2 receptor and the combination of interferon alfa and zidovudine, have been shown to be active in the treatment of patients with ATL. A small percentage of patients achieve long-lasting remissions [2,3].

Primary cutaneous T-cell lymphoma: review and current concepts.

PURPOSE: Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at presentation. Advances in molecular biologic techniques, including immunophenotyping and gene rearrangement studies to determine clonality, have led to more frequent diagnosis of CTCL as well as more consistent subclassification of these entities. However, there continues to be confusion in the classification, prognosis, and management of patients with CTCL. The purpose of this review is to present a summary of the diagnosis, prognosis, and treatment of CTCL, with specific emphasis on mycosis fungoides (MF) and Sézary syndrome (SS). We also present a detailed discussion of the entities that make up the differential diagnosis of CTCL. DESIGN: We reviewed the medical literature on CTCL and other diseases that make up the differential diagnosis of CTCL. RESULTS AND CONCLUSION: MF and SS are the most common forms of CTCL. The etiology of this disease is still unknown. Patients may go for months to years with skin abnormalities before being diagnosed. MF/SS is an indolent disease and patients with T1 disease have a normal life expectancy. Patients who undergo transformation to large-cell lymphoma (8% to 23% of patients) have a poor prognosis, with mean survival ranging from 2 to 19 months. Treatment for MF/SS continues to be palliative. There are many new therapies that are currently being investigated in clinical trials, and the DAB(389)IL-2 fusion protein was recently approved for the treatment of refractory MF/SS.

Primary cutaneous B-cell lymphoma: review and current concepts.

PURPOSE: Primary cutaneous B-cell lymphoma (PCBCL) has only recently been recognized as a distinct clinical entity. With the advent of improved immunophenotyping and immunogenotyping, increasing numbers of PCBCL cases are being diagnosed. However, there is much confusion regarding the classification, treatment, and prognosis of these patients. The purpose of this article is to review and analyze the available data to provide the clinician with a concise summary of the diagnosis, prognosis, and treatment of PCBCL. DESIGN: We conducted a thorough review of the medical literature on PCBCL, with a focus on classification, prognosis, and treatment trials. RESULTS AND CONCLUSION: PCBCL is defined as a B-cell lymphoma originating in the skin. There is no evidence of extracutaneous disease at presentation and for 6 months after diagnosis, as assessed by adequate staging procedures. Currently, the European Organization for Research and Treatment of Cancer classification is the most concise disease classification scheme, dividing the subtypes of PCBCL by clinical behavior and histopathologic findings. Based on this classification, the most common subtype of PCBCL is follicular center cell lymphoma. PCBCL is generally an indolent form of lymphoma with a good prognosis. Although local cutaneous recurrences are observed in 25% to 68% of patients, dissemination to internal organs is rare. Five-year survival rates typically range from 89% to 96%. A specific subtype, large B-cell lymphoma of the leg, is noted to have a poorer prognosis, with a 5-year survival rate of 58%. Overly aggressive treatment of PCBCL has not been shown to improve survival or prevent relapse. The treatment of choice usually varies depending on the type of PCBCL, the body surface area, and the location of the involvement, as well as the age and general health condition of the patient. The majority of studies indicate that PCBCL is highly responsive to radiation therapy. Polychemotherapy should be reserved for involvement of noncontiguous anatomic sites or those with extracutaneous spread.

Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides: evidence of a graft-versus-tumor effect.

Allogeneic hematopoietic stem cell transplantation should be considered as a therapeutic option for patients with generalized erythoderma or tumor stage MF. Indeed, the only curative option for MF may be an allogeneic transplant. Bone Marrow Transplantation (2000) 25, 111-113.

Cutaneous T-cell lymphoma/leukemia.

Effective treatment for cutaneous T-cell lymphomas (CTCL) requires an accurate and specific diagnosis based on the clinical presentation combined with evaluation of the histopathology, immunophenotyping, and gene rearrangement studies. Careful clinical and pathologic evaluation in centers familiar with the diverse forms of CTCL is most valuable for determining treatment options. The goals of treatment in mycosis fungoides (MF), which afflicts more than 50% of patients with CTCL, are the relief of symptoms and improvement in cosmetics. Despite some uncontrolled clinical trial results that have been reported to suggest "cures" in this disease, the general perception remains that this disease is not curable with standard therapies available today. Treatment is divided into topical (skin-directed) and systemic therapy. The most active systemic agent for the treatment of MF remains interferon-alpha, although many new modalities have recently been approved for the treatment of CTCL.

DAB(389)IL-2 (denileukin diftitox, ONTAK): review of clinical trials to date.

Clinical trials of DAB(389)IL-2 (denileukin diftitox, ONTAK) have been conducted in a variety of disease states as well as in normal volunteers. The individuals treated include 45 volunteers in pharmacokinetic testing, 195 patients with noncancer indications, and 216 patients with lymphoma, including ongoing trials. The noncancer trials involved patients with rheumatoid arthritis, psoriasis, HIV infection, and insulin-dependent diabetes mellitus. Two large trials involving 143 lymphoma patients provide the definitive data and formed the basis for seeking and receiving Food and Drug Administration approval for DAB(389)IL-2. The focus of this paper will be a review of the efficacy and toxicity trials with DAB(389)IL-2 completed to date in cancer, in particular those that involved patients with cutaneous T-cell lymphoma, as well as the rationale for these trials.

O6-alkylguanine-DNA alkyltransferase in cutaneous T-cell lymphoma: implications for treatment with alkylating agents.

Mycosis fungoides is a low-grade cutaneous T-cell lymphoma. Early treatment often involves the use of topical chemotherapy such as mechlorethamine or carmustine although single-agent oral chemotherapy with alkylators is common for advanced disease. Recently, in a Phase I study of the new alkylating agent temozolomide, two mycosis fungoides patients experienced a complete response. The mechanism of resistance to alkylating drugs such as temozolomide is thought to be due to the presence in tumor cells of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT). The protein mediates a reaction with the O6-position of guanine in DNA, removing the lesion and leaving guanine intact. We, therefore, examined the levels of AGT in CD4+ T lymphocytes obtained by negative antibody selection from the blood of noncancerous individuals and mycosis fungoides patients, and in paraffin-embedded sections from mycosis fungoides patch, plaque, or tumor lesions and cells from involved lymph nodes. AGT protein levels were measured by quantitative immunofluorescence microscopy using a monoclonal antibody against human AGT. Using this approach, the mean level of our positive control (AGT-expressing cells) was 84,807 molecules/nucleus; values below 5,000 molecules/nucleus are considered very low. The mean AGT level in CD4+ T lymphocytes from noncancerous and cancerous individuals was 18,618 (n = 12) and 8,593 (n = 5), respectively. The mean fraction of outliers in circulating CD4+ T lymphocytes from mycosis fungoides patients was statistically significantly lower than T cells in lymph nodes. AGT molecules/nucleus from lymph node biopsies from 8 of 10 patients showed low (< 10,000 molecules/nucleus) or undetectable levels (n = 5) of AGT. The mean AGT level from samples of mycosis fungoides patch/plaque and tumor was also low at 221 (n = 4) and 2,363 (n = 6), respectively. Surprisingly, Hut78, a mycosis fungoides T-cell lymphoma cell line, was positive for AGT activity (median: 77,700 molecules/nucleus), and Hut102--another mycosis fungoides cell line--was low (median: 5,990 molecules/nucleus). Because AGT is a primary means of cell resistance to alkylating agents, the low level of AGT in neoplastic T lymphocytes from patients with mycosis fungoides suggests that treatment with alkylating agents producing O6-alkylguanine adducts, such as carmustine or temozolomide, may produce improved clinical outcomes.

A multi-attribute model of prostate cancer patient's preferences for health states.

Multi-attribute utility theory (MAUT) provides a way to model decisions involving trade-offs among different aspects or goals of a problem. We used MAUT to model prostate cancer patients' preferences for their own health state and we compared this model to patients' global judgments of health state utility. 57 patients with prostate cancer (mean age = 70) at two Chicago Veterans Administration health clinics were asked to evaluate health states described in terms of five health attributes affected by prostate cancer: pain, mood, sexual function, bladder and bowel function, and fatigue and energy. Each attribute had three levels that were used to form three clinically realistic health state descriptions (A = high, B = moderate, C = low). A fourth personalized health description (P) matched the patient's current health. We first measured patients' preferences using time trade-off (TTO) judgments for the three health states (A, B, and C) and for their own current health state (P). The TTO for the patient's own health state (P) was standardized by comparing it to TTO judgments for states A and C. We next constructed a multi-attribute model using the relative importance of the five attributes. The MAU scores were moderately correlated with the TTO preference judgments for the personalized state (Pearson r = 0.38, N = 57, p < 0.01). Thus, patients' preference judgments are moderately consistent and systematic. MAUT appears to be a potentially feasible method for evaluating preferences of prostate cancer patients and may prove helpful in assisting with patient decision making.

Stem cell component therapy: supplementation of unmanipulated marrow with CD34 enriched peripheral blood stem cells.

Eleven patients with hematologic malignancies and two with aplastic anemia were treated using unmanipulated marrow and immunoselected CD34+ blood cells. Donors began G-CSF (10 microg/kg) injections 1 day after undergoing bone marrow harvest. Blood stem cells were collected on day 5 of G-CSF. Peripheral blood lymphocytes were depleted via CD34-positive selection. If, after marrow and blood harvest, less than 2.0 x 10(6) CD34 cells/kg were mobilized, leukapheresis was repeated on day 6. Median time to an absolute neutrophil count greater than 500 microl was day 10; transfusion-independent platelet count greater than 20,000/microl was day 13; average hospital discharge was day 14; and average inpatient hospital charges were 101,870 US dollars. Acute GVHD grade II occurred in five of 13 patients. No patient developed grade III or IV acute GVHD. At a median follow-up of 10 months, no patient has developed extensive chronic GVHD. Allografts of unmanipulated bone marrow supplemented with G-CSF-mobilized and CD34 immunoselected blood cells may prevent an increased risk of GVHD while preserving the rapid engraftment kinetics of peripheral blood. Supplementation of marrow with CD34 enriched blood cells appears to result in rapid engraftment, early hospital discharge, lower inpatient charges, decreased regimen-related toxicity, and no apparent increase in GVHD.

Angiosarcoma of the bladder: a review.

OBJECTIVES: To present a new case of angiosarcoma of the bladder, review 9 other previously reported cases, and discuss the unique features of our case with regard to presentation, treatment, and clinical course of patients with this exceedingly rare tumor. The utility of multimodality therapy is emphasized. METHODS: We report the latest case of angiosarcoma of the bladder. We also reviewed the world literature (MEDLINE) and discovered 9 previously reported cases of angiosarcoma of the bladder. Presentation, treatment, and clinical course were analyzed. RESULTS: Of the 10 cases, 2 were considered to have arisen from a preexisting bladder hemangioma. Two patients had a history of prior gynecologic malignancies treated with external beam radiotherapy, with subsequent sarcoma formation within the past treatment field. Two other patients presented with skin lesions that predated the discovery of bladder lesions. Only 4 patients presented with primary bladder lesions and no preexisting disease or previous carcinogenic exposure (except for tobacco use). Hematuria was a universal presentation, and treatment was widely variant. Of the 10 patients, 8 died during a period of follow-up of 23 months. Five patients died of tumor-related causes. Mean survival of these 5 was 10.6 months. The 2 most recent patients (including ours) were alive and tumor free at 8 and 32 months, respectively. Both of these patients underwent multimodality oncologic approaches as part of their treatment regimen. CONCLUSIONS: Angiosarcoma of the bladder is exceedingly rare and usually fatal. Prognosis is poorer than that of angiosarcomas in more traditional sites. Regional lymph nodes are typically spared, but local recurrence with eventual distant metastasis is the rule. Optimal therapy has not been determined, but it most likely should involve a multimodal approach combining radical surgery with chemotherapy and radiotherapy.

Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides.

BACKGROUND: DAB389IL-2 is a novel fusion toxin that retargets the cytotoxic A-chain of diphtheria toxin to interleukin-2 (IL-2) receptor-expressing tumors. OBJECTIVE: The purpose of this phase I trial was to study the toxicity, maximum tolerated dose, and clinical efficacy of DAB389IL-2 in IL-2 receptor expressing lymphoproliferative malignancies, including cutaneous T-cell lymphoma. METHODS: DAB389IL-2 was administered intravenously daily for 5 days every 3 weeks. Dose escalation occurred between patient groups. Patients were monitored for laboratory and clinical toxicity, kinetics, immune response, and clinical efficacy. RESULTS: Thirty-five patients with cutaneous T-cell lymphoma (including 30 patients with mycosis fungoides) were treated. Previously, conventional therapy had not worked for 34 of the patients. Thirteen patients (37%) achieved an objective response, including a complete response in five patients (14%). Complete response was achieved in patients with extensive erythroderma and tumor stage mycosis fungoides. Adverse events consisted of reversible fever/chills, hypotension, nausea/vomiting, and elevation of hepatic transaminase. Doses of less than 31 microg/kg per day were well tolerated. Clinical responses were observed at all dose levels. CONCLUSION: DAB389IL-2 is well tolerated at doses of less than 31 microg/kg per day, and it induced clinical responses in previously treated mycosis fungoides, providing evidence for the antitumor activity of this molecule.

Prostate cancer patients' utilities for health states: how it looks depends on where you stand.

Two versions of the time-tradeoff (TTO) method were compared. In the personal TTO version, 31 prostate cancer patients decided whether they personally would give up some longevity to have perfect health rather than a longer life in a state of poor health associated with prostate cancer. In the impersonal version, 28 patients compared two hypothetical friends, one of whom has perfect health but will live less time than the other who is in poor health, and decided which person they would rather be. All patients evaluated three hypothetical health states. The two TTO methods were assessed by examining 1) how well they distinguished three health states of varying degrees of dysfunction and 2) patients' willingness to trade time for quality of life. Patients using the impersonal TTO version were more likely than those using the personal version to order the three health states appropriately (68% vs 16%, p < 0.0001) and were more willing to trade off length of life for quality of life (p < 0.05).