PATIENT REPORTED OUTCOMES IN PROSTATE CANCER

PATIENT REPORTED OUTCOMES IN PROSTATE CANCER Derek Raghavan MD PhD Cleveland Clinic Taussig Cancer Center Cleveland, OH. Rationale & Problems    Difficulty of assessing response within “stable” disease category Use of patient reported symptom response widens the goalposts Contrast:    symptoms of age symptoms of cancer side effects of therapy   Dichotomy between objective vs. subjective vs. PSA response Optimal technology not defined Presentation of Advanced Prostate Cancer: Syndromes Bone pain  Constitutional symptoms – the great mimic  Urinary obstruction   Slow stream, nocturia, frequency, hematuria  Acute/chronic renal failure Bone marrow failure  Unusual sites – liver, lungs, nodes, skin  Urinary Obstruction Presentation of Advanced Prostate Cancer: Syndromes Bone pain  Constitutional symptoms – the great mimic  Urinary obstruction   Slow stream, nocturia, frequency, hematuria  Acute/chronic renal failure Bone marrow failure  Unusual sites – liver, lungs, nodes, skin  “New” pattern – asymptomatic rising PSA  Hormone Refractory Prostate Cancer: Median Time from Progression to Death PARAMETER PSA increase Bone scan change Alkaline phos increase Pain increase Performance status decline Hemoglobin decline Weight loss Liver metastases Newling, et al. Cancer. 1993;72:3793-3798. Weeks 52 41 35 32 24 22 12 10 Changing Endpoints in Prostate Cancer Therapy  Impact of stage migration  PSA only disease  Rising after radiotherapy or surgery  Asymptomatic disease with known metastases  Earlier intervention for +ve bone scans Measurement of quality of life  Measurement of time to progression  Adjuvant trials  Patient Reporting Domains  Non-specific     Tumor-related     Fevers, sweats Pruritis Malaise      Well-being Mood Activities Quality of life Sexuality Pain Weight Performance status Metastases Hormone effects RT effects Surgical effects Chemotherapy impact  Treatment-related     Examples of Patient Report Instruments o McGill Melzack – Present Pain Intensity o o o What is optimal reduction? Significance of 2 point reduction? Impact of baseline severity? o o o EORTC QLQ 30 EORTC Prostate Cancer Specific Module PROSQOLI Methodologic Problems Impact of baseline variables – e.g. pain  How to score  Dealing with missing data  Statistical analysis  under curve  Kaplan Meier vs. Wilcoxson  ROC curves   Area Confounding variables  e.g. knowledge of PSA fluxes  Race and socio-demographic factors Mitoxantrone for Prostate CA (Raghavan et al, 1989)    N = 50 patients Prior hormone Rx Sites:      Outcome:    mainly bone metastases prostate nodes liver skin  60% with less tumorrelated symptoms Objective response of 0-35%, depending on criteria of response Survival:  Median 10 mos from Rx Mitoxantrone vs Prostate CA: Results  Subjective Response: Decreased pain  Decreased symptoms  Weight gain (>2kg)  Improved ECOG status  18/46 (38%) 21/46 (46%) 19/46 (41%) 13/50 (26%) Mitoxantrone vs Prostate CA (variability of criteria of outcome) RESPONSE NPCP (1984) EORTC (1984) NCOG (1983) MDAH (1983) CR PR SD PD 0 0 23 15 0 0 23 15 0 10 13 15 0 7 16 15 Mitoxantrone Phase III Canadian Trial: Study Design Mitoxantrone R A N D O M I Z E + Prednisone Primary Endpoint: Palliation Prednisone* N=81 N=80 Symptomatic HRPC *Crossover on progression (N=50) Tannock, et al. J Clin Oncol. 1996;14:1756-1764. Mitoxantrone for Advanced Prostate Cancer: Overall Survival Tannock et al, J. Clin. Oncol., 1996 Mitoxantrone for Advanced Prostate Cancer: Quality of LIfe Tannock et al, J. Clin. Oncol., 1996 Mitoxantrone-Tesmilifene (DPPE)   All patients with pain, narcotics at baseline 75% with pain response      Reduction of 2 on PPI (McGill-Melzack) Self reported record sheets – some inconsistent Addressed covariance via AUC measurements EORTC QLQ 30 & Prostate Specific Module Discrepancies between pain reduction & QOL    66% with reduced analgesia 48% with PSA reduction >75% 2 year survival 21% (Raghavan et al, Proc ASCO, 2003) Summary of Estramustine-Based Chemotherapy: Nonrandomized Trials Study Amato Seidman Hudes Hudes Petrylak Phase II II II I+II I Agents Combined with EMP vinblastine vinblastine vinblastine paclitaxel docetaxel N 22 25 36 38 32 Number PR/ Number Measured 3/7 2/5 1/7 6/12 5/16 N (%)  50% PSA  11/22 (50) 13/24 (54) 11/36 (31) 19/35 (54) 20/32 (63) Imp. Pain N (%) — 6/9 (66) 12/28 (43) — 8/15 (53) Median Survival (Months) — — 11.5 17 — Amato, et al. Proc Am Assoc Cancer Res. 1999. Seidman, et al. J Urol. 1992;147:931-934. Hudes, et al. J Clin Oncol. 1992;10:1754-1761. Hudes, et al. J Clin Oncol. 1997;15:3156-3163. Petrylak, et al. Proc Am Soc Clin Oncol. 1997. (Courtesy of Maha Hussain, MD) TAX 327: Secondary Objectives Response Rates Docetaxel 3 wkly Pain Response Rate* n, evaluable Response rate (%) P-value (vs. mitoxantrone) PSA Response Rate* n, evaluable PSA response rate (%) P-value (vs. mitoxantrone) Tumor Response Rate* n, evaluable Response rate (%) P-value (vs. mitoxantrone) 153 35 0.01 291 45 0.0005 141 12 0.1 Docetaxel wkly 154 31 0.07 282 48 <0.0001 134 8 0.5 Mitoxantrone 157 22 ‒ 300 32 ‒ 137 7 ‒ * Determined only for patients with pain or PSA 20 or measurable disease at baseline, respectively Taxotere-Calcitriol (Beer et al, J Clin Oncol, 2004, 100: 758-763)  Indices: point reduction on PPI (or 0 if PPI=1)  50% reduction in analgesic use  Other measures of QOL 2 Analgesic response in 48%  BUT worse QOL on QLQ-C30QOL      Physical and role functioning Fatigue Appetite Global health status Patient Reported Outcomes: Summary      Assessment of symptomatic response leads to stage/response migration – c.f. “objective” response Measures of Quality of Life and Symptom Response still being developed and validated PSA response vs. Symptom Response vs. Toxicity of Treatment  “disconnect” Discordant QOL results – which should “dominate”? Confounding symptoms:   Toxicity of treatment Age-related disorders – BPH, arthritis, anemia  This area should be regarded as “work in progress” by FDA HRPC STATE - Subpopulations Types of Progression at the time of study entry + Bone Mets 90% Soft tissue/visceral No Bone Mets < 10 % Bone scan + PSA Progression 70% PSA Progression Alone 15-20% Symptomatic Progression Alone 10-15% ?? New Bone Mets Soft tissue Visceral Progression No Bone Mets