# Presentation: 894875

## 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_				      _Weeks_
- PSA increase					52
- Bone scan change					41
- Alkaline phos increase				35
- Pain increase					32
- Performance status decline			24
- Hemoglobin decline				22
- Weight loss						12
- Liver metastases					10

- Newling, et al. *Cancer. * 1993;72:3793-3798.

## 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
- Fevers, sweats
- Pruritis
- Malaise
- Well-being
- Mood
- Activities
- Quality of life
- Sexuality

- Tumor-related
- Pain
- Weight
- Performance status
- Metastases
- Treatment-related
- Hormone effects
- RT effects
- Surgical effects
- Chemotherapy impact

## Examples of Patient Report Instruments

- McGill Melzack – Present Pain Intensity
- What is optimal reduction?
- Significance of 2 point reduction?
- Impact of baseline severity?
- 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
- Area under curve
- Kaplan Meier vs. Wilcoxson
- ROC curves
- 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:
- mainly bone metastases
- prostate
- nodes
- liver
- skin

- Outcome:
- 60% with less tumor-related 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 			18/46 (38%)
- Decreased symptoms		21/46 (46%)
- Weight gain (>2kg)		19/46 (41%)
- Improved ECOG status		13/50 (26%)

## Mitoxantrone vs Prostate CA(variability of criteria of outcome)

| RESPONSE | NPCP
(1984) | EORTC
(1984) | NCOG
(1983) | MDAH
(1983) |
| --- | --- | --- | --- | --- |
| CR | 0 | 0 | 0 | 0 |
| PR | 0 | 0 | 10 | 7 |
| SD | 23 | 23 | 13 | 16 |
| PD | 15 | 15 | 15 | 15 |

## Mitoxantrone Phase III Canadian Trial:  Study Design

- Symptomatic
- HRPC

**RANDOMIZE**

- Mitoxantrone
- +
- Prednisone
- Prednisone*

- N=80

- N=81

- Primary Endpoint: Palliation

- *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

- 				 Number PR/ 		Imp.	Median
- 		Agents Combined		Number	N (%) 	Pain	Survival
- Study	Phase	with EMP	N	Measured	50% PSA 	N (%)	(Months)
- Amato	II	vinblastine	22	3/7	11/22 (50)	—	—
- Seidman	II	vinblastine	25	2/5	13/24 (54)	6/9 (66)	—
- Hudes	II	vinblastine	36	1/7	11/36 (31)	12/28 (43)	11.5
- Hudes	I+II	paclitaxel	38	6/12	19/35 (54)	—	17
- Petrylak	I	docetaxel	32	5/16	20/32 (63)	8/15 (53)	—

- 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 | Docetaxel wkly |  Mitoxantrone  |
| --- | --- | --- | --- |
| Pain Response Rate* |  |  |  |
| 	 n, evaluable | 153 | 154 | 157 |
| 	 Response rate (%) | 35 | 31 | 22 |
| 	 P-value (vs. mitoxantrone) | 0.01 | 0.07 | ‒ |
| PSA Response Rate* |  |  |  |
| 	 n, evaluable | 291 | 282 | 300 |
| 	 PSA response rate (%) | 45 | 48 | 32 |
| 	 P-value (vs. mitoxantrone) | 0.0005 | <0.0001 | ‒ |
| Tumor Response Rate* |  |  |  |
| 	 n, evaluable | 141 | 134 | 137 |
| 	 Response rate (%) | 12 | 8 | 7 |
| 	 P-value (vs. mitoxantrone) | 0.1 | 0.5 | ‒ |

**TAX 327:  Secondary Objectives ****Response Rates**

*******	****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:
- 2 point reduction on PPI (or 0 if PPI=1)
- 50% reduction in analgesic use
- Other measures of QOL
- 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**