Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage II prostate cancer, stage III prostate cancer
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase I/II trial is studying the side effects and best dose of docetaxel when given together with radiation therapy and to see how well they work in treating patients who are undergoing surgery for high-risk localized prostate cancer.
Detailed description
OBJECTIVES: Primary * Determine the maximum tolerated dose (MTD) of neoadjuvant radiotherapy and docetaxel in patients who are undergoing prostatectomy for high-risk localized prostate cancer. * Determine the pathologic response rate in patients treated at the phase II dose. Secondary * Determine the prostate-specific antigen (PSA) short-term response rate in patients treated with this regimen. * Determine the long-term safety of this regimen prior to radical prostatectomy in these patients. * Determine the clinical response to this regimen by urologic examination of these patients. * Determine the surgical margin status at the time of prostatectomy in patients treated with this regimen. * Determine the effect of this regimen, in terms of Health-Related Quality of Life by Expanded Prostate Cancer Index Composite (EPIC) and urinary symptom scores by the American Urological Association's measures, in these patients. * Determine the clinical progression-free rate in patients treated with this regimen. * Identify pretreatment predictors of response in these patients by examining tissue biomarkers in preserved pretreatment biopsy specimens. * Determine the biologic impact of this regimen on these patients by examining the prostatectomy specimens. * Collect frozen serum for future analysis of correlative biomarkers. * Compare the RNA content (gene expression profile) of pre- and post-treatment tumor specimens in order to describe the molecular impact of this regimen on prostate cancer. OUTLINE: This is a phase I, dose-escalation study of docetaxel followed by a phase II study. All patients undergo a biopsy of the prostate to gather research-only specimens prior to the beginning of treatment. * Phase I: Patients undergo radiotherapy once daily, 5 days a week, for 5 weeks. Patients also receive docetaxel IV on days 1, 8, 15, 22, and 29. Treatment continues in the absence of disease progression or unacceptable toxicity. Approximately 4-6 weeks after completion of chemoradiotherapy, patients undergo a radical prostatectomy. Cohorts of 3-6 patients receive escalating doses of docetaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity. At least 6 patients are treated at the MTD. * Phase II: Patients undergo radiotherapy as in phase I. Patients also receive docetaxel at the MTD determined in phase I and then undergo prostatectomy as in phase I. PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.
Interventions
RADIATIONIntensity-Modulated Radiation Therapy (IMRT)
Group 1=radiation only; All men in all Arms/Groups receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions)
DRUGDocetaxel+IMRT
Group 2=IV over 30mins, 10mg/m2; weekly x 5 weeks starting on day one of radiation; Group 3=IV over 30mins, 20mg/m2; weekly x 5 weeks starting on day one of radiation; Group 4=IV over 30mins, 30mg/m2; weekly x 5 weeks starting on day one of radiation; Phase II with no phase I dose-limiting toxicities=IV over 30mins, 30mg/m2; weekly x 5 weeks starting on day one of radiation Radiation: All men receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions)
Sponsors
OHSU Knight Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
; DISEASE CHARACTERISTICS: * Histologically confirmed adenocarcinoma of the prostate * Localized disease, meeting 1 of the following staging criteria: * Clinical stage T2b (palpable bilateral movement) disease * Surgically resectable T3 disease * Meets any of the following high-risk\* features: * PSA ≥ 15 ng/mL * Gleason grade ≥ 4+3 (4+3, 4+4, or 5+any, but not 3+4) NOTE: \*High risk defined as \> 50% chance of failure with local therapy * Plans to undergo prostatectomy as primary therapy * No evidence of lymph nodes ≥ 2 cm in diameter by pelvic CT scan * Scan only required in patients with a PSA ≥ 40 ng/mL * No evidence of bone metastases by bone scan PATIENT CHARACTERISTICS: * Life expectancy ≥ 10 years * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * White blood cell (WBC) \> 3,000/mm\^3 * Neutrophil count \> 1,500/mm\^3 * Platelet count \> 100,000/mm\^3 * Direct bilirubin normal * Alanine aminotransferase (ALT) \< 2.0 times upper limit of normal (ULN) (1.5 times ULN if alkaline phosphatase \[AP\] \> 2.5 times ULN) * Alkaline phosphatase (AP) \< 4.0 times ULN * No other serious medical condition that would preclude study treatment * No other malignancy within the past 5 years except nonmelanoma skin cancer * No peripheral neuropathy ≥ grade 2 * No hypersensitivity to drugs formulated with polysorbate 80 * No significant contraindications to corticosteroids * No history of scleroderma * No active inflammatory bowel disease (IBD) or IBD that is being medically treated * Inclusion of patients with a remote history of IBD is at the discretion of radiotherapist
Exclusion criteria
; PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior therapy for prostate cancer, including any of the following: * Conventional hormonal therapy (e.g., orchiectomy, luteinizing hormone-releasing hormone therapy, antiandrogen therapy, or estrogen therapy) * External-beam radiotherapy or brachytherapy * Cryotherapy * Cytotoxic chemotherapy * No prior pelvic radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 5 weeks | Maximal tolerated dose (MTD) of the combination radiation (45 Gy) and docetaxel. The dose of radiation will be fixed at 45 Gy while the dose of docetaxel will be escalated. The starting dose of docetaxel will be 10 mg/m2 and will be escalated in increments of 10 mg/m2 up to a dose of 30 mg/m2 the pre-planned ceiling). MTD will be the dose that is associated with no more than 1 dose limiting toxicity (DLT) up to 6 patients. The DLT will be defined as clinically significant grade 3 non-hematologic or grade 4 hematologic toxicity, attributable to the chemoirradiation. If 2 of 3 patients experience a DLT, dose escalation will stop and the previous dose level will be considered the MTD. If 1 of 3 has DLT, additional 3 patients will be enrolled at the same dose level. If none of the additional 3 patients has DLT, the dose escalation will continue. If 1 additional patient has DLT, the previous dose will be considered the MTD and dose escalation will be stopped. |
| Pathologic Response Rate at the Phase II Dose | 4-6 weeks after study treatment | Pathologic response rate is determined post-prostatectomy by pathologist laboratory analyses. The TNM system is the most widely used cancer staging system. Most hospitals and medical centers use the TNM system as their main method for cancer reporting. In the TNM system: The T refers to the size and extent of the main/primary tumor. T1, T2, T3, T4: Refers to the size and/or extent of the main tumor. The higher the number after the T, the larger the tumor or the more it has grown into nearby tissues. T's may be further divided to provide more detail, such as T3a and T3b. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response to Treatment as Measured by Urologic Examination | Each participant was examined 3, 6, 9, 12 months, and annually for an average of 10 years after surgery. | Biochemical Recurrence is defined as a detectable or rising PSA value after surgery that is 0.2 ng/mL or greater with a second confirmatory level of 0.2 ng/mL or greater. |
| Surgical Margin Status at Time of Prostatectomy (Count of Subjects With Negative Surgical Margins) | 5 weeks | Pathologic response rate is determined post-prostatectomy by pathologist laboratory analyses. The TNM system is the most widely used cancer staging system. Most hospitals and medical centers use the TNM system as their main method for cancer reporting. In the TNM system: The M refers to whether the cancer has metastasized. This means that the cancer has spread outside of the primary tumor to other parts of the body. |
| Prostate-specific Antigen Short-term Response Rate Measured as a Percentage Change in PSA | Baseline (pre-treatment) and 1 month after surgery (post-treatment) | All participants were combined for this assessment as pre-specified in the protocol. The percentage change for patients were determined from pre- and post- treatment PSA values. The mean percentage change in PSA will be reported. PSA will be monitored every 3-6 months during the first 5 years, then annually after surgery for up to 10 years |
| Clinical Progression-free Rate as Determined by <0.1ng PSA Results | 3, 6, 9, 12 months and annually, up to 5 years | The estimated percentage of participants who were progression-free at 5 years per analyses of PSA results post-study treatment. |
| Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | Baseline and 12 Months Post-Prostatectomy | Mean change in score from Baseline to 12-months pot-op. A single outcome, Health Related Quality of Life (QOL), was specified in the protocol. All 6 score means and confidence intervals are reported here as a single outcome; a separate row for each score. AUA Symptom Score is designed to measure lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia or other causes in men. Higher scores indicate more LUTS (scale 0-35). 1-7, mild; 8-19, moderate; 20-35, severe. EPIC quality of life instruments is a 32-item self-report questionnaire that measures the QOL of prostate cancer patients. 4 subscales measuring urinary (further consisting of two sub-components, EPIC Urinary Incontinence Score and EPIC Urinary Obstructive/Irritative Score), bowel, sexual and hormonal changes. Scores for each of the subscales, as well as for each sub-component within the Urinary sub scale, are transformed linearly to a 0-100 scale with higher scores representing better QOL. |
| Long-term Safety | Regular intervals both study-related and clinical standard of care-related; assessed at end of study treatment. Average timeframe to follow safety was 1 year and includes all grade 3-4 adverse events | An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. |
Countries
United States
Participant flow
Recruitment details
Subject accrual from Urology clinics started in April 2006; annual follow-up of 22 VA, 3 Oregon Health & Science University (OHSU) (25 total) subjects who completed ended in 2011; 10 year follow-up of these patients will be completed in 2021.
Pre-assignment details
Our 1 screen failure was excluded as a result of having a different type of cancer, other than non-melanoma skin cancer, within the past 5 years.
Participants by arm
| Arm | Count |
|---|---|
| Phase I, Radiation Only Drug: N/A
4 groups of men in phase I study.
Group 1=radiation only
Radiation: radiation therapy
All men receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions) | 3 |
| Phase I, Dose 1 Drug: docetaxel
4 groups of men in phase I study.
Group 2=IV over 30mins, 10mg/m2; weekly x 5 weeks starting on day one of radiation;
Radiation: radiation therapy
All men receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions) | 3 |
| Phase I, Dose 2 Drug: docetaxel
4 groups of men in phase I study.
Group 3=IV over 30mins, 20mg/m2; weekly x 5 weeks starting on day one of radiation;
Radiation: radiation therapy
All men receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions) | 3 |
| Phase I, Dose 3 Drug: docetaxel
4 groups of men in phase I study.
Group 4=IV over 30mins, 30mg/m2; weekly x 5 weeks starting on day one of radiation
Radiation: radiation therapy
All men receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions) | 3 |
| Phase II, MTD Dose Drug: docetaxel
Phase II with no phase I dose-limiting toxicities=IV over 30mins, 30mg/m2; weekly x 5 weeks starting on day one of radiation
Radiation: radiation therapy
All men receive same radiation treatment protocol. External Beam, 45 Gy (1.8 Gy fractions), 5 per week (daily) x 5 weeks (25 fractions) | 13 |
| Total | 25 |
Baseline characteristics
| Characteristic | Phase I, Dose 1 | Phase I, Dose 2 | Phase I, Dose 3 | Phase I, Radiation Only | Phase II, MTD Dose | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 11 Participants | 20 Participants |
| Age, Continuous | 62.67 years STANDARD_DEVIATION 7.64 | 66.33 years STANDARD_DEVIATION 4.93 | 58.00 years STANDARD_DEVIATION 6.56 | 66.67 years STANDARD_DEVIATION 8.14 | 60.54 years STANDARD_DEVIATION 4.58 | 61.92 years STANDARD_DEVIATION 5.89 |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 3 participants | 13 participants | 25 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 13 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 13 |
| serious Total, serious adverse events | 0 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 8 / 13 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Maximal tolerated dose (MTD) of the combination radiation (45 Gy) and docetaxel. The dose of radiation will be fixed at 45 Gy while the dose of docetaxel will be escalated. The starting dose of docetaxel will be 10 mg/m2 and will be escalated in increments of 10 mg/m2 up to a dose of 30 mg/m2 the pre-planned ceiling). MTD will be the dose that is associated with no more than 1 dose limiting toxicity (DLT) up to 6 patients. The DLT will be defined as clinically significant grade 3 non-hematologic or grade 4 hematologic toxicity, attributable to the chemoirradiation. If 2 of 3 patients experience a DLT, dose escalation will stop and the previous dose level will be considered the MTD. If 1 of 3 has DLT, additional 3 patients will be enrolled at the same dose level. If none of the additional 3 patients has DLT, the dose escalation will continue. If 1 additional patient has DLT, the previous dose will be considered the MTD and dose escalation will be stopped.
Time frame: 5 weeks
Population: Outcome analysis includes the subjects from all 4 phase I groups, inclusive of subjects who only received radiation, as all subjects across all phases received the same radiation dosage. Phase I, group 1 subjects were included in case MTD was zero.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose 1-4 | Maximum Tolerated Dose (MTD) | 30 mg/m^2 |
Primary
Pathologic Response Rate at the Phase II Dose
Pathologic response rate is determined post-prostatectomy by pathologist laboratory analyses. The TNM system is the most widely used cancer staging system. Most hospitals and medical centers use the TNM system as their main method for cancer reporting. In the TNM system: The T refers to the size and extent of the main/primary tumor. T1, T2, T3, T4: Refers to the size and/or extent of the main tumor. The higher the number after the T, the larger the tumor or the more it has grown into nearby tissues. T's may be further divided to provide more detail, such as T3a and T3b.
Time frame: 4-6 weeks after study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Dose 1-4 | Pathologic Response Rate at the Phase II Dose | Pathologic Stage pT2c | 7 participants |
| Phase I Dose 1-4 | Pathologic Response Rate at the Phase II Dose | Pathologic Stage pT3a | 3 participants |
| Phase I Dose 1-4 | Pathologic Response Rate at the Phase II Dose | Pathologic Stage pT3b | 3 participants |
Secondary
Clinical Progression-free Rate as Determined by <0.1ng PSA Results
The estimated percentage of participants who were progression-free at 5 years per analyses of PSA results post-study treatment.
Time frame: 3, 6, 9, 12 months and annually, up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose 1-4 | Clinical Progression-free Rate as Determined by <0.1ng PSA Results | 62.8 percentage of participants |
Secondary
Clinical Response to Treatment as Measured by Urologic Examination
Biochemical Recurrence is defined as a detectable or rising PSA value after surgery that is 0.2 ng/mL or greater with a second confirmatory level of 0.2 ng/mL or greater.
Time frame: Each participant was examined 3, 6, 9, 12 months, and annually for an average of 10 years after surgery.
Population: Clinical response to treatment was measured by regular Prostatic Specific Antigen (PSA) blood draws. The following men per chemotherapy dosage experienced a detectable or rising PSA value after surgery with a 2nd confirmatory level of 0.2ng/mL or higher (defined as biochemical recurrence of prostate cancer).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Dose 1-4 | Clinical Response to Treatment as Measured by Urologic Examination | 1 Participants |
| Phase II MTD Dose | Clinical Response to Treatment as Measured by Urologic Examination | 2 Participants |
| Phase I, Dose 2 | Clinical Response to Treatment as Measured by Urologic Examination | 0 Participants |
| Phase I, Dose 3 | Clinical Response to Treatment as Measured by Urologic Examination | 2 Participants |
| Phase II, MTD Dose | Clinical Response to Treatment as Measured by Urologic Examination | 5 Participants |
Secondary
Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures
Mean change in score from Baseline to 12-months pot-op. A single outcome, Health Related Quality of Life (QOL), was specified in the protocol. All 6 score means and confidence intervals are reported here as a single outcome; a separate row for each score. AUA Symptom Score is designed to measure lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia or other causes in men. Higher scores indicate more LUTS (scale 0-35). 1-7, mild; 8-19, moderate; 20-35, severe. EPIC quality of life instruments is a 32-item self-report questionnaire that measures the QOL of prostate cancer patients. 4 subscales measuring urinary (further consisting of two sub-components, EPIC Urinary Incontinence Score and EPIC Urinary Obstructive/Irritative Score), bowel, sexual and hormonal changes. Scores for each of the subscales, as well as for each sub-component within the Urinary sub scale, are transformed linearly to a 0-100 scale with higher scores representing better QOL.
Time frame: Baseline and 12 Months Post-Prostatectomy
Population: Scores not available for some participants
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I Dose 1-4 | Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | AUA Symptom Score | 0.67 units on a scale |
| Phase I Dose 1-4 | Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | EPIC Urinary Incontinence Score | -36.52 units on a scale |
| Phase I Dose 1-4 | Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | EPIC Urinary Obstructive/Irritative Score | 3.41 units on a scale |
| Phase I Dose 1-4 | Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | EPIC Bowel | 1.45 units on a scale |
| Phase I Dose 1-4 | Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | EPIC Hormonal | 0.00 units on a scale |
| Phase I Dose 1-4 | Efficacy Assessed Using Health-Related Quality of Life by Expanded Prostate Cancer Index Composite and Urinary Symptom Scores by American Urological Association's Measures | EPIC Sexual | -36.26 units on a scale |
Secondary
Long-term Safety
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.
Time frame: Regular intervals both study-related and clinical standard of care-related; assessed at end of study treatment. Average timeframe to follow safety was 1 year and includes all grade 3-4 adverse events
Population: Phase I participants numbered 12 (receiving different chemotherapy doses) and Phase II participants numbered 13 (receiving the maximally tolerated chemotherapy dose). This Outcome Measure was assessed in aggregate, combining participants from both phases of the study, per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose 1-4 | Long-term Safety | 9 grade 3-4 adverse events |
| Phase II MTD Dose | Long-term Safety | 8 grade 3-4 adverse events |
Secondary
Prostate-specific Antigen Short-term Response Rate Measured as a Percentage Change in PSA
All participants were combined for this assessment as pre-specified in the protocol. The percentage change for patients were determined from pre- and post- treatment PSA values. The mean percentage change in PSA will be reported. PSA will be monitored every 3-6 months during the first 5 years, then annually after surgery for up to 10 years
Time frame: Baseline (pre-treatment) and 1 month after surgery (post-treatment)
Population: Pre- and post-treatment PSA values were available in 22 of 25 patients.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase I Dose 1-4 | Prostate-specific Antigen Short-term Response Rate Measured as a Percentage Change in PSA | -49.1 percentage change |
Secondary
Surgical Margin Status at Time of Prostatectomy (Count of Subjects With Negative Surgical Margins)
Pathologic response rate is determined post-prostatectomy by pathologist laboratory analyses. The TNM system is the most widely used cancer staging system. Most hospitals and medical centers use the TNM system as their main method for cancer reporting. In the TNM system: The M refers to whether the cancer has metastasized. This means that the cancer has spread outside of the primary tumor to other parts of the body.
Time frame: 5 weeks
Population: For Phase I Dose 1-4, all participants were combined for this assessment as pre-specified in the protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Dose 1-4 | Surgical Margin Status at Time of Prostatectomy (Count of Subjects With Negative Surgical Margins) | 9 Participants |
| Phase II MTD Dose | Surgical Margin Status at Time of Prostatectomy (Count of Subjects With Negative Surgical Margins) | 13 Participants |