PHASE II PROSPECTIVE NON-RANDOMIZED TRIAL OF THE USE OF CONFORMAL HIGH DOSE RATE BRACHYTHERAPY ALONE FOR THE TREATMENT OF FAVORABLE STAGE ADENOCARCINOMA OF THE PROSTATE Trial Co-Chairs Radiation Oncology
Alvaro Martinez, M.D. William Beaumont Hospital 3601 W. Thirteen Mile Road Royal Oak, MI 48073 (248) 551-7058 (248) 551-7845 fax
[email protected] Luis Alberto Linares, M.D. East Jefferson Hospital 4200 Houma Blvd Metairie, LA 70006 (504) 456-5139 (504) 456-5064 fax
[email protected]
Data Managers
Michelle Wallace, RN, BSN, OCN Protocol Nurse Clinician William Beaumont Hospital Department of Radiation Oncology 3601 W. Thirteen Mile Road Royal Oak, MI 48073 (248) 551-7124 (248) 551-9260 fax
[email protected]
[North & South America; Asia Pacific]
Razvan Galelae, MD Associate Professor and Vice Chairman Clinic for Radiotherapy University Hospital Schleswig-Holstein Campus Kiel Arnold-Heller-Str. 9 24105 Kiel, Germany +49 (431) 597-3010 (or 3012) +49 (431) 597-3110 fax
[email protected]
[Europe]
Activation Date: June 8, 2007 Closure Date: December 31, 2008 _____________________________________________________________________________________________ This protocol was designed and developed by the Prostate Brachytherapy international Group (P-BIG). It is intended to be used in conjunction with institution-specific Internal Review Board (IRB) approval for trial entry. No other use or reproduction is authorized by P-BIG nor does P-BIG assume any responsibility for unauthorized use of this protocol.
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INDEX
Schema Eligibility Checklist 1.0 Introduction 2.0 Objectives 3.0 Patient Selection 4.0 Recommended Pretreatment Evaluations 5.0 Registration Procedures 6.0 Brachytherapy 7.0 Drug Therapy 8.0 Surgery 9.0 Other Therapy 10.0 Tissue/Specimen Submission 11.0 Patient Assessments 12.0 Data Collection 13.0 Statistical Considerations References Appendix I Appendix II Appendix III Appendix IV Appendix V
- Sample Consent Form - Performance Status Scoring - Staging System - Gleason Score - Protocol Forms
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SCHEMA
ASSESS PSA ≤ 10 ng/ml Combined Gleason Score T Stage
≤6
T1c, T2c
Prostate Size
≤ 60 cc
Expected Survival 5 years or longer
ENROLL TREAT Patients will receive 38.0 Gy High Dose Rate (HDR) brachytherapy in 4 fractions of 9.5 Gy each within 48 hours.
MONITOR
Patient Population: Histologically-confirmed adenocarcinoma of the prostate Clinical stage T1c and T2a Gleason score ≤ 6 PSA ≤ 10 Zubrod Performance Status 0-1 No prior pelvic or prostate radiation No distant metastases (M0) No clinically involved lymph nodes
Sample Size: 95 Maximum Enrollment per participant institution: 10
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1.0 INTRODUCTION
1.1 Background According to the American Cancer Society, an estimated 218,890 new cases of Prostate cancer will occur in the USA during 2007. Prostate cancer is the most frequently diagnosed cancer in men and more than 65% of all prostate cancer cases are diagnosed in men 65 years and older. For reasons that remain unclear, incidence rates are significantly higher in African American men and Jamaican men of African descent than in white men and rates in Asian and South American men are less common. Incidence rates of prostate cancer have changed substantially over the 20 years: rapidly increasing from 1988-1992, declining sharply from 1992-1995, and increasing modestly since 1995. These trends in large part reflect increased prostate cancer screening with the prostate-specific antigen (PSA) blood test. Moderate incidence increases in the last decade are most likely attributable to widespread PSA screening among men younger than 65 years of age. Because of the use of PSA, up to two thirds of these men will be diagnosed with organ confined diseased and low to intermediate grade histological pattern. Making these patients amenable to treatment with several potentially curative modalities that had included Radical prostatectomy, and Radiation Therapy in the forms of external beam or low dose rate permanent seed implantation using either I-125 or Pd-103 seeds. Because of the convenience and availability over the last 10 years, there has been a dramatic increase in the utilization of permanent seed implant for early disease prostate carcinoma. The local control reported by several centers nationally and internationally has been excellent. Because of the logistics and convenience, these treatments are very popular among patients and urologic surgeons. And they have been the ones driving this technology over the last few years. Despite the excellent results and simplicity of these procedures, there are some drawbacks. One, the implantation of radioactive material albeit with short half life still leaves the patient radioactive for several months, with some limitations as far as the normal patient routine. Possibility of displacement or loss of seeds represents both clinical and radiation safety problems. Although the technology has improved, there still are problems with seed distribution that is difficult to correct once the seeds have been placed.
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Currently there is a steep learning curve. Technically, the quality of temporary implants is higher because of the nature of the procedure that allows for corrections prior to treatment. That has been demonstrated in several institutions when HDR has been used as boost for high risk patients or as monotherapy for low risk patients Seeds are not re-usable therefore the cost of the seeds can be very high for some centers or countries; and the shipping and accessibility can be very difficult for some countries as well. Access to a re-usable source like the ones in used with HDR offers a very attractive option. A solution to some of the problems mentioned above could be through the utilization of a reusable Iridium-192 source used in High Dose Rate brachytherapy units. An advantage is that the re-usable source can be used in as many patients as needed during the usable half-life of the radioisotope. Dosimetry is easier and allows modifications of the implant and dose distribution during the placement of needles with real-time image guidance treatment planning systems. Alternatively, for institutions not using real time image guidance, placement of the needles is easily assessed by CT or MR imaging. There is extensive experience in the use of HDR monotherapy for the treatment of early prostate cancer such as the experience at the William Beaumont Hospital [1-8] with reported excellent results in tumor control, clinical and biochemical, survival and minimal morbidity. Results from single institutional clinical trials have shown the technique of HDR brachytherapy monotherapy for prostate cancer is feasible with minimal morbidity [7]. While HDR (Ir-192) and LDR (Pd-103) prostate monotherapy maintained similar biochemical control, the use of HDR brachytherapy as monotherapy was associated with decreased rates of acute urinary frequency, urgency, dysuria and rectal pain compared to LDR. Chronic urinary frequency, urgency and grade 2 rectal toxicities were also decreased with HDR. A dramatic decrease (66%) was noted in the rate of sexual impotency with HDR. In addition, patients treated with HDR did not remain radioactive after treatment. There was a decrease in the cost from not purchasing seeds per patient. HDR monotherapy as prostate cancer treatment resulted in the same biochemical control with much lower toxicity. A recent update of the HDR prostate monotherapy experience at William Beaumont Hospital (WBH) and California Endocurietherapy Center (CET) involves 248 patients treated between July 1993 and December of 2004 and all with a minimum follow up of 6 months. The 171 patients at WBH and 77 patients at CET treated with HDR monotherapy were compared with a group of 206 patients treated at WBH with permanent seeds using Palladium-103. The hypothesis tested for the phase II study was that, due to the radiobiological and physical dose distribution advantages, intensity modulated HDR prostate monotherapy should be less toxic than permanent seed brachytherapy while maintaining similar biochemical control rates. At WBH, a schedule of 9.5 Gy x 4 had a dose equivalence of EBRT of 75.6 Gy (42 fractions of 1.8 Gy) and at CET, the 7 Gy x 6 in two separate implants separated by a week had an equivalent EBRT dose to 76 Gy (38 fractions of 2 Gy). See Tables 1 – 5 and Figures 1 – 2 on pages 6 – 12.
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Table 1. Patient Characteristics According to Treatment Technique Table 1 depicts the patient characteristics of the three sets of patients. The main discrepancy is the length of follow-up since the HDR data began in 1995 as part of a phase II study with slow accrual at the beginning.
HDR Brachytherapy
LDR Brachytherapy
HDR Brachytherapy
WBH
WBH
CET
n=171
n=206
n=77
Mean Age
3.2 years
5.6 years
2.4 years
Mean Gland
64 years
66 years
63 years
Volume
38 cc (15-90)
34 cc (13-88)
38cc (9-134)
# Patients (%)
# Patients (%)
# Patients (%)
T1b-c
121 (71)
122 (59)
47 (61)
T2a
47 (27)
74 (36)
21 (27)
T2b
2 (1)
7 (3)
9 (12)
T2c
1 (1)
3 (2)
--
≤ 3.9
27(16)
39 (19)
14 (18)
4.0-9.9
137 (80)
157 (76)
61 (79)
> 10.0
7 (4)
10 (5)
13 (17)
≤5
5 (3)
37 (18)
14 (18)
6
145 (85)
154 (75)
61 (79)
>7
21 (12)
14 (7)
2 (3)
NAD*
47 (28)
73 (36)
19 (25)
Median follow-up
Clinical Stage
Pre-treatment PSA
Gleason Score
* NAD = Neoadjuvant Androgen Deprivation
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Table 2. Acute Toxicity According to Treatment Technique Table 2 shows the acute toxicity according to treatment technique. As predicted by the radiobiological model, higher toxicity from the LDR treated patients in terms of more dysuria, more frequency and urgency and almost three times the percentage of rectal pain. All were significant at a p 120 days prior to enrollment. 3.2.f Major medical or psychiatric illness which, in the investigator’s opinion, would prevent completion of treatment and would interfere with follow-up. 3.2.g Prior TURP 3.2.h Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the oral cavity or bladder are permissible). 3.2.i I-PSS score >12. 4.0 PRETREATMENT EVALUATIONS 4.1 History and physical (to include tumor measurements) and Zubrod performance status. 4.2 Lymph node evaluation must be performed within 90 days prior to registration by at least one of the following: CT or MRI. 4.3 Cystoscopy, if advised by the urologist, may be performed to check for urethral strictures, bladder pathology, or a large median prostate lobe. 4.4 Prostate specific antigen (PSA) prior to treatment (pre-hormone therapy, if given). 5.0 PATIENT ENROLLMENT PROCEDURES 5.1 Enrollment Requirements 5.1.a HDR Brachytherapy Only institutions that have completed the P-BIG Participant Enrollment Form and received acceptance acknowledgement from the Principle Trial Chairmen may enter patients into this trial. Upon review of the Participant Enrollment Form, the Principle Trial Chairmen will notify each registering institution that the institution is eligible to enroll patients onto this trial. 5.1.b All institutions must create and maintain electronic files of all enrolled patients (patient records, CT/MR series, associated structure sets, and treatment plans) for review by the P-BIG Chairmen at any time. All patient data will be anonymized and sent via ftp server to William Beaumont Hospital. Submission of the first data set should occur within one week of completion of patient treatment and follow-up data should arrive within one week of each assessment. 5.1.c A minimum of 95 patients will be enrolled in the P-BIG trail and each participating institution is required to enroll a minimum of 4 patients and limited to a maximum enrollment of 10 patients. If an institution continues to enroll patients after reaching the 10 patient limit, the additional patients may be compiled and treated as an additional registry trial. 6.0 HIGH DOSE RATE BRACHYTHERAPY 6.1 Brachytherapy 6.1.a The use of US, CT or MR treatment planning is acceptable.
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6.2 Brachytherapy 6.2.a Timing The overall brachytherapy treatment course of four fractions should be limited to no longer than 48 hours. 6.2.b Implant Procedure 6.2.b.1 Afterloading catheters may be placed with TRUS, CT or MR guidance. The implant catheters must be non-metallic for CT/MR guidance or may be metallic or non-metallic for TRUS guidance. The implant procedure may be done under epidural, spinal or general anesthesia. Epidural or patient controlled analgesia (PCA) may be used during the post-op period for pain control. During the implant, attention should be given to keep the catheters in the prostate without perforating the urethra. A Foley catheter should be inserted to allow visualization of the urethra. Posterior rows of catheters may be advanced into the seminal vesicles under TRUS guidance. 6.2.b.2 No fewer than 12 or more than 22 catheters must be in the clinical target volume for adequate coverage without excessive hot spots for a 60 cc gland. 6.2.b.3 Flexible cystoscopy should be done to ensure that no implant catheter is left in the prostate. Evaluation of the depth of insertion should be done by retroflexing the cystoscope 180 degrees in the bladder until the bladder neck is visualized. Advance the tip of the implant catheter until bladder mucosa tenting occurs. Efforts should be made to minimize accidental perforation of the bladder mucosa. 6.2.b.4 To facilitate with the identification of target and normal structures, fiducial marker seeds must be placed under TRUS guidance at the base (1-2 seeds) and the apex of the prostate (1 seed). A 14-16 French Foley catheter should be inserted in the urethra at the beginning of the implant procedure. 6.2.c Brachytherapy Treatment Planning 6.2.c.1 3D TRUS, CT or MR based brachytherapy treatment planning is required. 6.2.c.2 The TRUS treatment planning scan must be performed intraoperatively with the patient in the lithotomy position. This implies that all subsequent patient treatments will be delivered with the patient in the same position. 6.2.c.3 The treatment planning CT/MR scan must be performed with the patient in the supine position with the Foley catheter in place. Metallic obturators or non-CT/MR compatible dummy ribbons must be removed prior to scanning. The scan must include the all of the CTV with at least 9 mm superior and inferior margin, and the scan must include the tips of all the implanted catheters. The scan thickness must be ≤ 0.3 cm and the slices must be contiguous. The brachytherapy target volume and critical structures must be outlined on all imaging slices. 6.2.c.4 Dwell Selection and Dwell Time Optimization. The use of dwell time in dwell positions located outside of the PTV is discouraged to minimize normal tissue irradiation. A dwell time optimization program based on geometric or inverse planning algorithm may be used. Manual optimization is also accepted. 6.2.d Brachytherapy Target Volume 6.2.d.1 The definition of volumes will be in accordance with ICRU Report 58: Dose and Volume Specification for reporting interstitial therapy. [19] The Clinical Target Volume (CTV) is defined by the physician on the treatment planning TRUS, CT or MR scan. For T1cT2a, the brachytherapy CTV includes the prostate only. 6.2.d.2 The brachytherapy Planning Target Volume (PTV) is identical to the CTV.
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6.2.e Critical Structures Critical structures to be contoured include the bladder (not applicable for TRUS), rectum, seminal vesicles and urethra. When contouring the bladder and rectum, the outer most border of the mucosa must be contoured. For the urethra, the outer surface of the Foley catheter must be contoured. Critical structures must be contoured on every TRUS, CT or MR slice that contains a target volume. 6.2.f Dose Specifications The prescription dose of 38 Gy in four fractions will be given only to the CTV (a dose of 9.5 Gy (100% isodose) to prostate volume on CT/MR without expansion and to the SWIFT volume, if applicable. Dose to periphery of the Foley < 120% and dose to anterior rectal wall ≤ 90% and dose to total rectum ≤ 75 % (CT/MR) or ≤ 70% (TRUS). The brachytherapy dose will be prescribed to the periphery of the PTV. The goal is to deliver the prescription dose to at least 90% of the PTV. However, the dose to critical normal structures must be kept within the constraints mentioned above. The volume of bladder and rectum receiving 75% of the prescription dose must be kept to less than 1 cc (V80 rectum and V80 bladder < 1 cc) and the volume of urethra receiving 120% of the prescription dose must be kept to less than 1 cc (V120 urethra < 1 cc). If the dose to critical normal structures cannot be kept below the specified level, we recommend readjusting the needle position in the implant or repeating the implant procedure until a more optimal implant is obtained. 6.2.g Treatment Delivery The first and second HDR treatments will optimally be delivered on the day of the catheter placement. The third and fourth treatments will optimally be delivered within 24 hours after the first and second treatments, but no less than 6 hours between implants. 6.2.h Catheter Position Verification Visual inspection of the catheters prior to delivery of each treatment is required. Fluoroscopy, TRUS or CT/MR may be also used to verify the position of the catheters. The physician may adjust the catheters if catheter displacement is identified prior to the treatment. If the physician feels the catheters cannot be satisfactorily repositioned and cannot be corrected by a new plan, then the treatment should be postponed until a satisfactory implant may be done. If the planning process is repeated, then a second set or consecutive sets must be entered into the patient record. 6.2.i Catheter Removal After completion of the treatment all catheters should be removed. 6.2.j Data Submission All data must be submitted digitally to William Beaumont Hospital within one week of treatment. 6.2.j.1 HDR Treatment plan The overall treatment time, source activity, and dwell times of each fraction delivered should be recorded and submitted electronically to William Beaumont Hospital. 6.2.j.2 Treatment planning TRUS, CT or MR The scan must include the entire prostate. The tips of all the catheters must be included. The patient’s external body contours should not be included in the field of view (FOV) in order to maximize the image quality. The scan should be transmitted in DICOM form to WBH electronically.
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6.2.j.3 Contours and Isodose Distributions Isodose distributions of 70%, 75%, 90%, 100%, 125%, 150%, 200% of the prescription dose (based on the dose specifications described in 6.2.f), with contours of the PTV and critical structures. 6.2.j.4 Dose Volume Histograms The number of sample points used in these calculations should be stated. A minimum of 5,000 points should be sampled for the calculation of each DVH. A post implant data form that describes the volumes, the dose description, and the dose volume histograms of the PTV, rectum, bladder, and urethra will be completed. The post implant data form will be attached to the above material. 6.2.k Compliance Criteria Unacceptable deviation is any dose to bladder, rectum or urethra greater than the prescription guideline. Per Protocol: ≥ 90% of the PTV receives the prescription dose. 6.2.l Brachytherapy Quality Assurance Reviews The principal investigators, Drs. Martinez and Linares, will perform RT Quality Assurance Reviews after complete digital data for the first 20 cases enrolled have been received at WBH. Drs. Martinez and Linares will perform the next review after complete data for the next 20 cases enrolled have been received. The final cases will be reviewed within 3 months after this trial has reached the target accrual or as soon as complete data for all cases enrolled have been received at WBH. These reviews will be ongoing. 6.3 Radiation Toxicity 6.3.a All patients will be seen daily by their radiation oncologist during brachytherapy treatment. Any observations regarding radiation reactions will be recorded and should include attention toward the following potential side effects: 6.3.b Although rare, small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal urgency, proctitis, or hematochezia 6.3.c Bladder complications including urinary frequency, urgency, dysuria, hematuria, urinary tract infection, and incontinence 6.3.d Clinical discretion may be exercised to treat side effects from brachytherapy treatment. Rectal side effects such as diarrhea may be treated with drugs such as diphenoxylate or loperamide or similar drugs. Bladder or rectal spasms can be treated with anticholinergic or tolterodine. Bladder irritation can be managed with phenazopyridine and/or an alpha blocker. Erectile dysfunction can be treated with sildenafil or similar drugs. 6.4 Radiation Adverse Event Reporting 6.4.a Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting Requirements Adverse events (AEs) and serious adverse events (SAEs) will be reported to the Prostate – Brachytherapy International Group (P-BIG) as directed in this section. Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite).
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Definition of an SAE: Any adverse experience occurring at any dose that results in any of the following outcomes: o Death; o A life-threatening adverse experience; o Inpatient hospitalization or prolongation of existing hospitalization; o A persistent or significant disability/incapacity; o A congenital anomaly/birth defect. Important medical events that do not result in death, are not life threatening, or do not require hospitalization may be considered an SAE experience, when, based upon medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition. Note: All deaths on trial require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided. “On trial” is defined as during or within 30 days of completing protocol treatment. Adverse Events (AEs) and Serious Adverse Events (SAEs) that meet the criteria defined above experienced by patients accrued to this protocol must be reported to: P-BIG via WBH;
[email protected]; PHONE: +1 (248) 551-7124. 7.0 DRUG THERAPY Does not apply to this trial 8.0 SURGERY 8.1 Prostate Rebiopsy 8.1.1 A biopsy is suggested for all patients with evidence of biochemical failure or growth of a palpable abnormality. A PSA failure is defined as a consistent and significant rise in the PSA. The Phoenix definition of PSA failure will be used (nadir + 2). [20] 9.0 OTHER THERAPY 9.1 Neoadjuvant androgen suppression (nonsurgical) is permitted for protocol patients if downsizing of the gland is required. The following conditions apply: Must begin ≤ 120 days prior to registration to this trial. PSA prior to hormonal therapy must be available. 9.2 Diphenoxylate, loperamide or similar drugs may be used for diarrhea. 9.3 Tolterodine or anticholinergic drugs may be used to treat bladder or rectal spasms. 9.4 Phenazopyridine and or an alpha blocker may be used to treat bladder irritation. 9.5 Tadalafil (10mg 3x per week), or similar drugs, are recommended one week post implant for a few months and/or to treat erectile dysfunction. 10.0 TISSUE/SPECIMEN SUBMISSION Does not apply to this trial
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11.0 PATIENT ASSESSMENTS 11.1 Trial Parameters Assessments
Pre-Trial Entry
During Brachytherapyd
At 2 weeks from start of treatment, then at 3, 6, 9 and 12 months; then every 6 months x 5 years; annually thereafter.
Yes
Yesd
Yes
History/Physical Exam f
(DRE ) Zubrod Performance Status Status of hormonal therapy (duration of treatment, if given) PSA (Pre-HT, if given) Pelvic CT or MR Bone Scan TRUS Flexible Cystoscopy Prostate Biopsy GI/GU Toxicity Evaluation I-PSS Questionnaire Follow-up Forms
Yes
Yes
Yes
No
Yesa Optional Optional Yes Yesd Yes Yes Yes Yes
Yes Optional Optional Yes Yes Yesc Yes Yes Yes
a. PSA must be done prior to initiation of hormones for patients receiving neoadjuvant hormonal therapy b. Within 90 days prior to registration c. At time of PSA failure, and as indicated d. Per institutional standards e. DRE not required to be done weekly 11.2 Follow-up Schedule 11.2.a Initial follow-up visit at 2 weeks from start of treatment. 11.2.b After initial follow-up visit, follow-up will be done at 3, 6, 9, and 12 months post therapy. 11.2.c Then every six months until five years post-implant. 11.2.d Then annually thereafter. 11.2.e A bone scan is recommended for any patient who presents with complaints of bone pain that cannot be attributed to any intercurrent disease or if the PSA level exceeds 10 ng/ml. Discretionary plain films may be needed to evaluate lesions seen on bone scan to confirm the diagnosis of metastatic disease. 11.3 Measurement of Response 11.3.a PSA values and digital examinations must be recorded on the data collection forms for the initial and follow-up evaluations of the patient.
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11.3.b After trial entry, disease evaluations will be made and recorded using the following criteria: 11.3.b.1 No Evidence of Disease (NED): No clinical evidence of disease on digital rectal examination and no PSA failure. 11.3.b.2 Equivocal Disease (ED): This rating will be assigned under the following circumstances: a) If abnormalities are present on the prostate digital rectal examination but are thought to be abnormal due to treatment and felt not to represent tumor. b) If clinical evidence of residual tumor is present but this has regressed from a previous examination (initial registration). 11.3.b.3 Progressive Disease (PD): Progressive disease will be declared if one or more of the following criteria are met: a) Clinical evidence in the prostate gland of disease progression or recurrence. b) Clinical or radiographic evidence of tumor recurrence within the pelvic lymphatics or soft tissue beneath the bifurcation of the common iliac arteries, c) Clinical or radiographic evidence of hematogenous (osseous, hepatic, etc.) and/or extrapelvic lymphatic of soft tissue relapse. 11.4 Other Response Parameters 11.4.a Disease-Free Interval: The disease-free interval will be measured from the date of accession to the date of documentation of progression or until the date of death (from other causes). 11.4.b Time to Biochemical Failure: PSA failure is defined according to the Phoenix consensus guidelines. The PSA nadir will be defined as the lowest PSA value reached immediately before a biochemical failure. 11.4.c Time to Local Progression: The time to progression will be measured from the date of trial entry to the date of documented local progression as determined by clinical exam. 11.4.d Time to Distant Failure: The time to distant failure will be measured from the date of trial entry to the date of documented regional nodal recurrence or distant disease relapse. Patients with evidence of biochemical failure, but a negative prostate biopsy, will be considered as distant failure only. 11.5 Overall Survival: The survival time will be measured from the date of accession to the date of death. All patients will be followed for survival. Every effort should be made to document the cause of death. 11.5 Disease-Specific Survival: Disease-specific survival will be measured from the date of trial entry to the date of death due to prostate cancer. The following will be considered as failure events in assessing disease specific survival: Death certified as due to prostatic cancer. Death from other causes with active malignancy (clinical or biochemical progression). Death due to complications of treatment, irrespective of the status of malignancy. Death from other causes with previously documented relapse (either clinical or biochemical) but inactive at the time of death will not be considered in disease-specific survival, but will be analyzed separately.
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12.0 DATA COLLECTION Data should be submitted to: Michelle Wallace, RN, BSN, OCN Protocol Nurse Clinician William Beaumont Hospital Department of Radiation Oncology 3601 W. Thirteen Mile Road Royal Oak, MI 48073 (248) 551-7124 (248) 551-9260
[email protected]
[North & South America; Asia Pacific]
Razvan Galelae, MD Associate Professor and Vice Chairman Clinic for Radiotherapy University Hospital Schleswig-Holstein Campus Kiel Arnold-Heller-Str. 9 24105 Kiel, Germany +49 (431) 597-3010 (or 3012) +49 (431) 597-3110 fax
[email protected]
[Europe]
Patients will be identified by initials (first middle last); if there is no middle initial, a hyphen will be used (first-last) and birth date (DDMMYY). Last names with apostrophes will be identified by the first letter of the last name. For John H. Smith BD 24/02/1955 use JHS240255. 12.1 Summary of Data Submission to WBH Item Patient Eligibility Form (PE) Patient Demographic Form (PD) Initial Evaluation Form (IE) Brachtherapy Treatment Form (BT) GI Toxicity Baseline (GI-T) GU Toxicity Baseline (GU-T) Renal Function Baseline (RF) Concomitant Medications Baseline (CM) Prostate Symptom Score Baseline (IPSS) Erectile Function Baseline (IIEF) Brachytherapy Dosimetry Digital Data o HDR treatment plan o Contours and isodose distribution o Color DVH
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Due Within 2 weeks of trial entry
Within 1 week post brachytherapy
Patient Follow-up (PF) GI Toxicity (GI-T) GU Toxicity (GU-T) Renal Function (RF) Concomitant Medications (CM) Prostate Symptom Score (IPSS) Erectile Function (IIEF)
Post brachytherapy follow-up at 2 weeks; every three months for one year with QOL assessments; then every six months x 5 years; annually thereafter
Adverse Event Form (AE)
Post brachytherapy follow-up at 2 weeks and every 3 months for one year, longer if applicable
13.0 STATISTICAL CONSIDERATIONS 13.1 Trial Endpoints 13.1.a Primary Endpoint • Late Grade 3 genitourinary toxicity more than six months from the completion of treatment. 13.1.b Secondary Endpoints • Acute Grade 3 or up to a 5% increase in genitourinary toxicity as per the Phoenix definition. • Freedom from biochemical failure • Overall survival • Disease-specific survival • Clinical progression including local/regional and distant relapse 13.2 Sample Size 13.2.a Overview: The primary goal of this trial is to estimate the rate of late Grade 3 genitourinary toxicity following treatment with high dose rate (HDR) brachytherapy alone. Late toxicity will be defined as toxicity occurring more than six months from the completion of treatment. 13.2.b Sample Size Derivation: The sample size is calculated with type I error of 0.025 and type II error of 0.1, so 67 patients will detect a proportion of patients who do not have late grade 2-5 genitourinary and gastrointestinal toxicity to the treatment of no more than 85%, which is 10% improvement from 70% under the null hypothesis. Adjusting the number of cases for ineligible or unanalyzable cases by 10%, a minimum sample size of 75 patients is required for this study. As the P-BIG is new and will be establishing a track record of compliance and experience working on an International basis, the minimum sample size has been increased to 95 patients for this study. 13.3 Patient Accrual and Trial Duration It is expected that it will take approximately two years to complete the trial. The analysis for late toxicity will be carried out after each patient has had at least 18 months of followup. For the secondary endpoint of biochemical failure, an additional two years of followup are needed to estimate the 3-year failure rate. 13.4 Analysis Plan 13.4.a Interim Reports: Interim reports will be prepared every six months until the last patient has been entered to the trial. In general, the interim reports will contain information about patient accrual rate with projected completion dates of the trial, status of QA review and compliance rate of treatment per protocol, the frequencies and severity of toxicity.
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13.4.b The Analysis of Late Grade 3 Genitourinary Toxicity: This analysis will be carried out when each patient has had at least 18 months of follow-up. The time to the occurrence of late Grade 3 genitourinary toxicity is defined as the time interval from the start of protocol treatment to the date of onset of late Grade 3 genitourinary toxicity. If no such toxicity is observed till the time of the analysis, the patient will be censored at the time of the analysis. 13.4.c Estimation of Secondary Endpoints Related to the Efficacy: Cumulative incidence approach [21] will be used to estimate the failure rate for biochemical, disease-specific, local-regional and distant failures. Kaplan-Meier method [22] will used to estimate the overall survival rate.
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REFERENCES 1. Martinez, A., Gonzalez, J., Stromberg, J., et al., Conformal prostate brachytherapy: initial experience of a phase I/II dose-escalating trial. International Journal of Radiation Oncology, Biology, Physics, 1995. 33(5): p. 1019-27. 2. Martinez, A.A., Kestin, L.L., Stromberg, J.S., et al., Interim report of image-guided conformal high-doserate brachytherapy for patients with unfavorable prostate cancer: The William Beaumont Phase II dose-escalating trial. International Journal of Radiation Oncology Biology Physics, 2000. 47(2): p. 343-352. 3. Martinez, A.A., Pataki, I., Edmundson, G., et al., Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. International Journal of Radiation Oncology Biology Physics, 2001. 49(1): p. 61-69. 4. Stromberg, J.S., Martinez, A.A., Horwitz, E.M., et al., Conformal high dose rate iridium-192 boost brachytherapy in locally advanced prostate cancer: superior prostate-specific antigen response compared with external beam treatment [see comments]. Cancer Journal from Scientific American, 1997. 3(6): p. 346-52. 5. Stromberg, J., Martinez, A., Gonzalez, J., et al., Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a phase I/II clinical trial. International Journal of Radiation Oncology, Biology, Physics, 1995. 33(1): p. 16171. 6. Edmundson, G., Rizzo, N., Teahan, M., Brabbins, D., Vicini, F., Martinez, A., Concurrent Treatment Planning For Outpatient High Dose Rate Prostate Template Implants. Int J Radiation Oncology Biol Phys. 27(5): 1215-1223, 1993. 7. Grills, I., Martinez, A., Hollander, M., Huang, R., Goldman, K., Chen, P. and Gustafson, G., High Dose rate Brachytherapy as Prostate Cancer Monotherapy Reduces Toxicity Compared to Low Dose Rate Palladium Seeds. J Urology. 171: 1098-1104, 2004. 8. Martinez, A., Demanes, J., RTOG Abstract. February 2007. 9. Fu, K.K., Pajak, T.F., Trotti, A., et al., A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003 [see comments]. International Journal of Radiation Oncology, Biology, Physics, 2000. 48(1): p. 7-16. 10. Horiot, J.C., Bontemps, P., van den Bogaert, W., et al., Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial [see comments]. Radiotherapy and Oncology, 1997. 44(2): p. 111-21. 11. Brenner, D. and Hall, E., Fractionation and protraction for radiotherapy of prostate carcinoma. International Journal of Radiation Oncology Biology Physics, 1999. 43(5): p. 1095-1101. 12. King, C.R. and Fowler, J.F., A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. [Comment In: Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):1-3 UI: 21407940]. International Journal of Radiation Oncology, Biology, Physics, 2001. 51(1): p. 213-4. 13. Fowler, J., Chappell, R., and Ritter, M., Is alpha/beta for prostate tumors really low? International Journal of Radiation Oncology, Biology, Physics, 2001. 50(4): p. 1021-31. 14. Brenner, D., Martinez, A.A., Edmundson, G., et al., Direct evidence that prostate tumors show high sensitivity to fractionation (low a/b ratio), similar to late-responding normal tissue. International Journal of Radiation Oncology, Biology, Physics, 2002. 52: p. 6-13.
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15. D'Souza, W.D. and Thames, H.D., Is the alpha/beta ratio for prostate cancer low? [Comment On: Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):213-4 UI: 21407968]. International Journal of Radiation Oncology, Biology, Physics, 2001. 51(1): p. 1-3. 16. Duchesne, G.M. and Peters, L.J., What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-dose-rate brachytherapy [editorial]. International Journal of Radiation Oncology, Biology, Physics, 1999. 44(4): p. 747-8. 17. Fowler, J.F., Chappell, R.J., and Ritter, M.A., The prospects for new treatments for prostate cancer. International Journal of Radiation Oncology, Biology, Physics, 2002. 52: p. 3-5. 18. Fu, K.K., Pajak, T.F., Trotti, A., et al., A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003 [see comments]. Int J Radiat Oncol Biol Phys, 2000. 48(1): p. 7-16. 19. (ICRU Report 58) Dose and volume specification for reporting interstitial therapy. in International Commission on Radiation Units and Measurements. 1997. Bethesda, MD. 20. Roach M., Hanks G., Thames H., Schellhammer P., Shipley W.U., Sokol G.H., Sandler H., Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys, Jul 2006. 65(4): p 965-74. 21. Kalbfleish JD and Prentice RL, The statistical analysis of failure time data, New York, John Wiley & Sons, p. 167-169, 1980. 22. Kaplan, E.L. and Meier, P., Nonparametric estimation from incomplete observations. J. Amer. Statist. Assoc, 1958. 53: p. 457-481.
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APPENDIX I
PHASE II PROSPECTIVE NON-RANDOMIZED TRIAL OF THE USE OF CONFORMAL HIGH DOSE RATE BRACHYTHERAPY ALONE FOR THE TREATMENT OF FAVORABLE STAGE ADENOCARCINOMA OF THE PROSTATE This is a clinical trial. Clinical trials include only patients who choose to take part. Please take your time to make your decision. Discuss it with your friends and family. You are being asked to take part in this trial because you have prostate cancer. WHY IS THIS TRIAL BEING DONE? The purpose of this trial is to test the safety of a high dose rate (HDR) brachytherapy treatment delivered via a temporary implant to see what effect (good and bad) it has on you and your prostate cancer. This research is being done because although the use of brachytherapy for prostate cancer is not new, using a high dose rate monotherapy temporary implant is a treatment which needs more investigation. HOW MANY PEOPLE WILL TAKE PART IN THE TRIAL? A minimum of 95 people worldwide will take part in this trial.
WHAT IS INVOLVED IN THE TRIAL? If you take part in this trial, you will have the following tests and procedures: Work-up
Treatment
Follow-up
Physical Exam PSA Prostate Biopsy TRUS, CT or MR Scan I-PSS Questionnaire QOL Tools
High Dose Rate Brachytherapy
Start of treatment; 2 weeks following treatment; every three months for the first year; then every six months x 5 years; annually thereafter.
4 treatments in 48 hours
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You will be admitted to the hospital for an overnight stay. A temporary implant will be inserted into your prostate and high dose rate (HDR) brachytherapy (radiation therapy) will be given via the implant. This procedure will be done under anesthesia at your institution. Under the guidance of ultrasound, thin catheters will be inserted through the skin between the anus and scrotum into the prostate. After the implant a pelvic Ultrasound, CT or MR scan will be done to identify the location of the catheters, the prostate and normal structures (rectum, bladder, urethra). A typical brachytherapy treatment takes 5-30 minutes. You will receive a total of 4 treatments within a 48 hour period. Each treatment will be given in a treatment room protected with lead walls, like with a regular x-ray. You will not be radioactive while you wait for the treatment in your hospital room. After the last treatment is completed the implant will be removed before you are discharged.
The following procedures are part of regular cancer care and may be done even if you do not join the trial. Procedure Schedule History and Physical Exam Prior to trial entry and at follow-ups Tumor Measurements PSA Blood Test Prostate Biopsy Prior to trial entry Pelvic CT or MRI Scan Cystoscopy (bladder exam) As medically indicated The following standard procedures will be performed because you are in this trial. Procedure Schedule High Dose Rate 4 treatments; 2 per day over 48 hours Brachytherapy Hormonal May be given prior to brachytherapy starting ≤ 120 Therapy days prior to enrollment and during the brachytherapy and possibly for up to 2 years after the radiotherapy as medically indicated.
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Extra procedures being done because you are in this trial: Procedure Schedule TRUS (Transrectal During the implant ultrasound) Cystoscopy (bladder exam) During the implant Pelvic CT or MR Scan Prior to and/or after the implant Prostate Biopsy If the treatment is not successful
HOW LONG WILL I BE IN THE TRIAL? We think you will be in the treatment part of the trial for two days. Follow up visits with your physician will be scheduled for two weeks after you finish treatment, then every three months for one year, then every six months for five more years, and then annually for the rest of your life. The researcher may decide to take you off this trial if it is in your best medical interest, your condition worsens, or new information becomes available and this information suggests the treatment will be ineffective or unsafe for you. You can stop participating at any time. However, if you decide to stop participating in the trial, we encourage you to talk to the researcher and your regular doctor first. WHAT ARE THE RISKS OF THE TRIAL? While on the trial, you are at risk for these side effects. You should discuss these with the researcher and/or your regular doctor. There also may be other side effects that we cannot predict. Drugs may be given to make side effects less serious and uncomfortable. Many side effects go away shortly after the treatment is stopped, but in some cases side effects can be serious or long-lasting or permanent. - 28 -
Risks Associated with Brachytherapy Very Likely Infection that can be treated with antibiotics Soreness in the implant area Temporary fatigue, nausea or diarrhea Abdominal cramps Bladder irritation with some bleeding Impotence (may not be reversible) Urinary tract infection (UTI) Less Likely, But Serious Injury to the bladder, urethra, bowel or other tissues in the pelvis or abdomen Rectal bleeding, intestinal or urinary obstruction, and incontinence (may not be reversible) Serious infection Risks Associated with Anesthesia Less Likely Nausea, vomiting Headache Sore throat Less Likely, But Serious Blood pressure problems Heart rhythm problems Breathing changes Drug reactions Heart attack Stroke Death If you are a man able to father children, the treatment you receive may risk harm to an unborn child unless you use a form of birth control approved by - 29 -
your doctor. The treatment may cause sterility, however, adequate birth control measures must still be used. If you are unwilling to use adequate birth control measures to prevent pregnancy, you should not participate in this trial. If you suspect you have caused anyone to become pregnant while you are on this trial, you must tell your doctor immediately. ARE THERE BENEFITS TO TAKING PART IN THE TRIAL? If you agree to take part in this trial, there may or may not be direct medical benefit to you. We hope the information learned from this trial will benefit other patients with prostate cancer in the future. WHAT OTHER OPTIONS ARE THERE? You may choose to not participate in this trial. Other treatments that could be considered for your condition may include the following: (1) radiation therapy (external beam or Low Dose Rate brachytherapy; (2) hormone therapy; (3) surgery; or (4) no treatment except medications to make you feel better. With the latter choice, your tumor may continue to grow and your disease would spread. These treatments could be given either alone or in combination with each other. Your doctor can tell you more about your condition and the possible benefits of the different available treatments. Another option may be to get the treatment plan described in this trial at this center and other centers even if you do not take part in the trial. Please talk to your regular doctor about these and other options. WHAT ABOUT CONFIDENTIALITY? Efforts will be made to keep your personal information confidential. We cannot guarantee absolute confidentiality. Records of your progress while on the trial will be kept in a confidential form at this institution and in a computer file at the headquarters of the Prostate Brachytherapy International Group (P-BIG) data collection center. Your personal information may be disclosed if required by law. Organizations that may inspect and/or copy your research records for quality assurance and data analysis include the U.S. Food and Drug Administration (FDA), the National Cancer Institute (NCI) or its authorized representatives or any other International organization as required or appropriate. - 30 -
WHAT ARE THE COSTS? Taking part in this trial may lead to added costs to you or your insurance company. Please ask about any expected added costs or insurance problems. In the case of injury or illness resulting from this trial, emergency medical treatment is available but will be provided at the usual charge. No funds have been set aside to compensate you in the event of injury. You or your insurance company/government will be charged for continuing medical care and/or hospitalization. In the U.S., Medicare should be considered a health insurance provider. You will receive no payment for taking part in this trial. WHAT ARE MY RIGHTS AS A PARTICIPANT? Taking part in this trial is voluntary. You may choose not to take part or you may leave the trial at any time. If you choose to stop participating in the trial, you should first discuss this with your doctor. In order to provide important information that may add to the analysis of the trial, he/she may ask your permission to submit follow-up data as it relates to the trial. You may accept or refuse this request. Leaving the trial will not result in any penalty or loss of benefits to which you are entitled. We will tell you about new information that may affect your health, welfare, or willingness to stay in this trial.
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WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? (This section must be completed) For information about your disease and research-related injury, you may contact:
_______________________
________________________
NAME
TELEPHONE NUMBER
For information about this trial, you may contact:
_______________________
________________________
NAME
TELEPHONE NUMBER
SIGNATURES I have read all the above, asked questions, and received answers concerning areas I did not understand. I have had the opportunity to take this consent form home for review or discussion. I willingly give my consent to participate in this program. Upon signing this form I will receive a copy. I may also request a copy of the protocol.
_______________________
________________________
_____________
PATIENT NAME
SIGNATURE
DATE
_______________________
________________________
_____________
NAME OF PERSON OBTAINING CONSENT
SIGNATURE
DATE
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APPENDIX II: ZUBROD PERFORMANCE SCALE
0
Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100).
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work (Karnofsky 70-80).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours (Karnofsky 50-60).
3
Capable of only limited self-care, confined to bed or chair 50% or more of waking hours (Karnofsky 30-40).
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair (Karnofsky 10-20).
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APPENDIX III : AJCC STAGING SYSTEM; PROSTATE, 6th Edition DEFINITION OF TNM Primary Tumor, Clinical (T) TX T0
Primary tumor cannot be assessed No evidence of primary tumor
T1
Clinically unapparent tumor neither palpable nor visible by imaging T1a Tumor incidental histologic finding in 5% or less of tissue resected T1b Tumor incidental histologic finding in more than 5% of tissue resected T1c Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2
Tumor confined with prostate* T2a Tumor involves one-half of one lobe or less T2b Tumor involves more than one-half of one lobe but not both lobes T2c Tumor involves both lobes
T3
Tumor extends through prostate capsule** T3a Extracapsular extension (unilateral or bilateral) T3b Tumor involves the seminal vesicle(s)
T4
Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles and/or pelvic wall
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c **Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3, but as T2. Regional Lymph Nodes (N) NX N0 N1
Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in regional lymph node(s)
Primary Tumor, Pathologic (pT) pT2* pT2a pT2b pT2c pT3 pT3a pT3b pT4
Organ confined Unilateral, involving one-half of one lobe or less Unilateral, involving more than one-half of one lobe but not both lobes Bilateral disease Extraprostatic extension Extraprostatic extension** Seminal vesicle invasion Invasion of bladder, rectum
*Note: There is no pathologic T1 classification **Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).
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APPENDIX III (continued): AJCC STAGING SYSTEM; PROSTATE, 6th Edition
Distant Metastasis (M)* MX M0 M1
Presence of distant metastasis cannot be assessed (not evaluated by any modality) No distant metastasis Distant metastasis M1a Nonregional lymph node(s) M1b Bone(s) M1c Other site(s) with or without bone disease
*Note: When more than one site of metastasis is present, the most advanced category is used; pM1c is most advanced. Histopathologic Grade (G) GX G1 G2 G3-4
Grade cannot be assessed Well-differentiated (slight anaplasia [Gleason 2-4]) Moderately differentiated (moderate anaplasia [Gleason 5-6]) Poorly undifferentiated or undifferentiated (marked anaplasia [Gleason 7-10])
Stage Grouping Stage I
T1a
N0
M0
G1
Stage II
T1a T1b T1c T1 T2
N0 N0 N0 N0 N0
M0 M0 M0 M0 M0
G2, G3-4 Any G Any G Any G Any G
Stage III
T3
N0
M0
Any G
Stage IV
T4 Any T Any T
N0 N1 Any N
M0 M0 M1
Any G Any G Any G
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APPENDIX IV: GLEASON CLASSIFICATION Histologic patterns of adenocarcinoma of the prostate Pattern 1
Margins Tumor Areas Well defined
Gland Pattern Single, separate, round Single, separate rounded but more variable
Gland Size Medium
Gland Distribution Closely packed
Stromal Invasion Minimal, expansile
2
Less definite
Medium
Spaced up to one gland diameter, average
Mild, in larger stromal planes
3
Poorly defined
Single, separate more irregular
Small medium, or large
Spaced more than one gland diameter, rarely packed Rounded masses with smooth sharp edges
Moderate, in larger or smaller stromal planes
or 3
Poorly defined
Rounded masses of Medium cribriform or papillary or large epithelium
4
Ragged, infiltrating
Small
Fused in ragged masses
Marked, through smaller planes
5
Ragged, infiltrating
Fused glandular masses or "hypernephroid" Almost absent, few tiny glands or signet ring
Small
Ragged anaplastic masses of epithelium
Severe between stromal fibers or destructive
or 5
Poorly defined
Few small lumina in rounded masses of solid epithelium central necrosis
Small
Rounded masses and cords with smooth sharp edges
Expansile masses
Expansile masses
The Gleason Classification is a system of histologic grading based on over-all pattern of tumor growth at relatively low-magnification (40 to100x). Five patterns of growth are recognized and numbered in order of increasing malignancy. Because of histologic variation in the tumor, two patterns are recorded for each case, a primary or predominant pattern and a secondary or lesser pattern. The Gleason Score is the sum of the primary and secondary pattern, If only one pattern is present, the primary and secondary pattern receive the same designation. (Primary = 2, Secondary = 1, Gleason = 3) (Primary = 2. Secondary = 2, Gleason = 4) 1. Gleason, D.F. et al: Prediction of prognosis for prostatic carcinoma by combined histologic grading and clinical staging. J Urol 111:58, 1974.
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