Men with early-stage prostate cancer were more likely to participate in a clinical trial comparing radical prostatectomy and brachytherapy when specialists representing both treatment modalities presented patients with balanced information about the two options. That was the conclusion of a study by researchers from Princess Margaret Hospital in Toronto. The study was published in the September 1 issue of the Journal of Clinical Oncology (2006;24:4158–4162).
The Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT) was designed to study the efficacy and quality of life following radical prostatectomy and brachytherapy. After the initial accrual period proved disappointing, researchers developed a small-group, educational session to better explain the rationale for the trial to patients. Patients were more likely to consent to random assignment once they better understood, and thus became more comfortable with, both treatment modalities.
“It can take considerable effort to educate patients about the issues regarding specific clinical trials, but the effort does pay off in terms of accrual,” said the primary investigator, Juanita Crook, MD, Professor of Radiation Oncology.
Overall Message: Intervene Early
“The overall message from this trial is to intervene early if patient accrual appears to be wavering,” commented Al B. Benson, III, MD, Professor of Medicine and Associate Director for Clinical Investigations at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, whose 1991 Illinois Cancer Center study entitled “Oncologists' Reluctance to Accrue Patients onto Clinical Trials” was cited in Dr. Crook's article and who was asked his opinion of the study for this article.
“For multidisciplinary trials, it may be very important that representatives from each discipline discuss options with the patient, but in a way that is consistent across the disciplines whenever possible,” he continued.
“It was impressive that the study team could bring people together to provide this level of education for patients. Unfortunately, this is not practical for the bulk of clinical trials. However, this type of approach may give us insight as to the design of alternative education materials that may help both physicians and patients better understand a particular trial and improve the willingness to participate.”
Factors Affecting Decision-Making
Dr. Crook noted that patients with curable disease are less likely to join a clinical trial because treatment options are readily available. Typically it is only when standard modalities have been exhausted that patients are willing to join an experimental study.
Numerous variables, however, may play a role in a patient's decision-making process.
“The physician's attitude, a patient's personal experiences with relatives or friends who have had treatment x, y, or z, and exposure to sources of lay information are all very important factors,” Dr. Crook explained.
This latter variable was especially troubling to researchers. “The influence that information of dubious authenticity or veracity—i.e., the Internet, lay press—had on patients' decisions was disturbing.”
Another expert asked for his opinion, Peter Ellis, MD, a staff medical oncologist at the Juravinski Cancer Center and Associate Professor in the Departments of Oncology and Clinical Epidemiology & Biostatistics at McMaster University in Ontario, noted that there are a variety of reasons physicians may be reluctant to participate in clinical trials.
“A physician needs to be convinced that a randomized trial is ethically sound before asking a patient to take part. Going into the trial, the treatment under investigation should be considered as good as, or possibly better than, the standard treatment. If a physician is not convinced about trials in general, does not feel that a specific trial is asking a valid or important question, or believes they know the best treatment option for an individual patient, they are unlikely to offer a trial, or may do so in a way that suggests they do not strongly endorse it.”
Dr. Crook and her colleagues (first author was Kris Wallace, a postdoctoral fellow) cited two of Dr. Ellis's studies regarding patient accrual to clinical trials, one of which dealt with the difficulty of enrolling patients in breast cancer clinical trials.
“I previously surveyed medical and radiation oncologists plus surgeons involved in the treatment of breast cancer in Australia,” Dr. Ellis said. “Some of the reluctance to participate was logistical—for example, not having resources—but some of the reluctance was discomfort with clinical trials.”
“Offering a patient the option of participating in a clinical trial makes explicit the fact that a physician is not certain about the best treatment option for an individual patient.”
Dr. Benson noted that most randomized clinical trials, of course, compare a standard treatment versus an experimental treatment that has shown some degree of promise. “It is unknown whether one regimen is indeed superior to another. It is that uncertainty that may hinder physician participation in a trial.”
A patient, on the other hand, may fear that an experimental treatment regimen will prove inferior to standard therapy, and thus refuse to participate in a clinical trial.
“Unfortunately, even though the Illinois Cancer Center evaluation was published in 1991, many of the same barriers are present with us today,” he continued.
“We still have approximately less than three percent of all eligible cancer patients entering clinical trials. This older study also showed that across disciplines there may be differences in the willingness to treat patients on a clinical trial. Therefore, having the disciplines work closely together—as was done in this prostate trial—is an important concept.”
SPIRIT was launched in 2002 at the Princess Margaret Hospital and would eventually open in 31 centers across North America.
Patients were deemed eligible if they had a Gleason score of 6 or less, a prostate-specific antigen (PSA) level of 10.0 ng/mL or less, a prostrate transrectal ultrasound (TRUS) volume of 60 cc or less, and had a biopsy within the previous 120 days.
The clinical research associate who screened all candidates met individually with each eligible patient and presented them with a 25-minute Informed Consent Video, developed by the American College of Surgeons Oncology Group.
Afterwards, a radiation oncologist and/or urologist spoke directly to each patient regarding the trial's rationale. In this first attempt to educate patients about the trial, 27 men viewed the video and spoke with a specialist, but none consented to random assignment.
The researchers then devised a second step. This time, eligible patients were invited to attend a 90-minute meeting and advised to bring a companion. Dr. Crook explained that this tactic encouraged further discussion and helped patients assimilate and better understand the information.
A maximum of 10 patients attended each session and chairs were arranged in a semi-circle to encourage interactive dialogue. After viewing the Informed Consent Video, the group was introduced to a prostate cancer survivor who spoke about his experience of participating in a clinical trial.
Specialists Speak as One
Next, a radiation oncologist and urologist jointly addressed each group and presented a PowerPoint talk comparing and contrasting radical prostatectomy to brachytherapy.
“The joint educational session was necessary because our separate efforts were not perceived by patients as delivering the same message,” Dr. Crook explained.
“The involved specialists knew very well what message they wanted to communicate to patients and we knew that we had to communicate this at the same time during the same session. This helps to minimize misinterpretation of what one specialist has said compared with the other. Also, questions could be fielded together and answered jointly so that the response was clear for the patient and other group members.”
This joint presentation format was also necessary to prevent bias from negatively affecting accrual. In the first iteration of the patient education sessions, the urologist and radiation oncologist may have inadvertently expressed bias towards his or her particular treatment modality, a factor that may have confused patients, Dr. Crook said.
“If a physician thinks he or she already knows the answer to the question posed by a clinical trial, that attitude will be communicated to the patient and affect the decision about whether to participate. The SPIRIT educational sessions overcame this, because it involved both urologists and radiation oncologists openly admitting that they did not know if one treatment was better than the other for any given individual. We believed the two treatments to be equally effective in the population of patients being studied.”
In order to participate in the trial, patients had to agree to be randomized to either treatment modality. The joint educational presentation fostered a more objective environment, helping to reduce the confusion and anxiety patients may have experienced regarding their treatment options, she said.
The cooperative PowerPoint presentation focused on frequently asked questions regarding the operative procedure and recovery, urinary and erectile function, PSA response, and salvage therapy. Enrollment in SPIRIT was dependent on a patient being suitable for both surgery and brachytherapy.
By April 2004, 263 patients had attended 47 education sessions, resulting in 34 consents and 32 random assignments. Forty-five session attendees were assessed as unsuitable for SPIRIT because of voiding dysfunction or medical comorbidities and 15 patients were still undecided about participating by the time the study closed.
Of the 203 patients who were suitable for SPIRIT, 170 declined to participate—62 chose surgery, 94 chose brachytherapy, three chose external radiotherapy, and 11 opted for watchful waiting. The consent rate for eligible and suitable patients was one in six.
In May 2003, a questionnaire was introduced for patients to evaluate the education sessions—182 questionnaires were completed from 27 educational sessions. Seventy-nine percent of patients strongly agreed that their understanding of prostate cancer and their treatment options had improved.
Once SPIRIT had concluded, the clinical research associate contacted 190 session attendees to assess their satisfaction with the form of treatment they chose. Thirty-four of these patients participated in SPIRIT, 62 had radical prostatectomy, and 94 underwent brachytherapy. Treatment satisfaction was very high in all three groups with 94% of SPIRIT participants saying they would recommend their form of treatment to a friend.
There was no significant difference among all three groups in terms of demographic characteristics (i.e., urban residence, educational level, and marital status). Of the randomly assigned patients, 82% were city dwellers, 85% were married, and 79% had a postsecondary education.
Providing Information: Beneficial or Detrimental?
The paper by Dr. Crook and her coauthors cited two studies regarding the issue of patient education and the effect on clinical trial enrollment. In the first study, conducted in 1995 by Hilary A. Llewellyn-Thomas, PhD, patients with greater knowledge of a clinical trial were less likely to participate. In the second study, conducted by Dr. Ellis in 2000, patients with more knowledge about a clinical trial were more likely to participate.
Furthermore, Dr. Ellis evaluated whether providing patients with general information about clinical trials would affect their decision to enroll in a clinical study.
“We found this had little impact on their willingness to consider trial entry,” Dr. Ellis said. “The results of [Dr. Crook's] research suggests that trial-specific information, provided in advance of a consultation, may improve patients' willingness to consent to trial participation.”
Effect of Demographics on Accrual
There is still no general consensus about whether demographic characteristics such as socioeconomic status and gender affect a patient's willingness to participate in a clinical trial, Dr. Crook said.
“This is controversial. Typical factors cited include age, gender, and education level, but these factors do not always act consistently. However, these factors may determine whether a patient is a passive or proactive participant in their treatment process. Although a passive patient may more easily agree to a clinical trial, a pro-active patient may also agree to participate once he or she has a thorough appreciation of the issues.”
Despite the improvement in patient enrollment, SPIRIT did not meet accrual expectations and was closed in April 2004. Dr. Crook noted, however, that two other trials employed similar patient education sessions to facilitate enrollment.
“A center in the US and a center in Canada started to use the same approach just prior to the closure of SPIRIT and demonstrated that accrual was improved,” she said.
“I would recommend a similar approach for any future trials where different modalities of treatment are being compared, involving different specialties, or where patients may have access to a lot of controversial information that may prejudice their decision.”
“If institutions are experiencing difficulty in recruiting patients to a clinical trial, they should reexamine the processes by which patients are informed about treatment options included in the clinical trial,” Dr. Ellis added. “There is always an element of uncertainty associated with a clinical trial. However, patients may benefit from closer adherence to protocol therapy and closer follow-up on a clinical trial.”
There is no one answer for increasing patient accrual to a given trial, Dr. Benson said. “It is important to evaluate potential barriers to a specific trial and investigate alternative methods—including education efforts—to improve accrual.”
FDA Approves Two Oral Formulations of Oxymorphone
The Food and Drug Administration has approved extended-release and immediate-release formulations of oxymorphone for pain—Opana ER and Opana.
This is the first time oxymorphone will be available in an oral, extended-release formulation, noted a news release from Endo Pharmaceuticals Inc., the maker of the newly approved treatments.
The trials included the first two Phase III, placebo-controlled, double-blind studies of an oral opioid administered for 12 weeks to patients with chronic moderate-to-severe low back pain. One study included opioid-naïve patients, while the other enrolled opioid-experienced patients.
In both studies, patients treated with Opana ER experienced a significant reduction in average pain intensity compared with placebo. After titration, the same dose of the drug effectively maintained pain level over the course of the study.
Opana ER also has been studied in osteoarthritis pain and cancer pain. In clinical trials, the most common adverse drug reactions were nausea, constipation, dizziness, vomiting, pruritus, somnolence, headache, increased sweating, and sedation.
A study of immediate-release Opana in patients with moderate-to-severe pain following abdominal surgery showed a significant decrease in time to discontinuation for any reason in patients taking Opana, compared with placebo.
The most common adverse drug reactions reported in clinical trials of Opana were nausea and pyrexia.