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Accrual issues in genitourinary cancer clinical trials
Urologic Oncology: Seminars and Original Investigations 24 (2006) 379 –383
News and topics
Accrual issues in genitourinary cancer clinical trials夡 Introduction As a result of recent advances in the understanding of tumor biology in genitourinary cancers, coupled with the remarkable development in technology and informatics, new therapies for prostate, bladder, and renal cell cancers are being developed at an enhanced pace. These new treatments require testing for safety and efficacy through welldesigned clinical trials before approval by the U.S. Food and Drug Administration. Unfortunately, less than 3% of adult patients with cancer in the United States participate in National Cancer Institute-sponsored clinical trials annually, a rate that has not improved in more than 2 decades [1,2]. This rate is in contrast to pediatric oncology, in which the standard of care is enrollment of patients into peer-reviewed, cooperative group clinical trials, resulting in an accession rate exceeding 60% [3–5]. Low accrual rates result in prolongation of trial duration and/or leading to early closure of important studies, delaying drug development, and, subsequently, patient access to potentially active new agents [6,7]. Therefore, if prevention and treatment of genitourinary cancers are to progress at a more rapid rate, it is critical that barriers to patient accrual be identified to ensure timely trial completion. This article will attempt to present our views on why accrual to many genitourinary trials is slow. It also asks a germane question: Is it incumbent upon members of the Society of Urologic Oncology (SUO), who are leaders of the urologic oncology community, to undertake steps addressing the problems of accruing patients to clinical trials? Our view is that it is. As a disclaimer, please note that both authors are members of clinical trial groups and so are as guilty as others in not having solved this problem. The importance of clinical trials in advancing therapy for urologic cancer is well recognized. The federal commitment is evidenced through support of large, interactive clinical trial groups (principally cooperative groups), funding for translational research initiatives (most notably through the Special Program of Research Excellence process), and continued funding for prostate clinical trials through the De-
夡
This work was supported by R21 CA02501 (P.N.L.), American Cancer Society CRTG 0019701CCE (P.N.L.), NO1CM17101. 1078-1439/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2005.11.037
partment of Defense, among others. Importantly, the recent Lansdowne meeting specifically brought up the issue of how clinical trial accrual could be improved. Because the government commitment is so well established, there will be a tendency to leave accrual issues to the funded cooperative groups. Clearly, this is not the answer. With its high profile, the SUO can provide input and solutions to the accrual issue. In a prospective study of patient accrual patterns in cancer clinical trials by our group, fear of insurance denial appeared to be a concern to patients considering trial participation. Despite the fact that only 8% of the patients did not participate because of denial of coverage by third party payers, patients with nongovernmental insurance were statistically less likely to participate than those with government insurance [8]. The hypothesis generated is that patients with private insurance have a perception that their third party payer for clinical trial participation may not adequately cover them. However, it is clear that insurance coverage is but one of many potential barriers to genitourinary cancer accrual. Barriers to accrual can be classified into 4 broad groups: (1) physician barriers, (2) protocol or eligibility barriers, (3) patient barriers, and (4) funding barriers. In our view, the issue of physician barriers has not been appropriately addressed by recent studies and is a focus of this article. We do note that all these barriers are potentially modifiable in that efforts can be made by study investigators to reduce the influence of these barriers on accrual. In an effort to understand these and other potential barriers to accrual, we will examine recent examples of genitourinary cancer trials that have struggled with accrual difficulties and propose, where possible, potential solutions for similar trials. Clinical trial examples Radiation Therapy Oncology Group (RTOG) P-0014. A phase III randomized study of patients with high-risk, hormone-naïve prostate cancer: Androgen blockade with 4 cycles of immediate chemotherapy versus androgen blockade with delayed chemotherapy This trial aimed to compare the survival of patients with high-risk hormone-naïve prostate cancer treated with andro-
380
P.N. Lara, R. de Vere White / Urologic Oncology: Seminars and Original Investigations 24 (2006) 379 –383
gen blockade with concurrent chemotherapy versus delayed chemotherapy. Designed as an intergroup trial coordinated by the RTOG with participation from the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B, and Eastern Cooperative Oncology Group (through the National Cancer Institute-directed Clinical Trials Support Unit), this trial was designed to accrue approximately 1050 patients over 4 years. Instead, the study closed with only 26 patients enrolled in the 2 years it was open. As originally written, the RTOG P-0014 trial was looking for patients with prostate cancer who had: (1) local treatments fail, such as surgery and/or radiotherapy and/or brachytherapy, as defined by an increasing prostate-specific antigen level of at least 2.0 ng/mL (confirmed by 2 measurements at least 2 weeks apart) and a doubling time of ⱕ32 weeks; (2) no clinical or radiographic evidence of disease; and (3) an original Gleason score of at least 7, or 6, with capsular penetration or positive seminal vesicles or lymph nodes. Patients in the chemotherapy containing arm were allowed to receive any 1 of at least 6 different regimens previously used in hormone refractory disease; in essence, this represented a “dealer’s choice” arm. In addition, alternative chemotherapy regimens with sufficient phase II activity in prostate cancer were allowed as long as the protocol chair approved. This “dealer’s choice” design was thought initially to be a suitable strategy to attract a broad group of oncologists to enroll their patients into the study. Instead, the trial was met with decidedly lukewarm response from the cancer community, manifest by its very sluggish accrual. Could this reception have been a result of a backlash toward the liberalism in the choice of chemotherapy regimens offered in the experimental arm, which could potentially have been simplified with a single regimen, such as single agent docetaxel? Alternatively, one can hypothesize that the trial ultimately failed because at the time it was activated, there was no 1 chemotherapy regimen that had yet been shown to improve survival outcomes in refractory disease, therefore, the reluctance of the community to believe that chemotherapy use during earlier stage prostate cancer would be of any palpable benefit. To this day, it is unclear what specific issues plagued this study’s accrual difficulties. SWOG 8710/Intergroup 0080: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer This intergroup trial aimed to compare the survival among patients with stage T2–T4a bladder cancer treated with cystectomy alone versus those treated with 3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), followed by radical cystectomy [9]. A secondary objective was to quantify the effect of neoadjuvant M-VAC on the stage of the tumor. Patients were enrolled if they had muscle-invasive bladder cancer (stage T2–T4a) and were to be treated with radical cystectomy.
This trial took 11 long years (from August 1987 to July 1998) to accrue 317 patients with transitional cell carcinoma of the bladder. This prolonged accrual period occurred despite intergroup participation (SWOG, the Eastern Cooperative Oncology Group, and the Cancer and Leukemia Group B). As reported in the New England Journal of Medicine, survival was superior in the neoadjuvant chemotherapy arm (median survival time of 77 vs. 46 months, P ⬍0.05 1-sided). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38% vs. 15%, P ⬍ 0.001). Had this trial not remained open despite pressures to close it because of exceedingly slow accrual, its positive results, which ultimately changed the way patients with locally advanced bladder cancer are treated, would not have been evident. Fortunately, the study investigators persisted with a determination to complete the study. The difficulties encountered in this trial were actually anticipated. At protocol activation, many urologists viewed neoadjuvant chemotherapy, particularly the notoriously toxic M-VAC, with skepticism and disdain. At that point, a radical cystectomy was a well-established standard of care despite its suboptimal outcomes in the majority of patients. Furthermore, the experimental arm was considered radically different from the control arm, similar to the perceptions that first met the original breast cancer lumpectomy versus mastectomy trials. It is likely that this radical difference between the arms promoted the general reluctance toward the randomization process. SWOG 9921: Hormone therapy with or without mitoxantrone and prednisone in treating patients who have undergone radical prostatectomy for prostate cancer This intergroup trial, currently accruing through the Clinical Trials Support Unit, takes patients with prostate cancer who have undergone radical prostatectomy and are found to have pathologic features consistent with high-risk disease, randomly assigning them to 1 of 2 groups. One group receives an injection of goserelin once every 3 months and bicalutamide by mouth once a day for 2 years, while the other group receives goserelin and bicalutamide for 2 years plus an infusion of mitoxantrone on day 1 and prednisone by mouth twice a day for 3 weeks, repeated every 3 weeks for 6 courses. This trial was designed to accrue approximately 1360 patients. Early in its life, this protocol was in danger of early closure because of slow accrual. Of the reasons for the reluctance to enroll patients into this adjuvant trial was the selection of mitoxantrone-prednisone as the chemotherapy regimen in the experimental arm. At this trial’s activation, mitoxantrone-prednisone had principally shown palliative benefits in the hormone refractory setting, but it did not prolong life as compared to corticosteroids alone, partly because of allowance for crossover. Many believed that
P.N. Lara, R. de Vere White / Urologic Oncology: Seminars and Original Investigations 24 (2006) 379 –383
such a regimen would not be effective enough in the adjuvant setting. In addition, some were concerned about the lack of an observation arm in the study, inclusion of which would have represented a more scientifically “pure” design. However, it was argued that accrual to a study that randomizes high-risk patients to a no-treatment arm would be unacceptable to many patients with prostate cancer. Only after extensive efforts to generate interest in the protocol, including engagement of marketing specialists who developed supporting tools, such as informational pamphlets, compact discs, and videos, and directed a mass electronic mailing effort by the investigators, did this trial finally get into a reasonable accrual stride. As of April 2005, S9921 has accrued 656 patients, averaging 15–20 registrations per month. This reflects a 3-fold increase from the monthly accrual rate experienced by this trial early in its life. The experience from this trial shows that a commitment to trial completion as manifested by the infusion of resources to market appropriately the concept to the oncologic community can be effective in increasing patient accrual. Nevertheless, this trial is still far from being completed, and marketing efforts need to continue to ensure its survival. SWOG 8949: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal cell cancer This trial randomly assigned patients with metastatic renal cell cancer who were acceptable candidates for nephrectomy to undergo radical nephrectomy followed by therapy with interferon alfa-2b or to receive interferon alfa-2b therapy alone [10]. As reported in the New England Journal of Medicine, patients undergoing radical nephrectomy had better overall survival as compared to those who received interferon alone (11.1 vs. 8 months, P ⫽ 0.05). The positive results of this trial influenced the approach to many patients with metastatic renal cell cancer. Unfortunately, this trial took an unexpectedly long journey to completion, requiring more than 7 years to accrue 241 eligible patients. This result contrasts to the recent rapid completion of accrual to a randomized trial of Sorafenib (Bayer/Onyx, West Haven, CT, and Emeryville, CA) versus placebo in metastatic renal cell cancer; that phase III trial accrued more than 800 patients in less than 2 years. What plagued the accrual to S8949, and what lessons were learned from this experience? Similar to S8710, this trial was difficult to conduct because of a marked therapeutic difference between the arms because half the patients had to undergo radical surgery. Only dogged persistence by the investigators to keep the trial open despite the slow accrual led to its completion years after activation. In this case, a core group of investigators kept the momentum going, thereby providing the “inspiration” to others to consider enrolling their patients.
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Discussion How then can SUO members address problems with cancer clinical trial accrual? The easiest answer is to ensure that ongoing trials get completed quickly. This means placing patients with genitourinary cancers on clinical trials whenever possible. SUO members must commit to doing so, and, by their example, encourage others to do so. While others are studying barriers to recruiting patients to clinical trials, perhaps we should ask what the barriers are for physicians, specifically SUO members, in entering patients into such trials. This process necessitates a change in culture for many physicians, one that mimics pediatric oncology, in which clinical trial accrual is considered the top priority. For physicians in institutions with sparse clinical trial support, such as adequate data management and research nurses, we believe that the major barrier is time. Many have called it the “hassle factor.” In addition, lack of training on the day-to-day conduct of clinical trials as well as the burdens of increasingly more complex regulatory requirements emerge as important barriers, all compounded by the enormous expense of performing these trials. An added disadvantage is that these physicians often are not members of clinical trial groups, resulting in a lack of “ownership” of the trials. Finally, some believe that their job is to provide their patients the best available standard of care, believing it is up to academicians to perform the trials that will determine the new treatment standards. These are issues that are most difficult to tackle, more so overcome, and, in many ways, beyond the ability of SUO members to address. In contrast, SUO members who are already working in an environment supportive of the clinical trials process would theoretically have less of these challenges. We know that many of these physicians are, or can be, active members of clinical trial groups. So, the issue of not taking ownership of trials becomes less valid. In this situation, what are the real issues? First, there is the problem of timeliness in getting trials started in cooperative groups. Sometimes, this period may often be 2–3 or even more years. Thus, by the time the trial opens, enthusiasm may have waned, and those who were most passionate about the trial may have become frustrated and either started their own institutional study or have moved on to other questions of interest. Therefore, when the cooperative group trial eventually opens, interest and accrual decline in tandem. Those who make the effort to attend group meetings have good intentions, are willing to help, and do not wish to be seen as obstructionists. Therefore, it is likely that many tend to view these trials, and their willingness and ability to accrue patients through “rose-tinted” glasses. Regrettably, on returning home, the truth is somewhat different. An example is a trial comparing radiation therapy to radical prostatectomy, which closed with 4 patients accrued over 18 months (S8890). Was any trial discussed more before initiation? We almost certainly doubt it.
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Then there is SWOG 8710, already briefly discussed previously. This trial took 16 years to complete from start to publication. It is a positive trial, yet many say its findings are invalid, quoting stage migration, change in methods of statistical analysis, and, finally, that the chemotherapy used now is better than that used in 8710. If the participants in the clinical trial groups had each placed 1 patient in this study, all these time-related problems would have been avoided pretty quickly. However, after the trial was completed, all agreed that in those patients receiving the 3 cycles of M-VAC before their cystectomy there was a 38% pT0 rate at cystectomy. This rate in an M.D. Anderson trial of neoadjuvant chemotherapy was 40% [11]. All agreed that these patients enjoyed a 75% to 80% 5-year survival, while for the patients after chemotherapy with positive lymph nodes, this figure was 12%. SWOG investigators as a group decided to build on these results in S0219, a phase II trial of neoadjuvant gemcitabine, carboplatin, and paclitaxel in T2–T4 bladder cancer, with the goal of collecting tissue before and after chemotherapy for correlative studies. This was in an effort to identify molecular markers that would predict response to chemotherapy. The only difference between this trial and S8710 was that after chemotherapy and before cystectomy, patients would undergo a restaging transurethral resection of bladder tumor. These questions do not seem very controversial, and they do seem to offer great benefit, yet it took almost 3 years to get this trial started. The trial opened in 2003, requiring only 99 patients to complete. Yet, nearly 2 years later, only 27 patients have been accrued. Why is this occurring? When queried, investigator replies have ranged from “I would love to do it but have competing trials” to “I don’t believe 8710” to “we believe our own chemotherapy regimen is better than what is being used in this trial.” It seems the real issue is that some physicians are worried that if they commit to this trial, it will take years to perform. Unfortunately, such anxiety will translate into slow development of newer and more effective systemic therapy. This is obviously a valid concern. The answer, of course, is that if each SUO member placed just 1 patient on the S0219 trial, it would be completed within 18 months. There is then the problem of nonadherence to trials. In S8710, there was a protocol-defined lymph node dissection. All those participating in the trial agreed that at cystectomy, they would fulfill this dissection. One must remember that the surgeons participating in this study, both because of oncologic fellowship training and because they took the trouble to join the clinical trials group, should be considered in the upper quartile of urologic oncologists. Therefore, it is somewhat surprising that in only 54% of the operations did the patients actually undergo the node dissection that their surgeon had agreed to [12]. When one reads the report detailing this result, it is clear that those patients who did not undergo the full node dissection did not get the full benefit of the trial and had a higher cancer mortality.
We have focused on S8710 because it was a landmark study. Completion of this trial in a timely manner would have been of great benefit to patients with bladder cancer. Had there been rapid completion, there would not have been the arguments about stage migration, the same statistical methods would have been used, and, even more importantly, the subsequent questions could have been addressed, and we could have focused on trying to improve the chemotherapy regime. So, our question is: Do we as a group use our position in urologic oncology to help address the issue of placing patients on trials that we as group collectively say are important with the view of getting these trials completed rapidly? This is probably the single biggest contribution the SUO could make to furthering and improving the treatment of patients with urologic cancers.
Conclusions The examples discussed previously illustrate the complexities that swirl around genitourinary cancer clinical trial accrual. These issues are not confined to North American cooperative groups and are also being experienced by investigators in other countries, such as the European Union. Thus, solutions must be made as universally applicable as possible. Some of the examples illustrated previously show that given the proper motivation, clinical trial groups can overcome some of the most formidable barriers to accrual with persistence and creativity. No progress can be made in genitourinary cancer therapeutics unless the appropriately designed clinical trials are conducted and completed. It is the responsibility of every physician taking care of these patients to consider always a cancer trial as a therapeutic option. Primo N. Lara, Jr., M.D. Ralph de Vere White, M.D. The University of California Davis Cancer Center Sacramento, CA, USA
References [1] Kaluzny A, Brawley O, Garson-Angert D, et al. Assuring access to state-of-the-art care for U.S. minority populations: The first 2 years of Minority-Based Community Clinical Oncology Program. J Natl Cancer Inst 1993;85:1945–50. [2] Tejeda HA, Green SB, Trimble EL, et al. Representation of AfricanAmericans, Hispanics, and whites in National Cancer Institute treatment trials. J Natl Cancer Inst 1996;88:812– 6. [3] National Children’s Cancer Foundation Web site. Childhood cancer facts. Available at: http://www.nccf.org/. Accessed April 12, 2005. [4] Kolata G, Eichewald K. In pediatrics, a lesson in making use of experimental procedures. The New York Times (Sunday). October 3, 1999. [5] Sateren WB, Trimble EL, Abrams J, et al. How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 2002;20:2109 –17.
P.N. Lara, R. de Vere White / Urologic Oncology: Seminars and Original Investigations 24 (2006) 379 –383 [6] Ehrlich PF, Newman KD, Haase GM, et al. Lessons learned from a failed multi-institutional randomized controlled study. J Pediatr Surg 2002;37:431– 6. [7] Haidich AB, Ioannidis JP. Effect of early patient enrollment on the time to completion and publication of randomized controlled trials. Am J Epidemiol 2001;154:873– 80. [8] Lara PN Jr, Higdon R, Lim N, et al. Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment. J Clin Oncol 2001;19:1728 –33. [9] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859 – 66.
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[10] Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345: 1655–9. [11] Millikan R, Dinney C, Swanson D, et al. Integrated therapy for locally advanced bladder cancer: Final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001;19: 4005–13. [12] Herr HW, Faulkner JR, Grossman HB. Surgical factors influence bladder cancer outcomes: A cooperative group report. J Clin Oncol 2004;22:2781–9.
News and topics
Accrual issues in genitourinary cancer clinical trials夡 Introduction As a result of recent advances in the understanding of tumor biology in genitourinary cancers, coupled with the remarkable development in technology and informatics, new therapies for prostate, bladder, and renal cell cancers are being developed at an enhanced pace. These new treatments require testing for safety and efficacy through welldesigned clinical trials before approval by the U.S. Food and Drug Administration. Unfortunately, less than 3% of adult patients with cancer in the United States participate in National Cancer Institute-sponsored clinical trials annually, a rate that has not improved in more than 2 decades [1,2]. This rate is in contrast to pediatric oncology, in which the standard of care is enrollment of patients into peer-reviewed, cooperative group clinical trials, resulting in an accession rate exceeding 60% [3–5]. Low accrual rates result in prolongation of trial duration and/or leading to early closure of important studies, delaying drug development, and, subsequently, patient access to potentially active new agents [6,7]. Therefore, if prevention and treatment of genitourinary cancers are to progress at a more rapid rate, it is critical that barriers to patient accrual be identified to ensure timely trial completion. This article will attempt to present our views on why accrual to many genitourinary trials is slow. It also asks a germane question: Is it incumbent upon members of the Society of Urologic Oncology (SUO), who are leaders of the urologic oncology community, to undertake steps addressing the problems of accruing patients to clinical trials? Our view is that it is. As a disclaimer, please note that both authors are members of clinical trial groups and so are as guilty as others in not having solved this problem. The importance of clinical trials in advancing therapy for urologic cancer is well recognized. The federal commitment is evidenced through support of large, interactive clinical trial groups (principally cooperative groups), funding for translational research initiatives (most notably through the Special Program of Research Excellence process), and continued funding for prostate clinical trials through the De-
夡
This work was supported by R21 CA02501 (P.N.L.), American Cancer Society CRTG 0019701CCE (P.N.L.), NO1CM17101. 1078-1439/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2005.11.037
partment of Defense, among others. Importantly, the recent Lansdowne meeting specifically brought up the issue of how clinical trial accrual could be improved. Because the government commitment is so well established, there will be a tendency to leave accrual issues to the funded cooperative groups. Clearly, this is not the answer. With its high profile, the SUO can provide input and solutions to the accrual issue. In a prospective study of patient accrual patterns in cancer clinical trials by our group, fear of insurance denial appeared to be a concern to patients considering trial participation. Despite the fact that only 8% of the patients did not participate because of denial of coverage by third party payers, patients with nongovernmental insurance were statistically less likely to participate than those with government insurance [8]. The hypothesis generated is that patients with private insurance have a perception that their third party payer for clinical trial participation may not adequately cover them. However, it is clear that insurance coverage is but one of many potential barriers to genitourinary cancer accrual. Barriers to accrual can be classified into 4 broad groups: (1) physician barriers, (2) protocol or eligibility barriers, (3) patient barriers, and (4) funding barriers. In our view, the issue of physician barriers has not been appropriately addressed by recent studies and is a focus of this article. We do note that all these barriers are potentially modifiable in that efforts can be made by study investigators to reduce the influence of these barriers on accrual. In an effort to understand these and other potential barriers to accrual, we will examine recent examples of genitourinary cancer trials that have struggled with accrual difficulties and propose, where possible, potential solutions for similar trials. Clinical trial examples Radiation Therapy Oncology Group (RTOG) P-0014. A phase III randomized study of patients with high-risk, hormone-naïve prostate cancer: Androgen blockade with 4 cycles of immediate chemotherapy versus androgen blockade with delayed chemotherapy This trial aimed to compare the survival of patients with high-risk hormone-naïve prostate cancer treated with andro-
380
P.N. Lara, R. de Vere White / Urologic Oncology: Seminars and Original Investigations 24 (2006) 379 –383
gen blockade with concurrent chemotherapy versus delayed chemotherapy. Designed as an intergroup trial coordinated by the RTOG with participation from the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B, and Eastern Cooperative Oncology Group (through the National Cancer Institute-directed Clinical Trials Support Unit), this trial was designed to accrue approximately 1050 patients over 4 years. Instead, the study closed with only 26 patients enrolled in the 2 years it was open. As originally written, the RTOG P-0014 trial was looking for patients with prostate cancer who had: (1) local treatments fail, such as surgery and/or radiotherapy and/or brachytherapy, as defined by an increasing prostate-specific antigen level of at least 2.0 ng/mL (confirmed by 2 measurements at least 2 weeks apart) and a doubling time of ⱕ32 weeks; (2) no clinical or radiographic evidence of disease; and (3) an original Gleason score of at least 7, or 6, with capsular penetration or positive seminal vesicles or lymph nodes. Patients in the chemotherapy containing arm were allowed to receive any 1 of at least 6 different regimens previously used in hormone refractory disease; in essence, this represented a “dealer’s choice” arm. In addition, alternative chemotherapy regimens with sufficient phase II activity in prostate cancer were allowed as long as the protocol chair approved. This “dealer’s choice” design was thought initially to be a suitable strategy to attract a broad group of oncologists to enroll their patients into the study. Instead, the trial was met with decidedly lukewarm response from the cancer community, manifest by its very sluggish accrual. Could this reception have been a result of a backlash toward the liberalism in the choice of chemotherapy regimens offered in the experimental arm, which could potentially have been simplified with a single regimen, such as single agent docetaxel? Alternatively, one can hypothesize that the trial ultimately failed because at the time it was activated, there was no 1 chemotherapy regimen that had yet been shown to improve survival outcomes in refractory disease, therefore, the reluctance of the community to believe that chemotherapy use during earlier stage prostate cancer would be of any palpable benefit. To this day, it is unclear what specific issues plagued this study’s accrual difficulties. SWOG 8710/Intergroup 0080: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer This intergroup trial aimed to compare the survival among patients with stage T2–T4a bladder cancer treated with cystectomy alone versus those treated with 3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), followed by radical cystectomy [9]. A secondary objective was to quantify the effect of neoadjuvant M-VAC on the stage of the tumor. Patients were enrolled if they had muscle-invasive bladder cancer (stage T2–T4a) and were to be treated with radical cystectomy.
This trial took 11 long years (from August 1987 to July 1998) to accrue 317 patients with transitional cell carcinoma of the bladder. This prolonged accrual period occurred despite intergroup participation (SWOG, the Eastern Cooperative Oncology Group, and the Cancer and Leukemia Group B). As reported in the New England Journal of Medicine, survival was superior in the neoadjuvant chemotherapy arm (median survival time of 77 vs. 46 months, P ⬍0.05 1-sided). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38% vs. 15%, P ⬍ 0.001). Had this trial not remained open despite pressures to close it because of exceedingly slow accrual, its positive results, which ultimately changed the way patients with locally advanced bladder cancer are treated, would not have been evident. Fortunately, the study investigators persisted with a determination to complete the study. The difficulties encountered in this trial were actually anticipated. At protocol activation, many urologists viewed neoadjuvant chemotherapy, particularly the notoriously toxic M-VAC, with skepticism and disdain. At that point, a radical cystectomy was a well-established standard of care despite its suboptimal outcomes in the majority of patients. Furthermore, the experimental arm was considered radically different from the control arm, similar to the perceptions that first met the original breast cancer lumpectomy versus mastectomy trials. It is likely that this radical difference between the arms promoted the general reluctance toward the randomization process. SWOG 9921: Hormone therapy with or without mitoxantrone and prednisone in treating patients who have undergone radical prostatectomy for prostate cancer This intergroup trial, currently accruing through the Clinical Trials Support Unit, takes patients with prostate cancer who have undergone radical prostatectomy and are found to have pathologic features consistent with high-risk disease, randomly assigning them to 1 of 2 groups. One group receives an injection of goserelin once every 3 months and bicalutamide by mouth once a day for 2 years, while the other group receives goserelin and bicalutamide for 2 years plus an infusion of mitoxantrone on day 1 and prednisone by mouth twice a day for 3 weeks, repeated every 3 weeks for 6 courses. This trial was designed to accrue approximately 1360 patients. Early in its life, this protocol was in danger of early closure because of slow accrual. Of the reasons for the reluctance to enroll patients into this adjuvant trial was the selection of mitoxantrone-prednisone as the chemotherapy regimen in the experimental arm. At this trial’s activation, mitoxantrone-prednisone had principally shown palliative benefits in the hormone refractory setting, but it did not prolong life as compared to corticosteroids alone, partly because of allowance for crossover. Many believed that
P.N. Lara, R. de Vere White / Urologic Oncology: Seminars and Original Investigations 24 (2006) 379 –383
such a regimen would not be effective enough in the adjuvant setting. In addition, some were concerned about the lack of an observation arm in the study, inclusion of which would have represented a more scientifically “pure” design. However, it was argued that accrual to a study that randomizes high-risk patients to a no-treatment arm would be unacceptable to many patients with prostate cancer. Only after extensive efforts to generate interest in the protocol, including engagement of marketing specialists who developed supporting tools, such as informational pamphlets, compact discs, and videos, and directed a mass electronic mailing effort by the investigators, did this trial finally get into a reasonable accrual stride. As of April 2005, S9921 has accrued 656 patients, averaging 15–20 registrations per month. This reflects a 3-fold increase from the monthly accrual rate experienced by this trial early in its life. The experience from this trial shows that a commitment to trial completion as manifested by the infusion of resources to market appropriately the concept to the oncologic community can be effective in increasing patient accrual. Nevertheless, this trial is still far from being completed, and marketing efforts need to continue to ensure its survival. SWOG 8949: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal cell cancer This trial randomly assigned patients with metastatic renal cell cancer who were acceptable candidates for nephrectomy to undergo radical nephrectomy followed by therapy with interferon alfa-2b or to receive interferon alfa-2b therapy alone [10]. As reported in the New England Journal of Medicine, patients undergoing radical nephrectomy had better overall survival as compared to those who received interferon alone (11.1 vs. 8 months, P ⫽ 0.05). The positive results of this trial influenced the approach to many patients with metastatic renal cell cancer. Unfortunately, this trial took an unexpectedly long journey to completion, requiring more than 7 years to accrue 241 eligible patients. This result contrasts to the recent rapid completion of accrual to a randomized trial of Sorafenib (Bayer/Onyx, West Haven, CT, and Emeryville, CA) versus placebo in metastatic renal cell cancer; that phase III trial accrued more than 800 patients in less than 2 years. What plagued the accrual to S8949, and what lessons were learned from this experience? Similar to S8710, this trial was difficult to conduct because of a marked therapeutic difference between the arms because half the patients had to undergo radical surgery. Only dogged persistence by the investigators to keep the trial open despite the slow accrual led to its completion years after activation. In this case, a core group of investigators kept the momentum going, thereby providing the “inspiration” to others to consider enrolling their patients.
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Discussion How then can SUO members address problems with cancer clinical trial accrual? The easiest answer is to ensure that ongoing trials get completed quickly. This means placing patients with genitourinary cancers on clinical trials whenever possible. SUO members must commit to doing so, and, by their example, encourage others to do so. While others are studying barriers to recruiting patients to clinical trials, perhaps we should ask what the barriers are for physicians, specifically SUO members, in entering patients into such trials. This process necessitates a change in culture for many physicians, one that mimics pediatric oncology, in which clinical trial accrual is considered the top priority. For physicians in institutions with sparse clinical trial support, such as adequate data management and research nurses, we believe that the major barrier is time. Many have called it the “hassle factor.” In addition, lack of training on the day-to-day conduct of clinical trials as well as the burdens of increasingly more complex regulatory requirements emerge as important barriers, all compounded by the enormous expense of performing these trials. An added disadvantage is that these physicians often are not members of clinical trial groups, resulting in a lack of “ownership” of the trials. Finally, some believe that their job is to provide their patients the best available standard of care, believing it is up to academicians to perform the trials that will determine the new treatment standards. These are issues that are most difficult to tackle, more so overcome, and, in many ways, beyond the ability of SUO members to address. In contrast, SUO members who are already working in an environment supportive of the clinical trials process would theoretically have less of these challenges. We know that many of these physicians are, or can be, active members of clinical trial groups. So, the issue of not taking ownership of trials becomes less valid. In this situation, what are the real issues? First, there is the problem of timeliness in getting trials started in cooperative groups. Sometimes, this period may often be 2–3 or even more years. Thus, by the time the trial opens, enthusiasm may have waned, and those who were most passionate about the trial may have become frustrated and either started their own institutional study or have moved on to other questions of interest. Therefore, when the cooperative group trial eventually opens, interest and accrual decline in tandem. Those who make the effort to attend group meetings have good intentions, are willing to help, and do not wish to be seen as obstructionists. Therefore, it is likely that many tend to view these trials, and their willingness and ability to accrue patients through “rose-tinted” glasses. Regrettably, on returning home, the truth is somewhat different. An example is a trial comparing radiation therapy to radical prostatectomy, which closed with 4 patients accrued over 18 months (S8890). Was any trial discussed more before initiation? We almost certainly doubt it.
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Then there is SWOG 8710, already briefly discussed previously. This trial took 16 years to complete from start to publication. It is a positive trial, yet many say its findings are invalid, quoting stage migration, change in methods of statistical analysis, and, finally, that the chemotherapy used now is better than that used in 8710. If the participants in the clinical trial groups had each placed 1 patient in this study, all these time-related problems would have been avoided pretty quickly. However, after the trial was completed, all agreed that in those patients receiving the 3 cycles of M-VAC before their cystectomy there was a 38% pT0 rate at cystectomy. This rate in an M.D. Anderson trial of neoadjuvant chemotherapy was 40% [11]. All agreed that these patients enjoyed a 75% to 80% 5-year survival, while for the patients after chemotherapy with positive lymph nodes, this figure was 12%. SWOG investigators as a group decided to build on these results in S0219, a phase II trial of neoadjuvant gemcitabine, carboplatin, and paclitaxel in T2–T4 bladder cancer, with the goal of collecting tissue before and after chemotherapy for correlative studies. This was in an effort to identify molecular markers that would predict response to chemotherapy. The only difference between this trial and S8710 was that after chemotherapy and before cystectomy, patients would undergo a restaging transurethral resection of bladder tumor. These questions do not seem very controversial, and they do seem to offer great benefit, yet it took almost 3 years to get this trial started. The trial opened in 2003, requiring only 99 patients to complete. Yet, nearly 2 years later, only 27 patients have been accrued. Why is this occurring? When queried, investigator replies have ranged from “I would love to do it but have competing trials” to “I don’t believe 8710” to “we believe our own chemotherapy regimen is better than what is being used in this trial.” It seems the real issue is that some physicians are worried that if they commit to this trial, it will take years to perform. Unfortunately, such anxiety will translate into slow development of newer and more effective systemic therapy. This is obviously a valid concern. The answer, of course, is that if each SUO member placed just 1 patient on the S0219 trial, it would be completed within 18 months. There is then the problem of nonadherence to trials. In S8710, there was a protocol-defined lymph node dissection. All those participating in the trial agreed that at cystectomy, they would fulfill this dissection. One must remember that the surgeons participating in this study, both because of oncologic fellowship training and because they took the trouble to join the clinical trials group, should be considered in the upper quartile of urologic oncologists. Therefore, it is somewhat surprising that in only 54% of the operations did the patients actually undergo the node dissection that their surgeon had agreed to [12]. When one reads the report detailing this result, it is clear that those patients who did not undergo the full node dissection did not get the full benefit of the trial and had a higher cancer mortality.
We have focused on S8710 because it was a landmark study. Completion of this trial in a timely manner would have been of great benefit to patients with bladder cancer. Had there been rapid completion, there would not have been the arguments about stage migration, the same statistical methods would have been used, and, even more importantly, the subsequent questions could have been addressed, and we could have focused on trying to improve the chemotherapy regime. So, our question is: Do we as a group use our position in urologic oncology to help address the issue of placing patients on trials that we as group collectively say are important with the view of getting these trials completed rapidly? This is probably the single biggest contribution the SUO could make to furthering and improving the treatment of patients with urologic cancers.
Conclusions The examples discussed previously illustrate the complexities that swirl around genitourinary cancer clinical trial accrual. These issues are not confined to North American cooperative groups and are also being experienced by investigators in other countries, such as the European Union. Thus, solutions must be made as universally applicable as possible. Some of the examples illustrated previously show that given the proper motivation, clinical trial groups can overcome some of the most formidable barriers to accrual with persistence and creativity. No progress can be made in genitourinary cancer therapeutics unless the appropriately designed clinical trials are conducted and completed. It is the responsibility of every physician taking care of these patients to consider always a cancer trial as a therapeutic option. Primo N. Lara, Jr., M.D. Ralph de Vere White, M.D. The University of California Davis Cancer Center Sacramento, CA, USA
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