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A Breast Cancer Research Field of Dreams: If We Build It, Will They Come?
editorial Rachel Rabinovitch, MD Department of Radiation Oncology University of Colorado Comprehensive Cancer Center Aurora, CO
A Breast Cancer Research Field of Dreams: If We Build It, Will They Come? Do you like baseball? I’m actually not a big sports fan and do not know a whole lot about the game, but baseball serves as an excellent metaphor for almost any topic, even clinical breast cancer research. Last month, two teams from different leagues, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG), activated “a randomized phase III study of conventional whole breast irradiation versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer.” These two cooperative groups should be congratulated for overcoming politics, perspective, organizational structure, and finances to create this first-ever “cooperative cooperative-group” trial (NSABP B39/RTOG 0413) in the interest of answering a timely and mutually interesting oncologic question. Much has been written about accelerated PBI. There have been numerous publications about the various techniques, acute toxicities, and longish-term outcomes and lively discussions about the ethics, politics, and appropriateness of the approach for early-stage breast cancer. Given the promising data to date and widespread interest in shorter treatment courses for this prevalent disease, this trial will randomly compare standard whole breast radiation therapy (RT; with or without a boost) with any 1 of 3 accelerated PBI techniques (multicatheter interstitial brachytherapy, intracavitary brachytherapy using the MammoSite® Radiation Therapy System, or 3dimensional conformal external-beam RT). Radiation therapy for each of the accelerated partial breast techniques is delivered to the 1-2.5 cm of tissue immediately surrounding the lumpectomy cavity twice daily for 5 consecutive weekdays. The total dose delivered for PBI in this trial ranges from 3400 cGy (for brachytherapy techniques) to 3850 cGy (for external beam 3D). The treating physician is free to choose the partial breast technique he or she plans to use, assuming the patient is randomized to the accelerated arm. This trial is unique from numerous perspectives. For one, patients with ductual carcinoma in situ and invasive breast cancer lesions will be eligible for enrollment (tumors ≤ 3 cm with 0-3 positive axillary lymph nodes), unlike nearly every other RT breast cancer trial ever executed. It is also a truly modern trial from a technical standpoint, incorporating sophisticated partial breast treatment planning and delivery techniques into the PBI arm. This is striking in an era when most cooperative group clinical cancer trials are designed to use the “lowest common denominator” of RT to allow for the
widest possible participation. However, the downside is that as RT becomes ever more complex so does the quality assurance process necessary to verify that treatment delivered by unrelated facilities around the country meets acceptable standards. This trial, for example, will require credentialing by each facility before trial participation, which entails electronic and paper submission of a test case for each of the PBI techniques a facility plans to use. Thereafter, a “rapid review” (ie, within 24 hours) and approval of the treatment plan for the first enrolled PBI case within each technique will be required before the patient can be treated. The questions this trial (NSABP B-39/RTOG 0413) is attempting to answer are timely and exciting, and the questions remaining, even after successful completion of the trial, will still be numerous. The trial’s primary endpoint is testing for equivalence of local control (in the ipsilateral breast) between partial breast and standard whole breast RT in the setting of early-stage breast cancer. Other endpoints include disease-free and overall survival and differences in cosmesis, fatigue, toxicities, and quality of life parameters between the approaches. The trial will not randomize or stratify patients among the 3 partial breast techniques available for use in this trial; a future trial may be needed if a detailed comparison of the various PBI techniques is ever desired. So back to baseball: will this trial result in a shutout or a win for PBI? Whatever the outcome, the skinned knees and sore muscles experienced by many of the pioneering radiation oncologists who participated in spring training (singleinstitution protocols, phase II RTOG trials, and the MammoSite® registry study) and the sunburns sustained by the many fans who agreed to sit in the bleachers will have been well worth it. That outcome would, I believe, firmly move accelerated PBI into a standard or at least widely accepted alternative component of breast conservation therapy. However, even if PBI loses to whole breast radiation by just a few local control points, I can envision the fans still lining up for the losing team because of the value that shortened treatment courses hold for many in a busy and complex modern world. In other words, PBI may come out a winner even if it loses, which raises other questions to contemplate: in the 21st century, is it possible that patients with breast cancer would seek out a slightly inferior cancer treatment because of other benefits? Is it possible that it is not so important if you win or lose but how you play the game? This would be a
Clinical Breast Cancer April 2005 • 11
paradigm shift in the way cancer therapies and certainly breast conservation therapies are sought out and delivered. However, my primary concern at the moment is not what the outcome of the game will be but whether anyone will show up at the ballpark. With the availability of PBI offstudy (eg, nearly 7500 MammoSite® systems have been implanted since Food and Drug Administration approval of the device in May of 2002), it will take a concerted effort by clinicians (surgeons and radiation oncologists alike) and patients to ensure that the large accrual goal of this trial (3000 women in 2.5 years) is attained. This trial is really the only way to answer the questions about a treatment approach for which thousands of women have already declared preference. Baseball, after all, has yearly seasons, but this whole breast versus partial breast irradiation ballgame has just one. As the prevalence of all techniques of accelerated PBI increases, there will be only one chance, one season, to accomplish a randomized trial in North America, asking and answering this particular question before each team decides
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it is too good to bother competing with the opposing team. As one of the team cheerleaders, I implore you to aggressively educate and inform your colleagues and patients of the value of timely participation in this study. The trial is available not just to members of the big leagues (NSABP or RTOG) but to any clinician/medical facility through the Clinical Trials Support Unit (www.ctsu.org). With robust national physician and patient participation, we have the opportunity to collectively fulfill the prophecy in the Field of Dreams, “build it and they will come.” The sun is shining, the lawn has been freshly mowed, the stadium is sparkling, and the teams are ready and in uniform. So, “with the hope that springs eternal from within the breast,”1 let’s play ball.
Rachel Rabinovitch, MD 1. Thayer EL. “Casey at the Bat,” San Francisco Examiner, June 3, 1888.
A Breast Cancer Research Field of Dreams: If We Build It, Will They Come? Do you like baseball? I’m actually not a big sports fan and do not know a whole lot about the game, but baseball serves as an excellent metaphor for almost any topic, even clinical breast cancer research. Last month, two teams from different leagues, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG), activated “a randomized phase III study of conventional whole breast irradiation versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer.” These two cooperative groups should be congratulated for overcoming politics, perspective, organizational structure, and finances to create this first-ever “cooperative cooperative-group” trial (NSABP B39/RTOG 0413) in the interest of answering a timely and mutually interesting oncologic question. Much has been written about accelerated PBI. There have been numerous publications about the various techniques, acute toxicities, and longish-term outcomes and lively discussions about the ethics, politics, and appropriateness of the approach for early-stage breast cancer. Given the promising data to date and widespread interest in shorter treatment courses for this prevalent disease, this trial will randomly compare standard whole breast radiation therapy (RT; with or without a boost) with any 1 of 3 accelerated PBI techniques (multicatheter interstitial brachytherapy, intracavitary brachytherapy using the MammoSite® Radiation Therapy System, or 3dimensional conformal external-beam RT). Radiation therapy for each of the accelerated partial breast techniques is delivered to the 1-2.5 cm of tissue immediately surrounding the lumpectomy cavity twice daily for 5 consecutive weekdays. The total dose delivered for PBI in this trial ranges from 3400 cGy (for brachytherapy techniques) to 3850 cGy (for external beam 3D). The treating physician is free to choose the partial breast technique he or she plans to use, assuming the patient is randomized to the accelerated arm. This trial is unique from numerous perspectives. For one, patients with ductual carcinoma in situ and invasive breast cancer lesions will be eligible for enrollment (tumors ≤ 3 cm with 0-3 positive axillary lymph nodes), unlike nearly every other RT breast cancer trial ever executed. It is also a truly modern trial from a technical standpoint, incorporating sophisticated partial breast treatment planning and delivery techniques into the PBI arm. This is striking in an era when most cooperative group clinical cancer trials are designed to use the “lowest common denominator” of RT to allow for the
widest possible participation. However, the downside is that as RT becomes ever more complex so does the quality assurance process necessary to verify that treatment delivered by unrelated facilities around the country meets acceptable standards. This trial, for example, will require credentialing by each facility before trial participation, which entails electronic and paper submission of a test case for each of the PBI techniques a facility plans to use. Thereafter, a “rapid review” (ie, within 24 hours) and approval of the treatment plan for the first enrolled PBI case within each technique will be required before the patient can be treated. The questions this trial (NSABP B-39/RTOG 0413) is attempting to answer are timely and exciting, and the questions remaining, even after successful completion of the trial, will still be numerous. The trial’s primary endpoint is testing for equivalence of local control (in the ipsilateral breast) between partial breast and standard whole breast RT in the setting of early-stage breast cancer. Other endpoints include disease-free and overall survival and differences in cosmesis, fatigue, toxicities, and quality of life parameters between the approaches. The trial will not randomize or stratify patients among the 3 partial breast techniques available for use in this trial; a future trial may be needed if a detailed comparison of the various PBI techniques is ever desired. So back to baseball: will this trial result in a shutout or a win for PBI? Whatever the outcome, the skinned knees and sore muscles experienced by many of the pioneering radiation oncologists who participated in spring training (singleinstitution protocols, phase II RTOG trials, and the MammoSite® registry study) and the sunburns sustained by the many fans who agreed to sit in the bleachers will have been well worth it. That outcome would, I believe, firmly move accelerated PBI into a standard or at least widely accepted alternative component of breast conservation therapy. However, even if PBI loses to whole breast radiation by just a few local control points, I can envision the fans still lining up for the losing team because of the value that shortened treatment courses hold for many in a busy and complex modern world. In other words, PBI may come out a winner even if it loses, which raises other questions to contemplate: in the 21st century, is it possible that patients with breast cancer would seek out a slightly inferior cancer treatment because of other benefits? Is it possible that it is not so important if you win or lose but how you play the game? This would be a
Clinical Breast Cancer April 2005 • 11
paradigm shift in the way cancer therapies and certainly breast conservation therapies are sought out and delivered. However, my primary concern at the moment is not what the outcome of the game will be but whether anyone will show up at the ballpark. With the availability of PBI offstudy (eg, nearly 7500 MammoSite® systems have been implanted since Food and Drug Administration approval of the device in May of 2002), it will take a concerted effort by clinicians (surgeons and radiation oncologists alike) and patients to ensure that the large accrual goal of this trial (3000 women in 2.5 years) is attained. This trial is really the only way to answer the questions about a treatment approach for which thousands of women have already declared preference. Baseball, after all, has yearly seasons, but this whole breast versus partial breast irradiation ballgame has just one. As the prevalence of all techniques of accelerated PBI increases, there will be only one chance, one season, to accomplish a randomized trial in North America, asking and answering this particular question before each team decides
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it is too good to bother competing with the opposing team. As one of the team cheerleaders, I implore you to aggressively educate and inform your colleagues and patients of the value of timely participation in this study. The trial is available not just to members of the big leagues (NSABP or RTOG) but to any clinician/medical facility through the Clinical Trials Support Unit (www.ctsu.org). With robust national physician and patient participation, we have the opportunity to collectively fulfill the prophecy in the Field of Dreams, “build it and they will come.” The sun is shining, the lawn has been freshly mowed, the stadium is sparkling, and the teams are ready and in uniform. So, “with the hope that springs eternal from within the breast,”1 let’s play ball.
Rachel Rabinovitch, MD 1. Thayer EL. “Casey at the Bat,” San Francisco Examiner, June 3, 1888.