Comparative Review of Consensus- Based Clinical Target Volume Definitions for Prostate Radiotherapy

Background: A major obstacle in the delivery of postoperative radiation therapy (RT) for prostate cancer is accurate delineation of the tumor targets and organs at risk. Although postoperative prostate cancer contouring atlases are quite common, there is still no widely accepted contouring guideline. The purpose of this study is to critically review the various postoperative prostate RT treatment planning consensus guidelines or atlases currently available. Methods: A literature search was conducted using various electronic databases with the key terms: prostate, contour, planning tumour volume, clinical target volume, delineation or definition, guidelines or atlas, and radiation oncology. The search was limited to English publications from the years 1985 to 2011. Results: A total of seven publications relating to contouring guidelines for postoperative prostate radiotherapy were identified. There are four distinct consensus guidelines developed by major institutions: Princess Margaret Hospital, the Australian and New Zealand Radiation Oncology Genito-Urinary Group, the European Organization for Research and Treatment of Cancer, and the Radiation Therapy Oncology Group. Conclusions: After reviewing the consensus contouring guidelines for postoperative prostate cancer radiation therapy that were available in the literature, it is clear that there disagreement with regards to what anatomical borders should be used for delineating an appropriate prostate bed CTV. Additional studies comparing the reproducibility of the various guidelines as well as the performance of these guidelines on clinically important outcomes are needed. Introduction Postoperative radiation therapy (RT) is indicated in the treatment of post-prostatectomy patients with high-risk of local recurrence [1]. Recent studies have shown RT to be beneficial following radical prostatectomy in both the adjuvant setting, for patients with highrisk pathological features, such as positive surgical margins and seminal vesicle invasion [2-8], or as salvage for biochemical disease recurrence [9-10]. Two randomised controlled trials suggest adjuvant RT directly following surgery provides improved progression-free survival, biochemical relapse-free survival, and local control over watchful waiting protocols [3, 11]. Although a long-term follow-up of one of these trials also suggests that adjuvant RT also improves metastasis-free survival and overall survival compared with observation alone [2], there is insufficient long-term follow-up data available to adequately assess the effect on these treatment outcomes. A major obstacle in the delivery of postoperative radiation therapy for prostate cancer is accurate delineation of the tumor targets and Organs at Risk (OARs). Inter-observer variability between oncologist drawn contours in prostate radiation therapy is well documented [1215] and has been identified as a highly significant contributing factor to uncertainty in radiation therapy treatment planning [16]. Contouring consensus guidelines or atlases for postoperative prostate RT have been created to aid oncologists in the delineation of tumor targets and OARs with the hope of reducing this variability. Although postoperative prostate cancer contouring atlases are quite common, there is still no widely accepted contouring guideline. The purpose of this study is to critically review the various postoperative prostate RT treatment planning consensus guidelines or atlases currently available with emphases on the methodology and validity of each atlas. Materials And Methods A literature search was conducted using the electronic databases Pubmed, MEDLINE (OVID), EMBASE, Cochrane Library, and Google Scholar with the key terms: prostate, contour, planning tumour 2013 Smith et al. Cureus 5(7): e128. DOI 10.7759/cureus.128 Page 2 of 19 Scholar with the key terms: prostate, contour, planning tumour volume, clinical target volume, delineation or definition, guidelines or atlas, and radiation oncology. The search was limited to English publications from the years 1985 to 2011. Relevant studies found on references lists of identified articles were included as well as any articles found on national cooperative group websites, including the Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC). Only studies related to medicine or physics (including radiation oncology, imaging, oncology or cancer) were included. The methodology used in these articles including how each consensus was reached and study validity was reviewed, and any similarities and differences found in the contouring guidelines were detailed. Results Literature Search A total of seven publications relating to contouring guidelines for postoperative prostate radiotherapy were identified [17-23]. There are four distinct consensus guidelines developed by major institutions: Princess Margaret Hospital (PMH) [17], the Australian and New Zealand Radiation Oncology Genito-Urinary Group (FROGG) [19], the European Organization for Research and Treatment of Cancer (EORTC) [21], and the Radiation Therapy Oncology Group (RTOG) [22]. A fifth consensus statement was identified from the Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) group in their validation study [18], in which they used a modified version of the PMH consensus guideline. No publication outlining the contents of this version was found. There were five studies discussing the methodology used in the creation of the various consensus statements [17, 19, 21-23]. The information from the EORTC consensus was published in two separate articles [21, 23]. There were two validation publications, one from the RADICALS [18] and the other from EORTC [20]. The study by PMH [17] contains both a description of how their consensus was reached as well as a validation component. Although the article from Boehmer, et al. [23] was on guidelines for radiotherapy for intact prostate, it was referred to in the EORTC consensus for postoperative prostate radiotherapy by Poortman, et al. [21] and was included in this review. The studies were published between 2006 and 2011 and represent a large number of medical institutions from a wide range of countries (Table 1). Primary Oncology Number of Consensus 2013 Smith et al. Cureus 5(7): e128. DOI 10.7759/cureus.128 Page 3 of 19 Primary Author Group/Institution Responsible for Consensus Countries Involved Date Published Medical Institutions Involved [C] and/or Validation [V] Study K. Wiltshire PMH Australia, Canada, Switzerland 2007 4 C, V D. MitchellRADICALS United Kingdom 2009 2 V M. Sidhom FROGG-RANZCR Australia, Singapore, New Zealand 2008 7 C P. Ost EORTC Belgium 2011 1 V P. PoortmansEORTC Belgium, France, Germany, Netherlands, Switzerland, United Kingdom 2007 13 C J. Michalski RTOG Canada, USA 2010 13 C D. Boehmer* EORTC Belgium, France, Germany, Netherlands, Switzerland, United Kingdom 2006 10 C Table 1: Post-operative prostate radiation therapy contouring consensus guideline publications Abbreviations: PMH = Princess Margaret Hospital; RADICALS = Radiotherapy and Androgen Deprivation In Combination After Local Surgery; EORTC = European Organization for Research and Treatment of Cancer; RTOG = Radiation Therapy Oncology Group; FROGG-RANZCR = The Faculty of Radiation Oncology Genito-Urinary Group part of the Royal Australian and New Zealand College of Radiologists. * European Organization for Research and Treatment of Cancer consensus guidelines for intact prostate Discussion Consensus Methodology The methodology for creating the consensus atlases by the RTOG, FROGG and PMH began with delineation of preliminary contours by a small group of clinicians, involving at least one oncologist or urologist experienced with postoperative prostate radiotherapy or prostatectomy [17, 19, 22]. In these studies, the clinicians responsible for delineating the initial contours were given patients with specific clinical scenarios and were asked to delineate an appropriate clinical target volume (CTV) based on their expert knowledge of anatomy, tumor physiology and patterns of spread [17, 2013 Smith et al. Cureus 5(7): e128. DOI 10.7759/cureus.128 Page 4 of 19 19, 22]. Consensus guidelines from the RTOG, FROGG and PMH were finalized following a presentation and discussion of their preliminary contours at a conference or consensus workshop [17, 19, 22]. Interprofessional collaboration between diverse multi-disciplinary groups of health care professionals, specifically individuals with expertise in the treatment of prostate cancer, was utilized in the creation of the consensus atlases [17, 19, 21-23]. The study by PMH focused on postoperative prostate patients with or without seminal vesicle invasion [17], while the RTOG study focused on the clinical scenarios of seminal vesicle invasion and positive apex margins [22]. A review of relevant literature was present in the development of each of the consensus guidelines [17, 19, 21-23]. The initial contours generated by PMH were presented at the Australian Faculty of Radiation Oncology Genito-Urinary Oncology Group Consensus Workshop on Post-Prostatectomy Radiotherapy in June 2006 [17, 19]. The consensus guidelines created at this conference were further modified by the FROGG and were used in the creation of their own consensus atlas [19]. The RTOG used an imputation method of the expected maximum (EM) algorithms for simultaneous truth and performance level estimation (STAPLE) [24] to create their preliminary contours. The STAPLE algorithm has been previously identified as a useful tool in analyzing expert radiation oncologist consensus contours [25]. The RTOG STAPLE contours were presented at a RTOG conference where they were discussed and a consensus was finalized following a teleconference [22]. There was no information given by the EORTC regarding the exact process in which their consensus guideline was reached. Instead, the EORTC presents detailed manuscripts reviewing published works relevant to prostate cancer, specifically studies on surgery, anatomy and local recurrence [21, 23]. A detailed description of the methods involved in the creation of the four contouring guidelines is shown in Table 2. ConsensusHow Consensus was Reached Three urologists experienced with open or laparoscopic prostatectomy independently delineated the anatomical borders of the prostate bed at risk of microscopic cancer seeding on axial MRI scans of 2 patients (with and without seminal vesicles, selected randomly from the patient population) and presented these contours to a multi-disciplinary Genito2013 Smith et al. Cureus 5(7): e128. DOI 10.7759/cureus.128 Page 5 of 19 Wiltshire et al (PMH) Urinary (GU) tumor board. An Interdisciplinary discussion between all members of the GU board including radiation oncologists, medical oncologists, urologists, uroradiologists and uropathologists occurred and a review of the literature (patterns of failure, surgical practice, radiologic anatomy) was completed. Final consensus CTV was defined by 1 uroradiologist and 2 radiation oncologists and was approved by a GU board containing 10 rad oncologists, 4 urologists and 1 uroradiologist. Consensus was modified further following presentations of consensus at Australian Faculty of Radiation Oncology Genito-Urinary Oncology Group Consensus Workshop on Post Prostatectomy Radiotherapy June 2006 and Genito-Urinary Radiation Oncologists of Canada Meeting January 2007. FROGGRANZCR Consensus was reached following a 2-day consensus workshop. Prior to workshop extensive literature review was performed which led FROGG executives to generate a draft of post-prostatectomy guidelines. Guidelines from PMH were presented at the conference, discussed and refined. Expert speakers from radiation oncology, urology and radiology presented data on topics relevant to post-prostatectomy radiotherapy at 2-day workshop. 63 delegates from Radiation Oncology, Radiology, Urology, Medical Physics, and Radiation Therapy attended. Unresolved issues handled by workshop parties for final revision RTOG 11 oncologist observers contoured 2 post-op prostate patients with 2 separate clinical scenario cases: 1) positive apex margin or 2) invasion of seminal vesicles and evaluated the inter-observer variability between oncologists (each oncologist was to use their own institution's contouring policy). From these contours they used an imputation method of the expected maximum (EM) algorithms for simultaneous truth and performance level estimation (STAPLE), to create a consensus contour derived from the collection of observer contours. The STAPLE contour represents the 'true' contour for each patient. The RTOG held a conference where they presented a review of patterns of failure, anatomy and surgical findings related to radical prostatectomy. Each STAPLE contour (for each patient case) was used as a starting point for discussion and creation of consensus guidelines. The RTOG reviewed and modified the consensus contours at a conference and finalized them via teleconference. EORTC Presented a manuscript reviewing published work on local recurrence sites in post-op prostate cancer, surgery and anatomy. It is unclear as to how their consensus was reached. Table 2: Description of consensus guideline methodology Abbreviations: PMH = Princess Margaret Hospital; RADICALS = Radiotherapy and Androgen Deprivation In Combination After Local Surgery; EORTC = European Organization for Research and Treatment of Cancer; RTOG = Radiation Therapy Oncology Group; 2013 Smith et al. Cureus 5(7): e128. DOI 10.7759/cureus.128 Page 6 of 19 FROGG-RANZCR = The Faculty of Radiation Oncology Genito-Urinary Group part of the Royal Australian and New Zealand College of Radiologists. Validation Studies There were three publications validating consensus guidelines for postoperative prostate radiotherapy found in the literature [17-18, 20]. Consensus statements from the EORTC, PMH as well as a modified version of the PMH consensus (RADICALS) were evaluated in these studies [17-18, 20]. There were no validation studies found from the RTOG or the FROGG. A summary of the validation studies is presented in Table 3. Author (Country) Consensus Validated Study Population (# Patients) Health Care Professionals Involved (#) Description Results Wiltshire et al (Canada) PMH Study 1) 25 Study 2) 16 Study 3) 20 Study 1) 3 oncologist observers. Study 2) 2 oncologist observers. Study 3) No information given. Study 1) Assessing consensus CTV coverage using prostate bed surgical clips. Study 2) Intraand interobserver variability study to determine reproducibility of consensus. Study 3) Retrospective study to determine the impact of the consensus guidelines on clinical practice using dose volume histograms. Study 1) Surgical clips well distributed, with a lower clip density appreciated at anteriorsuperior and posteriormost extent of CTV. Surgical Clips were contained (338 out of 339 clips) within consensus CTV. Study 2) Small systematic inter-observer errors were observed in the AP dimension. Most uncertainty was observed in superior/posterior/lateral aspect of CTV. Intraand inter-observer variability was described as random and not systemic. Study 3) CTV volume and field size increased with consensus. Less that 50% of patients received prescribed 2013 Smith et al. Cureus 5(7): e128. DOI 10.7759/cureus.128 Page 7 of 19 microscopic dose (V100