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Improving target volume delineation in intact cervical carcinoma: Literature review and step-by-step pictorial atlas to aid contouring
Improving target volume delineation in intact cervical carcinoma: literature review and step-by-step pictorial atlas to aid contouring Gemma Eminowicz FRCR, MSc, Margaret-Hall Craggs FRCR, MD, Patricia Diez MSci, MSc, Mary McCormack PhD, MBBS, FRCR PII: DOI: Reference:
S1879-8500(16)00008-4 doi: 10.1016/j.prro.2016.01.006 PRRO 593
To appear in:
Practical Radiation Oncology
Received date: Revised date: Accepted date:
14 November 2015 21 December 2015 8 January 2016
Please cite this article as: Eminowicz Gemma, Craggs Margaret-Hall, Diez Patricia, McCormack Mary, Improving target volume delineation in intact cervical carcinoma: literature review and step-by-step pictorial atlas to aid contouring, Practical Radiation Oncology (2016), doi: 10.1016/j.prro.2016.01.006
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ACCEPTED MANUSCRIPT Improving target volume delineation in intact cervical carcinoma: literature review and step-by-step pictorial atlas to aid contouring. Short title: A cervical cancer delineation pictorial atlas.
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Authors:
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Dr Gemma Eminowicz FRCR, MSc, University College Hospital London, UK Dr Margaret-Hall-Craggs1 FRCR, MD, University College Hospital London, UK Ms Patricia Diez MSci MSc, Mount Vernon Cancer Centre, Northwood, UK Dr Mary McCormack PhD MBBS FRCR, University College Hospital London, UK 1
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Corresponding author: Dr Gemma Eminowicz Upper flat 103 Lady Margaret Road London N19 5ER Mobile: 00447974219684 Email: [email protected]
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This work was undertaken at UCLH/UCL, which receives funding from the Department of Health’s NIHR Biomedical Research Centre funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health.
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Type of paper: Special article/pictorial guidelines Abstract word count: 218
Full word count excluding references and tables: 3438 No. of Pages: 16 No. of Tables: 4 No. of Figures: 3
Key words: Cervix cancer radiotherapy; Delineation guidelines; Nodal contouring
Acknowledgments: To the INTERLACE Trial Management Group, the INTERLACE participating centres and Cancer Research UK for funding the INTERLACE trial.
The authors declare that they have no conflict of interest or financial disclosure and that ethical research standards were observed.
ACCEPTED MANUSCRIPT Abstract
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Background Accurate delineation of target volume and normal tissue is critical for Intensity-Modulated
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Radiotherapy (IMRT) use in cervical cancer. The INTERLACE trial radiotherapy quality assurance
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(RTQA) has highlighted significant inter-observer delineation variation. Prescriptive guidelines
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reduce inter-observer variation in other cancers. Methods
A literature search using pubmed/medline database of guidelines for target anatomy delineation in cervical cancer was undertaken. Differences in practice in these publications and INTERLACE trial
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RTQA were identified. Consensus best practice delineation was derived and pictorial atlas produced. The proportion of outlines complying with protocol in test and real-time cases was compared before
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Results
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and after atlas implementation within the INTERLACE RTQA pack.
Seven key papers were reviewed. Eleven areas of variation were identified. These include the definition and editing of bowel, definition of the femur, vagina, parametria, inferior and superior nodal borders, nodal CTV editing, para-aortic nodal CTV definition, and the margin to be used around enlarged nodes. The average proportion of outlines (out of 4; primary CTV, nodal CTV, bladder, rectum) complying with protocol in test and real-time cases improved from 1.8 to 2.7 (difference 0.9;95%CI0.3-1.5,p=0.003) with atlas use. Conclusion Differences exist in the published literature and clinical practice. This pictorial atlas reflects consensus recommendations and is now available to INTERLACE participating centres. Atlas use has reduced inter-observer delineation variation in this trial setting.
ACCEPTED MANUSCRIPT Chemo-radiotherapy is given with curative intent for locally advanced cervical cancer. Intensity Modulated Radiotherapy(IMRT) reduces organs at risk(OARs) dose compared to three-dimensional
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conformal radiotherapy(3D-CRT)(1, 2) as it conforms closer to target volumes reducing toxicity
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rates(3, 4). IMRT is now used for locally advanced cervical cancer across Europe, the United
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Kingdom(UK) and has increased four-fold in the United States(US) between 2004 and 2011 (5). Accurate target volume delineation is critical to ensure tumour coverage and OAR sparing.
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Significant delineation variation exists between clinicians (inter-observer variation) across multiple tumour sites(6-11). This has been demonstrated for cervical gross tumour volume(GTV) and high risk clinical target volume(HR-CTV) for image guided brachytherapy(IGBT)(12, 13). This has also been demonstrated for cervical clinical target volume(CTV) for external beam radiotherapy (EBRT) within
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the INTERLACE trial radiotherapy quality assurance(RTQA)(14). This is in line with other
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publications(15, 16). Use of detailed delineation guidelines has been shown to reduce inter-observer variation in prostate bed radiotherapy within the RADICALS trial(17) and HR-CTV in cervical
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brachytherapy(12, 13).
The aim of this study was to review the recent literature, highlight and resolve inconsistencies in current published guidelines, and produce a detailed pictorial delineation atlas for cervical cancer radiotherapy, attempting to reduce inter-observer variation. The impact of this atlas was assessed after inclusion within the INTERLACE RTQA pack. The simulation process including precautions to minimise and methods to account for internal organ position variation are not discussed. The atlas presented here is applicable to all patients independent of simulation process. Brachytherapy delineation is also beyond this study’s scope and detailed guidance exists(18). Methods A literature search was performed using the Pubmed/Medline central database with the MESH terms ‘uterine cervical neoplasm’, ‘radiotherapy’ and ‘guidelines as topic’ in combination with the Pubmed search terms ‘contouring’, ‘outlining’, ‘atlas’ and ‘target volume definition’. Articles
ACCEPTED MANUSCRIPT published within the last ten years that included delineation guidelines for cervical cancer were selected and reviewed. The references within these articles were reviewed to ensure no key articles
primary CTV, to include GTV, uterus, bilateral ovaries if seen, bilateral parametria,
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were missed. The articles referred to delineation of:
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uterosacral ligaments, and vagina (referred to as CTV1)
pelvic nodal CTV, to include common iliac, internal and external iliac, subaortic pre-sacral
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and obturator nodal regions (referred to as CTV2)
para-aortic nodal CTV (referred to as CTV3)
OARs; anorectum, bladder, right femur, left femur, bowel, right kidney, left kidney and
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spinal cord
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CERR(19) was used to review 21 participating centres’ INTERLACE RTQA cases outlining. The quantitative analysis is previously published(14). To identify areas of variation, outlines were viewed
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simultaneously. The proportion of centres outlining specified anatomical areas was calculated. Inconsistencies within and between the published guidelines, routine UK practice and the INTERLACE RTQA experience were highlighted as variations in practice. These identified variations were reviewed within the INTERLACE Trial Management Group(TMG). The TMG includes 6 clinical oncologists, 1 RTQA physicist and 3 medical oncologists. The TMG discussed the identified variations and collated individual expert opinion. Subsequent best practice was agreed. Anonymised example patients were used to demonstrate the agreed step by step instructions and produce the complete pictorial atlas. An expert gynaecological radiologist reviewed the atlas to ensure anatomical accuracy. Oncologists at our institute applied the atlas in clinical practice to ensure comprehension. All chemoradiotherapy cases with involved para-aortic nodes treated between 2010 and 2014 at our institute were reviewed. The diagnostic imaging was examined to record the location of enlarged para-aortic nodes. This assisted with CTV3 outlining recommendations.
ACCEPTED MANUSCRIPT To validate this atlas, protocol compliance was monitored within INTERLACE RTQA. For each test and real time case the RTQA team reports changes necessary. Using these reports the number of
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structures requiring changes out of Bladder, Rectum, CTV1 and CTV2 was recorded. A well
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delineated case with no changes recommended scores 4. If all structures required changes the score
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is 0. Score comparison before and after atlas inclusion in the RTQA pack was made using an independent samples t-test.
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Results and Discussion Literature review results
Seven key articles on gynaecology radiotherapy guidelines were identified and reviewed(Table 1).
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Five were written by collaborative groups; Radiation Therapy Oncology Group(RTOG), Japan Clinical Oncology Group(JCOG), European Society of Therapeutic Radiology and Oncology(ESTRO) and
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National Cancer Institute of Canada(NCIC). Two were from a single institution. The guideline topics
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were delineation of OARs(20), primary CTV(CTV1)(21, 22), pelvic nodal CTV(CTV2)(23-25), and both primary and nodal CTV(26). All contained pictorial images to aid explanation. Whilst there are no published guidelines for para-aortic nodal(CTV3) delineation, there are articles describing cervical cancer para-aortic node distribution with delineation suggestions(27-29). RTOG published a consensus panel atlas in 2012 for normal pelvic tissues(20) as variability had been observed within gynaecological, urological and gastrointestinal trials. These are the only OAR delineation guidelines published. In 2011 an international Gynaecology IMRT consortium published guidelines for primary CTV(CTV1) delineation in the definitive treatment of cervical cancer(21). This consortium included RTOG, NCIC, JCOG and ESTRO representatives. In the same year the Radiation Therapy Study Group of JCOG published guidelines following increased IMRT use in Japan. They undertook a comprehensive literature review and examined multiple test cases prior to reaching a consensus(22). In 2013, Bansal
ACCEPTED MANUSCRIPT et al from the Postgraduate Institute of Medical Education and Research(PGI) in Chandighar, India
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published a literature review and their guidelines for cervical primary and nodal CTV(26). Taylor et al(2005) investigated pelvic lymph node distribution by intravenous administration of iron
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oxide particles before MRI. They demonstrated that a 7mm margin around blood vessels with minor
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modifications achieves 99% pelvic nodal coverage. This led to their 7mm margin recommendation for pelvic nodal delineation(23). Dinniwell et al(2009) applied a similar investigation method based
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on a cohort including only 5 cervical cancer cases and recommend a 9-12mm expansion depending upon the anatomic region(30). Shih et al recommend a 20mm margin after applying a similar technique for prostate cancer without considering the implications for normal tissue coverage(31).
PGI(24-26).
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Positive para-aortic nodal case review
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The 7mm margin proposed by Taylor et al has been adopted by RTOG collaboration, JCOG and
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Eleven cervical cancer patients with radiologically enlarged para-aortic nodes at presentation were treated with chemoradiotherapy between 2010 and 2014. Imaging review showed 3 cases with left para-aortic nodes only, 2 with aortocaval and left para-aortic, 6 with aortocaval only, and no cases with right para-caval nodes, in line with published data(28, 29). Areas of variation and best practice recommendations Ten areas of variation in practice were identified; three for OARs, three for CTV1 and four for CTV2. No complete guidance was found for para-aortic nodal CTV delineation. OAR definition Discrepancies between RTOG published recommendations(20) and clinical practice observed in INTERLACE relate to the femur and bowel outlines(Table 2). Pragmatically, our atlas includes anus and rectum as one structure. As knowledge increases regarding dose toxicity effects anus and rectum may be delineated separately. Dose delivered to bone marrow should be considered when
ACCEPTED MANUSCRIPT using IMRT chemo-radiation. However, no published recommendations exist for bone marrow delineation and many centres use automated pelvic bone delineation as a surrogate. We have
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therefore not included this OAR in our atlas.
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Femur definition
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Differences were observed between INTERLACE centres in defining the femoral outline. The INTERLACE protocol version 1 recommended delineation of femoral head alone, consistent with
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many centres’ observed practice. However, hip osteoradionecrosis is a rare but significant late complication, impacting on quality of life(32). The mechanism of osteoradionecrosis is not fully understood and may relate to femoral neck radiation dose. It was therefore agreed to follow the RTOG recommendation and include the whole proximal femur to the inferior margin of the lesser
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Bowel definition
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trochanter(20)(Fig.1a,1b).
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Differences in UK practice were observed in INTERLACE regarding bowel delineation with some centres outlining the abdominal cavity (bowel bag) whilst others outline individual bowel loops. Dose volume parameters predict acute toxicity for both bowel loops and bowel bag(33-35). Bowel volume receiving 45Gy is a documented toxicity predictor(36). Approximately 80% of bowel loops move location during a course of treatment. This leads to underestimation of bowel volume receiving 45Gy by approximately 10% if bowel loops are outlined(35). It was therefore agreed best practice is delineation of the RTOG ‘bowel bag’ to ensure safer practice(20). This ‘bowel bag’ concept is novel for some UK centres. Clarity of the steps required to create this structure is essential for consistency. The first step is to outline the abdominal cavity. RTOG then recommend clinicians ‘subtract any overlapping non-GI normal structures’. The bladder and uterus(CTV1) should therefore be subtracted. No clear guidance exists regarding whether CTV2(pelvic nodal CTV) should be subtracted. CTV2, discussed below in detail, represents the location of nodes at risk of microscopic disease. Bowel loops can overlap with this area but this is unlikely to happen daily. Overlapping
ACCEPTED MANUSCRIPT competing structures are problematic for some IMRT treatment planning systems so it was agreed
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that best practice is to subtract CTV2 from bowel bag(Fig.1c-f). CTV1 definition
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Published guidelines for CTV1 tissue coverage are consistent and include uterus, ovaries if visible,
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GTV (with no margin) to include whole cervix and entire extent of local disease, vagina and bilateral parametria(Fig.2a-h). There are practice differences observed in INTERLACE and these guidelines
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regarding the extent and definition of vagina and parametria(Table 2). INTERLACE CTV1 to PTV1 margins are 15-20mm anterior-posteriorly, superior-inferiorly and 7-10mm laterally for 3D-CRT. If using IMRT these may be increased to encompass organ motion or adaptive radiotherapy should be
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applied, the details of which are beyond this study’s scope. Vagina
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Published guidelines recommend treating the upper half if there is no vaginal involvement, upper
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2/3 if upper vagina is involved and whole vagina if there is extensive involvement. INTERLACE protocol recommends treating the upper half of the vagina or 2cm below known disease, whichever is longer. In practice, the difference between these two definitions is small. Sometimes, including 2cm below known disease creates shorter outlines. It was concluded that inclusion of 2cm below known disease is adequate. This is a more consistent method and avoids the ambiguity of differentiating ‘upper’ from ‘extensive’ involvement. INTERLACE RTQA experience has highlighted difficulty in vagina outlining, in particular defining the superior and inferior(introitus) aspects on CT. Agreement was to recommend using the clitoral crura as a marker for the introitus(Appendix Fig.2.6)(37). In addition to clinical examination and MRI some centres use fiducial markers(38, 39) and vaginal dobbies(40) to localise vagina or tumour extent. Vaginal dobbies distort anatomy and fiducial markers involve a surgical procedure and can move. Neither method is routine UK practice.
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The lateral border of the parametrial volume in the Gyn IMRT consortium, JCOG and PGI guidelines is quoted as the pelvic sidewall, which they define as the ‘medial edge of the internal obturator muscle
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and ischial ramus’. However observed practice in INTERLACE and anatomical definition of the lateral
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parametria is the peritoneal reflection. Surgically, parametrial resection will not extend beyond the vessels(41). Despite these discrepancies we agreed to use the medial edge of muscle or bone as the
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lateral border. This is a more readily reproducible anatomical boundary. This does lead to overlap between CTV1 and CTV2 which should not be edited.
Posterior parametrial border definition varies between guidelines and according to FIGO stage. RTOG and PGI recommend inclusion of the whole mesorectum in patients with FIGO IIIb disease.
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JCOG guidance suggests inclusion of perirectal tissue when there is bulky central tumour or
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extensive parametrial involvement. These approaches ensure inclusion of mesorectal pre-sacral nodes. Modern imaging more easily identifies mesorectal involvement. Including the mesorectum
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within the CTV increases the irradiated volume. On balance, it was decided to only include the mesorectum or perirectal tissue where there is clinical or radiological involvement by tumour. Table 3 and appendix Fig.2.4 define the parametrial borders. CTV2 definition
RTOG, Taylor et al and PGI guidelines agree regarding which nodal groups to include in CTV2. However, variation exists regarding the superior and inferior nodal extent, the inclusion or otherwise of the sacral foramina, the subtraction of OARs and the margin around enlarged nodes. Superior border of CTV2 RTOG define the superior transverse slice of CTV2 by bony anatomy; 7mm inferior to the L4/5 junction(24). This approach was adopted when two-dimensional imaging was used. Taylor et al,
ACCEPTED MANUSCRIPT JCOG and PGI recommend that CTV2 should extend to the aortic bifurcation(23, 25, 26). We agree
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with this as the risk of nodal micro-metastases is not limited by bony anatomy. Inferior border of CTV2
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RTQA experience highlights clinical CTV2 inferior border definition varies widely. This relates to
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obturator nodal coverage which is still debated. Taylor et al illustrated coverage of nodes inferiorly to the level of the mid-femoral heads(42). RTOG define the inferior extent at the superior border of
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the femoral heads. JCOG extend coverage inferiorly to the level of the superior aspect of the obturator foramen(25). Anatomically the obturator nodes extend inferiorly to obturator foramen which is lower than the superior border of the femoral heads. We therefore agree with Taylor et al and recommend outlining up to approximately 1cm above the obturator foramen. Depending upon
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Steps to create CTV2
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pelvic tilt, this often corresponds to the mid femoral head.
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RTOG guidance recommends subtraction of bladder and bowel from CTV2. This has been observed practice in INTERLACE. However, concern exists because bowel is not a fixed structure and bladder filling is variable. For this reason we do not recommend editing CTV2 for bladder and bowel as it may result in inadequate nodal coverage.
Inferiorly, Taylor et al recommend using an 18mm wide strip to cover the obturator nodal region. Previously, editing for bladder would narrow this outline. Therefore it was agreed to recommend a narrower strip(10-18mm) to cover the obturator nodes. This is only applicable below the superior margin of the femoral head, i.e. below the external iliac volume(Appendix Fig.3.7). Sacral foramina Within the INTERLACE study variation was noted regarding inclusion of the sacral foramina in CTV2. Published guidelines give no recommendation regarding coverage of the foramina. Inclusion leads to
ACCEPTED MANUSCRIPT an increased risk of insufficiency fractures and impaired quality of life(43). In view of this, it was
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decided to exclude the sacral foramina but include the presacral space(Appendix Fig.3.3). Margin around enlarged nodes
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PGI guidelines suggest a 10mm margin from enlarged nodes to CTV. RTOG and JCOG guidance do not
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make any recommendation. Enlarged nodes are usually well defined on CT and MR. It was therefore agreed that the CTV2 around an enlarged node would be achieved by adding the 7mm margin
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around blood vessels plus an additional 5mm margin to allow for extracapsular nodal extension. Fig.3 depicts CTV2 outlining instructions. This step-by-step approach can be laborious. Therefore, clinicians with extensive experience may freehand delineate CTV2 using a tool such as pearl to
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ensure a 7mm margin around blood vessels.
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CTV3 definition
Whilst there are no published guidelines addressing delineation of the para-aortic nodal volume
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there are articles describing para-aortic node distribution using fluorodeoxyglucose positron emission tomography(27-29). Extrapolating from pelvic nodal contouring the para-aortic nodal outline is often created by adding a 7mm margin around blood vessels and editing for bone and muscle. In practice this is often edited to minimise kidney dose especially near the inferior vena cava(IVC). This is neither consistent nor easily reproducible. Following the case review described above, it is proposed that a 7mm margin around the entire IVC is unnecessary. Inclusion of the aortocaval space is essential. This recommendation is consistent with published data. Less than 6% of nodes are found in the right para-caval region(28, 29). Guidelines exist for para-aortic nodal delineation for other cancers, e.g. pancreatic cancer, which recommend a margin around the aorta only. This is unlikely to ensure adequate coverage in cervical cancer(29). Thus it is proposed that a 7mm margin is used around the aorta and medial half of the IVC(Appendix Fig.4.1). This should only be edited to minimise renal dose as a last resort.
ACCEPTED MANUSCRIPT The pictorial atlas illustrating the entire delineation process for CTV1, CTV2, CTV3 and all OARs is in
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Appendix 1. Atlas validation (Table 4)
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64 cases were reviewed before atlas use and 30 after. Mean score(maximum 4) was 1.8 before and
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2.7 after;difference 0.9(95%CI0.3-1.5,p=0.003). The score distribution also improved. Before atlas implementation 67% scored 0-2 compared with 40% after. 25% less cases scored 0 after atlas
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implementation and 19% more cases scored 3 after implementation. All four structures’ compliance improved significantly (p=0.004). Rectum improved most(33%) and CTV1 least(18%). As expected, CTV1 and CTV2 were less compliant than bladder and rectum.
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These results suggest an improvement in delineation standards with atlas use. CTV2 is least compliant pre and post atlas despite existing guidance and substantial detail. This may represent
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differences in usual practice. The overall improvement may be due to increasing protocol familiarity
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and ongoing RTQA feedback. The cases before atlas use were proportionately more test cases. However, when outlining trial test cases more effort is made to follow protocol and therefore compliance should not be affected. Finally, this comparison is not like for like. The compared cases are not identical as some are real-time review. Results could therefore represent inter-observer variation. Even considering these confounders the results suggest that atlas use improves practice. Conclusion With an increasing focus on minimising radiotherapy toxicity, IMRT is being adopted in the treatment of cervical cancer(44, 45). An essential component of this process is accurate delineation of target volumes and OARs. This paper has attempted to refine best practice for contour delineation by combining data from 7 published guidelines and an in-depth analysis of the INTERLACE trial RTQA. The complete step-by-step atlas(Appendix 1) includes more detailed images than previously available. This atlas is included in the INTERLACE RTQA manual and ongoing RTQA
ACCEPTED MANUSCRIPT monitoring has already shown the beneficial impact. This publication together with the detailed step-by-step pictorial atlas will hopefully provide an additional resource for oncologists and continue
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to reduce inter-observer variation.
ACCEPTED MANUSCRIPT Fig.1: Transverse (a,c,d,e), coronal (b) and sagittal (f) CT with left femur (solid arrows in a,b) and right femur (dashed arrows in a,b) outlined. Bowel bag is outlined (arrowed in c-f) and bladder (triangle in
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e,f), rectum (square in e,f), uterus/CTV1 (cross in e,f) and CTV2 (diamond in e) edited out of initial
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volume seen in e and f.
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Fig.2: Transverse (a,c,e-h) and sagittal (b,d) CT with uterine corpus (cross, arrowed in a,b), ovaries (arrowed in e,f,h), uterine cervix (star, arrowed in c,d) and vagina (triangle) outlined.
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Fig.3: CTV2(nodal) step-by-step outlining guidance with 3d,h,l illustrating completed outline: Transverse CT 1cm inferior to aortic bifurcation (a-d), at iliac bifurcation (e-h) and at distal internal and external iliac vessels (i-l). Vessels (common iliac in a) are outlined (a,e,i), a circumferential 7mm margin added (b,f,j), muscle and bone is edited out (c,g,k), the outline is extended to include the area between psoas muscle and vertebral body (solid
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arrow in d, h), presacral strip is added (dashed arrow in h) and an 18mm (solid arrows in l) strip is added to cover
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obturator/infra-iliac nodal region. The gluteal vessels (dashed arrows in l) should not be included.
ACCEPTED MANUSCRIPT References
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19. Deasy JO, Blanco AI, Clark VH. CERR: a computational environment for radiotherapy research. Med Phys 2003;30(5):979-85. 20. Gay HA, Barthold HJ, O'Meara E, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys 2012 Jul 1;83(3):e353-62. 21. Lim K, Small W, Jr., Portelance L, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys 2011 Feb 1;79(2):348-55. 22. Toita T, Ohno T, Kaneyasu Y, et al. A consensus-based guideline defining clinical target volume for primary disease in external beam radiotherapy for intact uterine cervical cancer. Jpn J Clin Oncol 2011 Sep;41(9):1119-26. 23. Taylor A, Rockall AG, Reznek RH, Powell ME. Mapping pelvic lymph nodes: guidelines for delineation in intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2005;63(5):1604-12. 24. Small W, Jr., Mell LK, Anderson P, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol Phys 2008 Jun 1;71(2):428-34. 25. Toita T, Ohno T, Kaneyasu Y, et al. A consensus-based guideline defining the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer. Jpn J Clin Oncol 2010 May;40(5):456-63. 26. Bansal A, Patel FD, Rai B, et al. Literature review with PGI guidelines for delineation of clinical target volume for intact carcinoma cervix. J Cancer Res Ther 2013 Oct-Dec;9(4):574-82. 27. Fontanilla HP, Klopp A, Lindberg BS, et al. Anatomic distribution of (18F) fluorodeoxyglucoseavid lymph nodes in patients with cervical cancer. Prac Radiat Oncol 2013;3:45-53. 28. Takiar V, Fontanilla HP, Eifel PJ, et al. Anatomic distribution of fluorodeoxyglucose-avid paraaortic lymph nodes in patients with cervical cancer. Int J Radiat Oncol Biol Phys 2013;85(4):1045-50. 29. Kabolizadeh P, Fulay S, Beriwal S. Are Radiation Therapy Oncology Group para-aortic contouring guidelines for pancreatic neoplasm applicable to other malignancies- Assessment of nodal distribution in gynecological malignancies. Int J Radiat Oncol Biol Phys 2013;87(1):106-10. 30. Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009 Jul 1;74(3):844-51. 31. Shih HA, Harisinghani M, Zietman A, et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume for pelvic nodal irradiation based on vascular rather than bony anatomy. Int J Radiat Oncol Biol Phys 2005;63(4):1262-9. 32. Mehmood Q, Beardwood M, Swindell R, et al. Insufficiency fractures in patients treated with pelvic radiotherapy and chemotherapy for uterine and cervical cancer. Eur J Cancer care 2014;23(1):43-50. 33. Banerjee R, Chakraborty S, Nygren I, Sinha R. Small bowel dose parameters predicting grade 3 acute toxicity in rectal cancer patients treated with neoadjuvant chemoradiation: an independent validation study comparing peritoneal space versus small bowel loop contouring techniques. Int J Radiat Oncol Biol Phys 2013;85(5):1225-31. 34. Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy. Radiother Oncol 2003;69(2):201-7. 35. Sanguineti G, Little M, Endres EJ, et al. Comparison of three strategies to delineate the bowel for whole pelvis IMRT of prostate cancer. Radiother Oncol 2008;88:95-101. 36. Simpson DR, Song WY, Moiseenko V, et al. Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. Int J Radiat Oncol Biol Phys 2012;83(1):e81-6. 37. O'Connell HE, DeLancey JOL. Clitoral anatomy in the nulliparous, healthy, premenopausal volunteers using unenhanced magnetic resonance imaging. J Urol 2005;173:2060-3.
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38. Jhingran A, Salehpour M, Sam M, et al. Vaginal motion and bladder and rectal volumes during pelvic intensity-modulated radiation therapy after hysterectomy. Int J Radiat Oncol Biol Phys 2012 Jan 1;82(1):256-62. 39. Heijkoop ST, Langerak TR, Quint S, et al. Clinical implementation of an Online Adaptive Planof-the-Day Protocol for Nonrigid Motion Management in Locally Advanced Cervical Cancer IMRT. Int J Radiat Oncol Biol Phys 2014;90(3):673-9. 40. Ma DJ, Michaletz-Lorenz M, Goddu SM, Grigsby PW. Magnitude of interfractional vaginal cuff movement: implications for external irradiation. Int J Radiat Oncol Biol Phys 2012 Mar 15;82(4):1439-44. 41. Nakamura M, Fujii T, Imanishi N, et al. Surgical anatomy imaging associated with cervical cancer treatment: A cadaveric study. Clin Anat 2014;27(3):503-10. 42. Taylor A, Rockall AG, Powell ME. An atlas of the pelvic lymph node regions to aid radiotherapy target volume definition. Clin Oncol 2007 Sep;19(7):542-50. 43. Ikushima H, Osaki K, Furuntani S, et al. Pelvic bone complications following radiation therapy of gynaecologic malignancies: clinical evaluation of radiation-induced pelvic insufficiency fractures. Gynecol Oncol 2006;103:1100-4. 44. Mundt AJ, Lujan AE, Rotmensch J, et al. Intensity-modulated whole pelvic radiotherapy in women with gynaecologic malignancies. Int J Radiat Oncol Biol Phys 2002;52(5):1330-7. 45. Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56(5):1354-60.
ACCEPTED MANUSCRIPT
Year 2013
Title Literature review with PGI guidelines for delineation of clinical target volume for intact carcinoma cervix
Gay(18) RTOG Panel
2012
Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy:A Radiation Therapy Oncology Group Consensus
Lim(19) RTOG Gyn IMRT consortium Small(22) RTOG (GOG, ESTRO, NCIC, ACRIN) Taylor(21)
2011
Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer Mapping Pelvic Lymph nodes:guidelines for delineation in intensity-modulated radiotherapy
Toita(23) JCOG
2010
Toita(20) JCOG
2011
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Contents Definition of nodal and primary CTV; CTV nodal to include common, external and internal iliac, pre-sacral and obturator, CTV primary includes GTV, uterine cervix, uterine corpus, parametrium, upper vagina and uterosacral ligaments Definition of pelvic normal tissue contouring atlas: for gynae details AnoRectum, Sigmoid, BowelBag, Bladder, Uterocervix, Adnexa, Femur CTV including GTV, cervix, uterus, parametria (borders defined ovaries, vaginal tissues
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Authors(ref) Bansal(24) PGI
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Table 1:Published cervical cancer radiotherapy delineation guidelines.
A consensus-based guideline defining the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer A consensus-based guideline defining clinical target volume for primary disease in external beam radiotherapy for intact uterine cervical cancer
CTV definition for postoperative cervical/endo including common, external, internal iliac, presacral nodal regions, Upper vagina and paravaginal tissue lateral to vagina also Recommended nodal CTV guidelines based on modified 7mm margin around blood vessels;common, internal/external iliac, obturator and presacral regions Pelvic nodal CTV definition;common, external/ obturator, presacral regions Primary CTV definition for cervical cancer; GTV, uterine cervix, uterine corpus, parametrium (borders defined), vagina
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Lateral parametrial border
Posterior parametrial border
CTV2 Nodal (21-24)
Inferior obturator nodal border Subtraction of bladder/bowel Sacral foramina inclusion Superior CTV2 border
CTV3 PAnodes
Enlarged nodes margin Definition
RTOG: bony anatomy Taylor et al, JCOG, PGI: aortic bifurcation PGI: 10mm around enlarged node No guidance
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Discussion Beams travel through proximal femur, osteoradionecrosis aetiology unclear Bowel moves daily in abdominal cavity therefore bag representative CTV1 should be subtracted CTV2 should also be subtracted as bowel unlikely to overlap daily Volumes similar; 2cm below disease smaller. 2cm margin on disease (EUA/MRI) adequate and clearer to define/reproducible Even though medial sidewall is peritoneal reflection RTOG/JCOG definition is more reproducible and practical Improved imaging techniques detect uterosacral ligaments and mesorectum involvement Obturator nodes are at risk and leave pelvis just above the obturator foramen
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RTOG, JCOG, PGI:upper 1/2 if no vaginal disease, 2/3 if upper, 3/3 if extensive INTERLACE: upper ½/2cm below disease RTOG, JCOG and PGI:pelvic sidewall defined as muscle/ischial ramus Medial sidewall is peritoneal reflection RTOG, PGI:entire mesorectum if FIGO 3b JCOG:include perirectal tissue if significant parametrial involvement PGI, JCOG: superior obturator foramen RTOG:superior femoral head Taylor:mid femoral head JCOG:bowel not excluded RTOG bowel and bladder excluded RTOG, JCOG, PGI: exclude sacral foramina
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Vaginal length
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CTV1 Primary (19,20, 24)
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Subtract CTV from bowel
Published guidance/clinical practice RTOG:proximal femur Observed practice variable RTOG:bowel bag Observed practice variable RTOG:subtraction of ‘any overlapping nonGI structures’
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OAR (17)
Area of variation Femoral head vs proximal femur Bowel bag vs loops
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Table 2:Areas of variation regarding cervical cancer radiotherapy OAR and CTV definition Our recommendation Proximal femur Bowel bag Subtract CTV1&CTV2 from bowel Upper ½ or 2cm below disease
Bowel and bladder position varies according to daily variation, bladder filling etc. No evidence inclusion necessary, increases bone toxicity Should relate to nodal not bony anatomy
Medial edge of internal obturator muscle/ischial ramus Include mesorectum only if radiologically or clinically involved 1cm superior to obturator foramen/ mid-femoral head Only subtract bone and muscle Exclude sacral foramina Aortic bifurcation
Nodes well defined but margin needed Nodal disease seen around aorta/aortocaval area
3-5mm margin Aorta and medial half IVC with 7mm margin
ACCEPTED MANUSCRIPT Table 3:Parametrial border definitions Definition (arrowed and numbered Appendix Fig.2.4) Fallopian tube or broad ligament(1)(RTOG) Uterine artery enters uterus(2)(JJCO) Inferior Levator ani/pelvic floor muscles(3) Anterior Posterior bladder(4) or posterior border of external iliac vessels(5) Posterior Mesorectal fascia and uterosacral ligaments(6) Lateral Lateral pelvic sidewall; medial internal obturator(7)/piriformis muscle(8)/ischial ramus(9) Medial Cervix
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Border Superior
No after (30)
% after
Difference (%)
0 1 2 3 4
18 12 13 9 12
28 19 20 14 19
1 3 8 10 8
3 10 27 33 27
-25 -9 7 19 8
Bladder Rectum CTV1 CTV2
38 30 25 16
25 24 17 15
83 80 57 50
24 33 18 25
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% before
59 47 39 25
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Structure Compliance
No before (64)
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Total score (max 4)
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Table 4:Proportion of protocol compliant outlines before and after atlas use.
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Figure 1
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S1879-8500(16)00008-4 doi: 10.1016/j.prro.2016.01.006 PRRO 593
To appear in:
Practical Radiation Oncology
Received date: Revised date: Accepted date:
14 November 2015 21 December 2015 8 January 2016
Please cite this article as: Eminowicz Gemma, Craggs Margaret-Hall, Diez Patricia, McCormack Mary, Improving target volume delineation in intact cervical carcinoma: literature review and step-by-step pictorial atlas to aid contouring, Practical Radiation Oncology (2016), doi: 10.1016/j.prro.2016.01.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Improving target volume delineation in intact cervical carcinoma: literature review and step-by-step pictorial atlas to aid contouring. Short title: A cervical cancer delineation pictorial atlas.
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Authors:
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Dr Gemma Eminowicz FRCR, MSc, University College Hospital London, UK Dr Margaret-Hall-Craggs1 FRCR, MD, University College Hospital London, UK Ms Patricia Diez MSci MSc, Mount Vernon Cancer Centre, Northwood, UK Dr Mary McCormack PhD MBBS FRCR, University College Hospital London, UK 1
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Corresponding author: Dr Gemma Eminowicz Upper flat 103 Lady Margaret Road London N19 5ER Mobile: 00447974219684 Email: [email protected]
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This work was undertaken at UCLH/UCL, which receives funding from the Department of Health’s NIHR Biomedical Research Centre funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health.
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Type of paper: Special article/pictorial guidelines Abstract word count: 218
Full word count excluding references and tables: 3438 No. of Pages: 16 No. of Tables: 4 No. of Figures: 3
Key words: Cervix cancer radiotherapy; Delineation guidelines; Nodal contouring
Acknowledgments: To the INTERLACE Trial Management Group, the INTERLACE participating centres and Cancer Research UK for funding the INTERLACE trial.
The authors declare that they have no conflict of interest or financial disclosure and that ethical research standards were observed.
ACCEPTED MANUSCRIPT Abstract
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Background Accurate delineation of target volume and normal tissue is critical for Intensity-Modulated
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Radiotherapy (IMRT) use in cervical cancer. The INTERLACE trial radiotherapy quality assurance
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(RTQA) has highlighted significant inter-observer delineation variation. Prescriptive guidelines
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reduce inter-observer variation in other cancers. Methods
A literature search using pubmed/medline database of guidelines for target anatomy delineation in cervical cancer was undertaken. Differences in practice in these publications and INTERLACE trial
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RTQA were identified. Consensus best practice delineation was derived and pictorial atlas produced. The proportion of outlines complying with protocol in test and real-time cases was compared before
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Results
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and after atlas implementation within the INTERLACE RTQA pack.
Seven key papers were reviewed. Eleven areas of variation were identified. These include the definition and editing of bowel, definition of the femur, vagina, parametria, inferior and superior nodal borders, nodal CTV editing, para-aortic nodal CTV definition, and the margin to be used around enlarged nodes. The average proportion of outlines (out of 4; primary CTV, nodal CTV, bladder, rectum) complying with protocol in test and real-time cases improved from 1.8 to 2.7 (difference 0.9;95%CI0.3-1.5,p=0.003) with atlas use. Conclusion Differences exist in the published literature and clinical practice. This pictorial atlas reflects consensus recommendations and is now available to INTERLACE participating centres. Atlas use has reduced inter-observer delineation variation in this trial setting.
ACCEPTED MANUSCRIPT Chemo-radiotherapy is given with curative intent for locally advanced cervical cancer. Intensity Modulated Radiotherapy(IMRT) reduces organs at risk(OARs) dose compared to three-dimensional
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conformal radiotherapy(3D-CRT)(1, 2) as it conforms closer to target volumes reducing toxicity
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rates(3, 4). IMRT is now used for locally advanced cervical cancer across Europe, the United
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Kingdom(UK) and has increased four-fold in the United States(US) between 2004 and 2011 (5). Accurate target volume delineation is critical to ensure tumour coverage and OAR sparing.
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Significant delineation variation exists between clinicians (inter-observer variation) across multiple tumour sites(6-11). This has been demonstrated for cervical gross tumour volume(GTV) and high risk clinical target volume(HR-CTV) for image guided brachytherapy(IGBT)(12, 13). This has also been demonstrated for cervical clinical target volume(CTV) for external beam radiotherapy (EBRT) within
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the INTERLACE trial radiotherapy quality assurance(RTQA)(14). This is in line with other
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publications(15, 16). Use of detailed delineation guidelines has been shown to reduce inter-observer variation in prostate bed radiotherapy within the RADICALS trial(17) and HR-CTV in cervical
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brachytherapy(12, 13).
The aim of this study was to review the recent literature, highlight and resolve inconsistencies in current published guidelines, and produce a detailed pictorial delineation atlas for cervical cancer radiotherapy, attempting to reduce inter-observer variation. The impact of this atlas was assessed after inclusion within the INTERLACE RTQA pack. The simulation process including precautions to minimise and methods to account for internal organ position variation are not discussed. The atlas presented here is applicable to all patients independent of simulation process. Brachytherapy delineation is also beyond this study’s scope and detailed guidance exists(18). Methods A literature search was performed using the Pubmed/Medline central database with the MESH terms ‘uterine cervical neoplasm’, ‘radiotherapy’ and ‘guidelines as topic’ in combination with the Pubmed search terms ‘contouring’, ‘outlining’, ‘atlas’ and ‘target volume definition’. Articles
ACCEPTED MANUSCRIPT published within the last ten years that included delineation guidelines for cervical cancer were selected and reviewed. The references within these articles were reviewed to ensure no key articles
primary CTV, to include GTV, uterus, bilateral ovaries if seen, bilateral parametria,
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were missed. The articles referred to delineation of:
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uterosacral ligaments, and vagina (referred to as CTV1)
pelvic nodal CTV, to include common iliac, internal and external iliac, subaortic pre-sacral
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and obturator nodal regions (referred to as CTV2)
para-aortic nodal CTV (referred to as CTV3)
OARs; anorectum, bladder, right femur, left femur, bowel, right kidney, left kidney and
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spinal cord
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CERR(19) was used to review 21 participating centres’ INTERLACE RTQA cases outlining. The quantitative analysis is previously published(14). To identify areas of variation, outlines were viewed
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simultaneously. The proportion of centres outlining specified anatomical areas was calculated. Inconsistencies within and between the published guidelines, routine UK practice and the INTERLACE RTQA experience were highlighted as variations in practice. These identified variations were reviewed within the INTERLACE Trial Management Group(TMG). The TMG includes 6 clinical oncologists, 1 RTQA physicist and 3 medical oncologists. The TMG discussed the identified variations and collated individual expert opinion. Subsequent best practice was agreed. Anonymised example patients were used to demonstrate the agreed step by step instructions and produce the complete pictorial atlas. An expert gynaecological radiologist reviewed the atlas to ensure anatomical accuracy. Oncologists at our institute applied the atlas in clinical practice to ensure comprehension. All chemoradiotherapy cases with involved para-aortic nodes treated between 2010 and 2014 at our institute were reviewed. The diagnostic imaging was examined to record the location of enlarged para-aortic nodes. This assisted with CTV3 outlining recommendations.
ACCEPTED MANUSCRIPT To validate this atlas, protocol compliance was monitored within INTERLACE RTQA. For each test and real time case the RTQA team reports changes necessary. Using these reports the number of
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structures requiring changes out of Bladder, Rectum, CTV1 and CTV2 was recorded. A well
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delineated case with no changes recommended scores 4. If all structures required changes the score
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is 0. Score comparison before and after atlas inclusion in the RTQA pack was made using an independent samples t-test.
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Results and Discussion Literature review results
Seven key articles on gynaecology radiotherapy guidelines were identified and reviewed(Table 1).
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Five were written by collaborative groups; Radiation Therapy Oncology Group(RTOG), Japan Clinical Oncology Group(JCOG), European Society of Therapeutic Radiology and Oncology(ESTRO) and
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National Cancer Institute of Canada(NCIC). Two were from a single institution. The guideline topics
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were delineation of OARs(20), primary CTV(CTV1)(21, 22), pelvic nodal CTV(CTV2)(23-25), and both primary and nodal CTV(26). All contained pictorial images to aid explanation. Whilst there are no published guidelines for para-aortic nodal(CTV3) delineation, there are articles describing cervical cancer para-aortic node distribution with delineation suggestions(27-29). RTOG published a consensus panel atlas in 2012 for normal pelvic tissues(20) as variability had been observed within gynaecological, urological and gastrointestinal trials. These are the only OAR delineation guidelines published. In 2011 an international Gynaecology IMRT consortium published guidelines for primary CTV(CTV1) delineation in the definitive treatment of cervical cancer(21). This consortium included RTOG, NCIC, JCOG and ESTRO representatives. In the same year the Radiation Therapy Study Group of JCOG published guidelines following increased IMRT use in Japan. They undertook a comprehensive literature review and examined multiple test cases prior to reaching a consensus(22). In 2013, Bansal
ACCEPTED MANUSCRIPT et al from the Postgraduate Institute of Medical Education and Research(PGI) in Chandighar, India
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published a literature review and their guidelines for cervical primary and nodal CTV(26). Taylor et al(2005) investigated pelvic lymph node distribution by intravenous administration of iron
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oxide particles before MRI. They demonstrated that a 7mm margin around blood vessels with minor
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modifications achieves 99% pelvic nodal coverage. This led to their 7mm margin recommendation for pelvic nodal delineation(23). Dinniwell et al(2009) applied a similar investigation method based
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on a cohort including only 5 cervical cancer cases and recommend a 9-12mm expansion depending upon the anatomic region(30). Shih et al recommend a 20mm margin after applying a similar technique for prostate cancer without considering the implications for normal tissue coverage(31).
PGI(24-26).
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Positive para-aortic nodal case review
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The 7mm margin proposed by Taylor et al has been adopted by RTOG collaboration, JCOG and
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Eleven cervical cancer patients with radiologically enlarged para-aortic nodes at presentation were treated with chemoradiotherapy between 2010 and 2014. Imaging review showed 3 cases with left para-aortic nodes only, 2 with aortocaval and left para-aortic, 6 with aortocaval only, and no cases with right para-caval nodes, in line with published data(28, 29). Areas of variation and best practice recommendations Ten areas of variation in practice were identified; three for OARs, three for CTV1 and four for CTV2. No complete guidance was found for para-aortic nodal CTV delineation. OAR definition Discrepancies between RTOG published recommendations(20) and clinical practice observed in INTERLACE relate to the femur and bowel outlines(Table 2). Pragmatically, our atlas includes anus and rectum as one structure. As knowledge increases regarding dose toxicity effects anus and rectum may be delineated separately. Dose delivered to bone marrow should be considered when
ACCEPTED MANUSCRIPT using IMRT chemo-radiation. However, no published recommendations exist for bone marrow delineation and many centres use automated pelvic bone delineation as a surrogate. We have
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therefore not included this OAR in our atlas.
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Femur definition
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Differences were observed between INTERLACE centres in defining the femoral outline. The INTERLACE protocol version 1 recommended delineation of femoral head alone, consistent with
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many centres’ observed practice. However, hip osteoradionecrosis is a rare but significant late complication, impacting on quality of life(32). The mechanism of osteoradionecrosis is not fully understood and may relate to femoral neck radiation dose. It was therefore agreed to follow the RTOG recommendation and include the whole proximal femur to the inferior margin of the lesser
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Bowel definition
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trochanter(20)(Fig.1a,1b).
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Differences in UK practice were observed in INTERLACE regarding bowel delineation with some centres outlining the abdominal cavity (bowel bag) whilst others outline individual bowel loops. Dose volume parameters predict acute toxicity for both bowel loops and bowel bag(33-35). Bowel volume receiving 45Gy is a documented toxicity predictor(36). Approximately 80% of bowel loops move location during a course of treatment. This leads to underestimation of bowel volume receiving 45Gy by approximately 10% if bowel loops are outlined(35). It was therefore agreed best practice is delineation of the RTOG ‘bowel bag’ to ensure safer practice(20). This ‘bowel bag’ concept is novel for some UK centres. Clarity of the steps required to create this structure is essential for consistency. The first step is to outline the abdominal cavity. RTOG then recommend clinicians ‘subtract any overlapping non-GI normal structures’. The bladder and uterus(CTV1) should therefore be subtracted. No clear guidance exists regarding whether CTV2(pelvic nodal CTV) should be subtracted. CTV2, discussed below in detail, represents the location of nodes at risk of microscopic disease. Bowel loops can overlap with this area but this is unlikely to happen daily. Overlapping
ACCEPTED MANUSCRIPT competing structures are problematic for some IMRT treatment planning systems so it was agreed
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that best practice is to subtract CTV2 from bowel bag(Fig.1c-f). CTV1 definition
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Published guidelines for CTV1 tissue coverage are consistent and include uterus, ovaries if visible,
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GTV (with no margin) to include whole cervix and entire extent of local disease, vagina and bilateral parametria(Fig.2a-h). There are practice differences observed in INTERLACE and these guidelines
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regarding the extent and definition of vagina and parametria(Table 2). INTERLACE CTV1 to PTV1 margins are 15-20mm anterior-posteriorly, superior-inferiorly and 7-10mm laterally for 3D-CRT. If using IMRT these may be increased to encompass organ motion or adaptive radiotherapy should be
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applied, the details of which are beyond this study’s scope. Vagina
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Published guidelines recommend treating the upper half if there is no vaginal involvement, upper
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2/3 if upper vagina is involved and whole vagina if there is extensive involvement. INTERLACE protocol recommends treating the upper half of the vagina or 2cm below known disease, whichever is longer. In practice, the difference between these two definitions is small. Sometimes, including 2cm below known disease creates shorter outlines. It was concluded that inclusion of 2cm below known disease is adequate. This is a more consistent method and avoids the ambiguity of differentiating ‘upper’ from ‘extensive’ involvement. INTERLACE RTQA experience has highlighted difficulty in vagina outlining, in particular defining the superior and inferior(introitus) aspects on CT. Agreement was to recommend using the clitoral crura as a marker for the introitus(Appendix Fig.2.6)(37). In addition to clinical examination and MRI some centres use fiducial markers(38, 39) and vaginal dobbies(40) to localise vagina or tumour extent. Vaginal dobbies distort anatomy and fiducial markers involve a surgical procedure and can move. Neither method is routine UK practice.
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The lateral border of the parametrial volume in the Gyn IMRT consortium, JCOG and PGI guidelines is quoted as the pelvic sidewall, which they define as the ‘medial edge of the internal obturator muscle
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and ischial ramus’. However observed practice in INTERLACE and anatomical definition of the lateral
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parametria is the peritoneal reflection. Surgically, parametrial resection will not extend beyond the vessels(41). Despite these discrepancies we agreed to use the medial edge of muscle or bone as the
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lateral border. This is a more readily reproducible anatomical boundary. This does lead to overlap between CTV1 and CTV2 which should not be edited.
Posterior parametrial border definition varies between guidelines and according to FIGO stage. RTOG and PGI recommend inclusion of the whole mesorectum in patients with FIGO IIIb disease.
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JCOG guidance suggests inclusion of perirectal tissue when there is bulky central tumour or
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extensive parametrial involvement. These approaches ensure inclusion of mesorectal pre-sacral nodes. Modern imaging more easily identifies mesorectal involvement. Including the mesorectum
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within the CTV increases the irradiated volume. On balance, it was decided to only include the mesorectum or perirectal tissue where there is clinical or radiological involvement by tumour. Table 3 and appendix Fig.2.4 define the parametrial borders. CTV2 definition
RTOG, Taylor et al and PGI guidelines agree regarding which nodal groups to include in CTV2. However, variation exists regarding the superior and inferior nodal extent, the inclusion or otherwise of the sacral foramina, the subtraction of OARs and the margin around enlarged nodes. Superior border of CTV2 RTOG define the superior transverse slice of CTV2 by bony anatomy; 7mm inferior to the L4/5 junction(24). This approach was adopted when two-dimensional imaging was used. Taylor et al,
ACCEPTED MANUSCRIPT JCOG and PGI recommend that CTV2 should extend to the aortic bifurcation(23, 25, 26). We agree
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with this as the risk of nodal micro-metastases is not limited by bony anatomy. Inferior border of CTV2
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RTQA experience highlights clinical CTV2 inferior border definition varies widely. This relates to
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obturator nodal coverage which is still debated. Taylor et al illustrated coverage of nodes inferiorly to the level of the mid-femoral heads(42). RTOG define the inferior extent at the superior border of
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the femoral heads. JCOG extend coverage inferiorly to the level of the superior aspect of the obturator foramen(25). Anatomically the obturator nodes extend inferiorly to obturator foramen which is lower than the superior border of the femoral heads. We therefore agree with Taylor et al and recommend outlining up to approximately 1cm above the obturator foramen. Depending upon
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pelvic tilt, this often corresponds to the mid femoral head.
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RTOG guidance recommends subtraction of bladder and bowel from CTV2. This has been observed practice in INTERLACE. However, concern exists because bowel is not a fixed structure and bladder filling is variable. For this reason we do not recommend editing CTV2 for bladder and bowel as it may result in inadequate nodal coverage.
Inferiorly, Taylor et al recommend using an 18mm wide strip to cover the obturator nodal region. Previously, editing for bladder would narrow this outline. Therefore it was agreed to recommend a narrower strip(10-18mm) to cover the obturator nodes. This is only applicable below the superior margin of the femoral head, i.e. below the external iliac volume(Appendix Fig.3.7). Sacral foramina Within the INTERLACE study variation was noted regarding inclusion of the sacral foramina in CTV2. Published guidelines give no recommendation regarding coverage of the foramina. Inclusion leads to
ACCEPTED MANUSCRIPT an increased risk of insufficiency fractures and impaired quality of life(43). In view of this, it was
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decided to exclude the sacral foramina but include the presacral space(Appendix Fig.3.3). Margin around enlarged nodes
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PGI guidelines suggest a 10mm margin from enlarged nodes to CTV. RTOG and JCOG guidance do not
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around blood vessels plus an additional 5mm margin to allow for extracapsular nodal extension. Fig.3 depicts CTV2 outlining instructions. This step-by-step approach can be laborious. Therefore, clinicians with extensive experience may freehand delineate CTV2 using a tool such as pearl to
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CTV3 definition
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there are articles describing para-aortic node distribution using fluorodeoxyglucose positron emission tomography(27-29). Extrapolating from pelvic nodal contouring the para-aortic nodal outline is often created by adding a 7mm margin around blood vessels and editing for bone and muscle. In practice this is often edited to minimise kidney dose especially near the inferior vena cava(IVC). This is neither consistent nor easily reproducible. Following the case review described above, it is proposed that a 7mm margin around the entire IVC is unnecessary. Inclusion of the aortocaval space is essential. This recommendation is consistent with published data. Less than 6% of nodes are found in the right para-caval region(28, 29). Guidelines exist for para-aortic nodal delineation for other cancers, e.g. pancreatic cancer, which recommend a margin around the aorta only. This is unlikely to ensure adequate coverage in cervical cancer(29). Thus it is proposed that a 7mm margin is used around the aorta and medial half of the IVC(Appendix Fig.4.1). This should only be edited to minimise renal dose as a last resort.
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Appendix 1. Atlas validation (Table 4)
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64 cases were reviewed before atlas use and 30 after. Mean score(maximum 4) was 1.8 before and
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2.7 after;difference 0.9(95%CI0.3-1.5,p=0.003). The score distribution also improved. Before atlas implementation 67% scored 0-2 compared with 40% after. 25% less cases scored 0 after atlas
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implementation and 19% more cases scored 3 after implementation. All four structures’ compliance improved significantly (p=0.004). Rectum improved most(33%) and CTV1 least(18%). As expected, CTV1 and CTV2 were less compliant than bladder and rectum.
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These results suggest an improvement in delineation standards with atlas use. CTV2 is least compliant pre and post atlas despite existing guidance and substantial detail. This may represent
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differences in usual practice. The overall improvement may be due to increasing protocol familiarity
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and ongoing RTQA feedback. The cases before atlas use were proportionately more test cases. However, when outlining trial test cases more effort is made to follow protocol and therefore compliance should not be affected. Finally, this comparison is not like for like. The compared cases are not identical as some are real-time review. Results could therefore represent inter-observer variation. Even considering these confounders the results suggest that atlas use improves practice. Conclusion With an increasing focus on minimising radiotherapy toxicity, IMRT is being adopted in the treatment of cervical cancer(44, 45). An essential component of this process is accurate delineation of target volumes and OARs. This paper has attempted to refine best practice for contour delineation by combining data from 7 published guidelines and an in-depth analysis of the INTERLACE trial RTQA. The complete step-by-step atlas(Appendix 1) includes more detailed images than previously available. This atlas is included in the INTERLACE RTQA manual and ongoing RTQA
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to reduce inter-observer variation.
ACCEPTED MANUSCRIPT Fig.1: Transverse (a,c,d,e), coronal (b) and sagittal (f) CT with left femur (solid arrows in a,b) and right femur (dashed arrows in a,b) outlined. Bowel bag is outlined (arrowed in c-f) and bladder (triangle in
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e,f), rectum (square in e,f), uterus/CTV1 (cross in e,f) and CTV2 (diamond in e) edited out of initial
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volume seen in e and f.
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Fig.2: Transverse (a,c,e-h) and sagittal (b,d) CT with uterine corpus (cross, arrowed in a,b), ovaries (arrowed in e,f,h), uterine cervix (star, arrowed in c,d) and vagina (triangle) outlined.
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Fig.3: CTV2(nodal) step-by-step outlining guidance with 3d,h,l illustrating completed outline: Transverse CT 1cm inferior to aortic bifurcation (a-d), at iliac bifurcation (e-h) and at distal internal and external iliac vessels (i-l). Vessels (common iliac in a) are outlined (a,e,i), a circumferential 7mm margin added (b,f,j), muscle and bone is edited out (c,g,k), the outline is extended to include the area between psoas muscle and vertebral body (solid
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arrow in d, h), presacral strip is added (dashed arrow in h) and an 18mm (solid arrows in l) strip is added to cover
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obturator/infra-iliac nodal region. The gluteal vessels (dashed arrows in l) should not be included.
ACCEPTED MANUSCRIPT References
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1. Portelance L, Chao KSC, Grigsby PW, et al. Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys 2001;51(1):261-6. 2. Forrest J, Presutti J, Davidson M, et al. A Dosimetric Planning Study Comparing Intensitymodulated Radiotherapy with Four-field Conformal Pelvic Radiotherapy for the Definitive Treatment of Cervical Carcinoma. Clin Oncol 2012;24:e63-e70. 3. Mundt A, Roeske JC, Lujan AE, et al. Initial Clinical Experience with Intensity-Modulated Whole-Pelvis Radiation Therapy in Women with Gynecologic Malignancies. Gynecol Oncol 2001;82(3):456-63. 4. Salama JK, Roeske JC, Mehta N, Mundt A. Intensity-modulated Radiation Therapy in Gynecologic Malignancies. Curr Treat Options Oncol 2004;5(2):97-108. 5. Gill BS, Lin JF, Krivak TC, et al. National Cancer Data Base analysis of radiation therapy consolidation modality for cervical cancer: the impact of new technological advancements. Int J Radiat Oncol Biol Phys 2014 Dec 1;90(5):1083-90. 6. Gwynne S, Spezi E, Staffurth J, et al. Inter-observer Variation in Outlining of Pre-trial Test Case in the SCOPE1 Trial: A United Kingdom Definitive Chemoradiotherapy Trial for Esophageal Cancer. Int J Radiat Oncol Biol Phys 2011;81:S67-8. 7. Cazzaniga LF, Marinoni MA, Bossi A, et al. Interphysician variability in defining the planning target volume in the irradiation of prostate and seminal vesicles. Radiother Oncol 1998;47(3):293-6. 8. Valley J, Bernier J, Tercier PA, et al. Quality assurance of the EORTC radiotherapy trial 22931 for head and neck carcinomas: the dummy run. Radiother Oncol 1998;47(1):37-44. 9. Meijer GJ, Rasch C, Remeijer P, Lebesque JV. Three-dimensional analysis of delineation errors, setup errors, and organ motion during radiotherapy of bladder cancer. Int J Radiat Oncol Biol Phys 2003;55(5):1277-87. 10. Li XA, Tai A, Arthur DW, et al. Variability of target and normal structure delineation for breast cancer radiotherapy: an RTOG Multi-Institutional and Multiobserver Study. Int J Radiat Oncol Biol Phys 2009;73(3):944-51. 11. Vorwerk H, Beckmann G, Bremer M, et al. The delineation of target volumes for radiotherapy of lung cancer patients. Radiother Oncol 2009;91(3):455-60. 12. Petric P, Dimopoulos J, Kirisits C, et al. Inter- and intraobserver variation in HR-CTV contouring: intercomparison of transverse and paratransverse image orientation in 3D-MRI assisted cervix cancer brachytherapy. Radiother oncol 2008 Nov;89(2):164-71. 13. Dimopoulos JC, De Vos V, Berger D, et al. Inter-observer comparison of target delineation for MRI-assisted cervical cancer brachytherapy: application of the GYN GEC-ESTRO recommendations. Radiother oncol 2009 May;91(2):166-72. 14. Eminowicz G, McCormack M. Variability of clinical target volume delineation for definitive radiotherapy in cervix cancer. Radiother Oncol 2015;117:542-7. 15. Weiss E, Richter S, Krauss T, et al. Conformal radiotherapy planning of cervix carcinoma: differences in the delineation of the clinical target volume. Radiother Oncol 2003;67(1):87-95. 16. Wu DH, Mayr N, Karatas Y, et al. Interobserver variation in cervical cancer tumor delineation for image-based radiotherapy planning among and within different specialties. J App Clin Med Phys 2005;6(4). 17. Mitchell DM, Perry L, Smith S, et al. Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation. Int J Radiat Oncol Biol Phys 2009 Nov 15;75(4):990-3. 18. Haie-Meder C, Pötter R, Van Limbergen E, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group☆ (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiotherapy and Oncology 2005;74(3):235-45.
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19. Deasy JO, Blanco AI, Clark VH. CERR: a computational environment for radiotherapy research. Med Phys 2003;30(5):979-85. 20. Gay HA, Barthold HJ, O'Meara E, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys 2012 Jul 1;83(3):e353-62. 21. Lim K, Small W, Jr., Portelance L, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys 2011 Feb 1;79(2):348-55. 22. Toita T, Ohno T, Kaneyasu Y, et al. A consensus-based guideline defining clinical target volume for primary disease in external beam radiotherapy for intact uterine cervical cancer. Jpn J Clin Oncol 2011 Sep;41(9):1119-26. 23. Taylor A, Rockall AG, Reznek RH, Powell ME. Mapping pelvic lymph nodes: guidelines for delineation in intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2005;63(5):1604-12. 24. Small W, Jr., Mell LK, Anderson P, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol Phys 2008 Jun 1;71(2):428-34. 25. Toita T, Ohno T, Kaneyasu Y, et al. A consensus-based guideline defining the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer. Jpn J Clin Oncol 2010 May;40(5):456-63. 26. Bansal A, Patel FD, Rai B, et al. Literature review with PGI guidelines for delineation of clinical target volume for intact carcinoma cervix. J Cancer Res Ther 2013 Oct-Dec;9(4):574-82. 27. Fontanilla HP, Klopp A, Lindberg BS, et al. Anatomic distribution of (18F) fluorodeoxyglucoseavid lymph nodes in patients with cervical cancer. Prac Radiat Oncol 2013;3:45-53. 28. Takiar V, Fontanilla HP, Eifel PJ, et al. Anatomic distribution of fluorodeoxyglucose-avid paraaortic lymph nodes in patients with cervical cancer. Int J Radiat Oncol Biol Phys 2013;85(4):1045-50. 29. Kabolizadeh P, Fulay S, Beriwal S. Are Radiation Therapy Oncology Group para-aortic contouring guidelines for pancreatic neoplasm applicable to other malignancies- Assessment of nodal distribution in gynecological malignancies. Int J Radiat Oncol Biol Phys 2013;87(1):106-10. 30. Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009 Jul 1;74(3):844-51. 31. Shih HA, Harisinghani M, Zietman A, et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume for pelvic nodal irradiation based on vascular rather than bony anatomy. Int J Radiat Oncol Biol Phys 2005;63(4):1262-9. 32. Mehmood Q, Beardwood M, Swindell R, et al. Insufficiency fractures in patients treated with pelvic radiotherapy and chemotherapy for uterine and cervical cancer. Eur J Cancer care 2014;23(1):43-50. 33. Banerjee R, Chakraborty S, Nygren I, Sinha R. Small bowel dose parameters predicting grade 3 acute toxicity in rectal cancer patients treated with neoadjuvant chemoradiation: an independent validation study comparing peritoneal space versus small bowel loop contouring techniques. Int J Radiat Oncol Biol Phys 2013;85(5):1225-31. 34. Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy. Radiother Oncol 2003;69(2):201-7. 35. Sanguineti G, Little M, Endres EJ, et al. Comparison of three strategies to delineate the bowel for whole pelvis IMRT of prostate cancer. Radiother Oncol 2008;88:95-101. 36. Simpson DR, Song WY, Moiseenko V, et al. Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. Int J Radiat Oncol Biol Phys 2012;83(1):e81-6. 37. O'Connell HE, DeLancey JOL. Clitoral anatomy in the nulliparous, healthy, premenopausal volunteers using unenhanced magnetic resonance imaging. J Urol 2005;173:2060-3.
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38. Jhingran A, Salehpour M, Sam M, et al. Vaginal motion and bladder and rectal volumes during pelvic intensity-modulated radiation therapy after hysterectomy. Int J Radiat Oncol Biol Phys 2012 Jan 1;82(1):256-62. 39. Heijkoop ST, Langerak TR, Quint S, et al. Clinical implementation of an Online Adaptive Planof-the-Day Protocol for Nonrigid Motion Management in Locally Advanced Cervical Cancer IMRT. Int J Radiat Oncol Biol Phys 2014;90(3):673-9. 40. Ma DJ, Michaletz-Lorenz M, Goddu SM, Grigsby PW. Magnitude of interfractional vaginal cuff movement: implications for external irradiation. Int J Radiat Oncol Biol Phys 2012 Mar 15;82(4):1439-44. 41. Nakamura M, Fujii T, Imanishi N, et al. Surgical anatomy imaging associated with cervical cancer treatment: A cadaveric study. Clin Anat 2014;27(3):503-10. 42. Taylor A, Rockall AG, Powell ME. An atlas of the pelvic lymph node regions to aid radiotherapy target volume definition. Clin Oncol 2007 Sep;19(7):542-50. 43. Ikushima H, Osaki K, Furuntani S, et al. Pelvic bone complications following radiation therapy of gynaecologic malignancies: clinical evaluation of radiation-induced pelvic insufficiency fractures. Gynecol Oncol 2006;103:1100-4. 44. Mundt AJ, Lujan AE, Rotmensch J, et al. Intensity-modulated whole pelvic radiotherapy in women with gynaecologic malignancies. Int J Radiat Oncol Biol Phys 2002;52(5):1330-7. 45. Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56(5):1354-60.
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Year 2013
Title Literature review with PGI guidelines for delineation of clinical target volume for intact carcinoma cervix
Gay(18) RTOG Panel
2012
Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy:A Radiation Therapy Oncology Group Consensus
Lim(19) RTOG Gyn IMRT consortium Small(22) RTOG (GOG, ESTRO, NCIC, ACRIN) Taylor(21)
2011
Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer Mapping Pelvic Lymph nodes:guidelines for delineation in intensity-modulated radiotherapy
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Contents Definition of nodal and primary CTV; CTV nodal to include common, external and internal iliac, pre-sacral and obturator, CTV primary includes GTV, uterine cervix, uterine corpus, parametrium, upper vagina and uterosacral ligaments Definition of pelvic normal tissue contouring atlas: for gynae details AnoRectum, Sigmoid, BowelBag, Bladder, Uterocervix, Adnexa, Femur CTV including GTV, cervix, uterus, parametria (borders defined ovaries, vaginal tissues
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Authors(ref) Bansal(24) PGI
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Table 1:Published cervical cancer radiotherapy delineation guidelines.
A consensus-based guideline defining the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer A consensus-based guideline defining clinical target volume for primary disease in external beam radiotherapy for intact uterine cervical cancer
CTV definition for postoperative cervical/endo including common, external, internal iliac, presacral nodal regions, Upper vagina and paravaginal tissue lateral to vagina also Recommended nodal CTV guidelines based on modified 7mm margin around blood vessels;common, internal/external iliac, obturator and presacral regions Pelvic nodal CTV definition;common, external/ obturator, presacral regions Primary CTV definition for cervical cancer; GTV, uterine cervix, uterine corpus, parametrium (borders defined), vagina
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Lateral parametrial border
Posterior parametrial border
CTV2 Nodal (21-24)
Inferior obturator nodal border Subtraction of bladder/bowel Sacral foramina inclusion Superior CTV2 border
CTV3 PAnodes
Enlarged nodes margin Definition
RTOG: bony anatomy Taylor et al, JCOG, PGI: aortic bifurcation PGI: 10mm around enlarged node No guidance
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Discussion Beams travel through proximal femur, osteoradionecrosis aetiology unclear Bowel moves daily in abdominal cavity therefore bag representative CTV1 should be subtracted CTV2 should also be subtracted as bowel unlikely to overlap daily Volumes similar; 2cm below disease smaller. 2cm margin on disease (EUA/MRI) adequate and clearer to define/reproducible Even though medial sidewall is peritoneal reflection RTOG/JCOG definition is more reproducible and practical Improved imaging techniques detect uterosacral ligaments and mesorectum involvement Obturator nodes are at risk and leave pelvis just above the obturator foramen
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RTOG, JCOG, PGI:upper 1/2 if no vaginal disease, 2/3 if upper, 3/3 if extensive INTERLACE: upper ½/2cm below disease RTOG, JCOG and PGI:pelvic sidewall defined as muscle/ischial ramus Medial sidewall is peritoneal reflection RTOG, PGI:entire mesorectum if FIGO 3b JCOG:include perirectal tissue if significant parametrial involvement PGI, JCOG: superior obturator foramen RTOG:superior femoral head Taylor:mid femoral head JCOG:bowel not excluded RTOG bowel and bladder excluded RTOG, JCOG, PGI: exclude sacral foramina
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Vaginal length
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Subtract CTV from bowel
Published guidance/clinical practice RTOG:proximal femur Observed practice variable RTOG:bowel bag Observed practice variable RTOG:subtraction of ‘any overlapping nonGI structures’
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OAR (17)
Area of variation Femoral head vs proximal femur Bowel bag vs loops
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Table 2:Areas of variation regarding cervical cancer radiotherapy OAR and CTV definition Our recommendation Proximal femur Bowel bag Subtract CTV1&CTV2 from bowel Upper ½ or 2cm below disease
Bowel and bladder position varies according to daily variation, bladder filling etc. No evidence inclusion necessary, increases bone toxicity Should relate to nodal not bony anatomy
Medial edge of internal obturator muscle/ischial ramus Include mesorectum only if radiologically or clinically involved 1cm superior to obturator foramen/ mid-femoral head Only subtract bone and muscle Exclude sacral foramina Aortic bifurcation
Nodes well defined but margin needed Nodal disease seen around aorta/aortocaval area
3-5mm margin Aorta and medial half IVC with 7mm margin
ACCEPTED MANUSCRIPT Table 3:Parametrial border definitions Definition (arrowed and numbered Appendix Fig.2.4) Fallopian tube or broad ligament(1)(RTOG) Uterine artery enters uterus(2)(JJCO) Inferior Levator ani/pelvic floor muscles(3) Anterior Posterior bladder(4) or posterior border of external iliac vessels(5) Posterior Mesorectal fascia and uterosacral ligaments(6) Lateral Lateral pelvic sidewall; medial internal obturator(7)/piriformis muscle(8)/ischial ramus(9) Medial Cervix
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Border Superior
No after (30)
% after
Difference (%)
0 1 2 3 4
18 12 13 9 12
28 19 20 14 19
1 3 8 10 8
3 10 27 33 27
-25 -9 7 19 8
Bladder Rectum CTV1 CTV2
38 30 25 16
25 24 17 15
83 80 57 50
24 33 18 25
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Structure Compliance
No before (64)
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Total score (max 4)
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Table 4:Proportion of protocol compliant outlines before and after atlas use.
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Figure 1
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Figure 2
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Figure 3