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      Have we achieved adequate recommendations for target volume definitions in anal cancer? A PET imaging based patterns of failure analysis in the context of established contouring guidelines

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          Abstract

          Background

          There are different contouring guidelines for the clinical target volume (CTV) in anal cancer (AC) which vary concerning recommendations for radiation margins in different anatomical regions, especially on inguinal site. PET imaging has become more important in primary staging of AC as a very sensitive method to detect lymph node (LN) metastases. Using PET imaging, we evaluated patterns of LN spread, and examined the differences of the respective contouring guidelines on the basis of our results.

          Methods

          We carried out a retrospective study of thirty-seven AC patients treated with chemoradiation (CRT) who underwent FDG-PET imaging for primary staging in our department between 2011 and 2018. Patients showing PET positive LN were included in this analysis. Using a color code, LN metastases of all patients were delineated on a template with “standard anatomy” and were divided indicating whether their location was in- or out-field of the standard CTV as recommended by the Radiation Therapy Oncology Group (RTOG), the Australasian Gastrointestinal Trials Group (AGITG) or the British National Guidance (BNG). Furthermore, a detailed analysis of the location of LN of the inguinal region was performed.

          Results

          Twenty-two out of thirty-seven AC patients with pre-treatment PET imaging had PET positive LN metastases, accumulating to a total of 154 LN. The most commonly affected anatomical region was inguinal (49 LN, 32%). All para-rectal, external/internal iliac, and pre-sacral LN were covered by the recommended CTVs of the three different guidelines. Of forty-nine involved inguinal LN, fourteen (29%), seven (14%) and five (10%) were situated outside of the recommended CTVs by RTOG, AGITG and BNG. Inguinal LN could be located up to 5.7 cm inferiorly to the femoral saphenous junction and 2.8 cm medial or laterally to the big femoral vessels.

          Conclusion

          Pelvis-related, various recommendations are largely consistent, and all LN are covered by the recommended CTVs. LN “misses” appear generally cranially (common iliac or para-aortic) or caudally (inguinal) to the recommended CTVs. The established guidelines differ significantly, particular regarding the inguinal region. Based on our results, we presented our suggestions for CTV definition of the inguinal region. LN involvement of a larger number of patients should be investigated to enable final recommendations.

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          Most cited references 19

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          Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.

          Chemoradiation as definitive therapy is the preferred primary therapy for patients with anal canal carcinoma; however, the 5-year disease-free survival rate from concurrent fluorouracil/mitomycin and radiation is only approximately 65%. To compare the efficacy of cisplatin-based (experimental) therapy vs mitomycin-based (standard) therapy in treatment of anal canal carcinoma. US Gastrointestinal Intergroup trial RTOG 98-11, a multicenter, phase 3, randomized controlled trial comparing treatment with fluorouracil plus mitomycin and radiotherapy vs treatment with fluorouracil plus cisplatin and radiotherapy in 682 patients with anal canal carcinoma enrolled between October 31, 1998, and June 27, 2005. Stratifications included sex, clinical nodal status, and tumor diameter. Participants were randomly assigned to 1 of 2 intervention groups: (1) the mitomycin-based group (n = 341), who received fluorouracil (1000 mg/m2 on days 1-4 and 29-32) plus mitomycin (10 mg/m2 on days 1 and 29) and radiotherapy (45-59 Gy) or (2) the cisplatin-based group (n = 341), who received fluorouracil (1000 mg/m2 on days 1-4, 29-32, 57-60, and 85-88) plus cisplatin (75 mg/m2 on days 1, 29, 57, and 85) and radiotherapy (45-59 Gy; start day = day 57). The primary end point was 5-year disease-free survival; secondary end points were overall survival and time to relapse. A total of 644 patients were assessable. The median follow-up for all patients was 2.51 years. Median age was 55 years, 69% were women, 27% had a tumor diameter greater than 5 cm, and 26% had clinically positive nodes. The 5-year disease-free survival rate was 60% (95% confidence interval [CI], 53%-67%) in the mitomycin-based group and 54% (95% CI, 46%-60%) in the cisplatin-based group (P = .17). The 5-year overall survival rate was 75% (95% CI, 67%-81%) in the mitomycin-based group and 70% (95% CI, 63%-76%) in the cisplatin-based group (P = .10). The 5-year local-regional recurrence and distant metastasis rates were 25% (95% CI, 20%-30%) and 15% (95% CI, 10%-20%), respectively, for mitomycin-based treatment and 33% (95% CI, 27%-40%) and 19% (95% CI, 14%-24%), respectively, for cisplatin-based treatment. The cumulative rate of colostomy was significantly better for mitomycin-based than cisplatin-based treatment (10% vs 19%; P = .02). Severe hematologic toxicity was worse with mitomycin-based treatment (P < .001). In this population of patients with anal canal carcinoma, cisplatin-based therapy failed to improve disease-free-survival compared with mitomycin-based therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate. These findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma. clinicaltrials.gov Identifier: NCT00003596.
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            Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.

            Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. In this 2 × 2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m(2) on day 1) or cisplatin (60 mg/m(2) on days 1 and 29), with fluorouracil (1000 mg/m(2) per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5.1 years (IQR 3.9-6.9). 391 of 432 (90.5%) patients in the mitomycin group versus 386 of 431 (89.6%) in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0.95, 95% CI 0.75-1.21; p=0.70). The results of our trial--the largest in anal cancer to date--show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. Cancer Research UK. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas.

              To develop a Radiation Therapy Oncology Group (RTOG) atlas of the elective clinical target volume (CTV) definitions to be used for planning pelvic intensity-modulated radiotherapy (IMRT) for anal and rectal cancers. The Gastrointestinal Committee of the RTOG established a task group (the nine physician co-authors) to develop this atlas. They responded to a questionnaire concerning three elective CTVs (CTVA: internal iliac, presacral, and perirectal nodal regions for both anal and rectal case planning; CTVB: external iliac nodal region for anal case planning and for selected rectal cases; CTVC: inguinal nodal region for anal case planning and for select rectal cases), and to outline these areas on individual computed tomographic images. The imaging files were shared via the Advanced Technology Consortium. A program developed by one of the co-authors (I.E.N.) used binomial maximum-likelihood estimates to generate a 95% group consensus contour. The computer-estimated consensus contours were then reviewed by the group and modified to provide a final contouring consensus atlas. The panel achieved consensus CTV definitions to be used as guidelines for the adjuvant therapy of rectal cancer and definitive therapy for anal cancer. The most important difference from similar atlases for gynecologic or genitourinary cancer is mesorectal coverage. Detailed target volume contouring guidelines and images are discussed. This report serves as a template for the definition of the elective CTVs to be used in IMRT planning for anal and rectal cancers, as part of prospective RTOG trials.
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                Author and article information

                Contributors
                +491776003329 , hendrik-dapper@gmx.de
                Kilian.Schiller@mri.tum.de
                Stefan.Muench@mri.tum.de
                Jan.Peeken@tum.de
                Kai.Borm@mri.tum.de
                W.Weber@tum.de
                Stephanie.Combs@tum.de
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                29 July 2019
                29 July 2019
                2019
                : 19
                Affiliations
                [1 ]Department of Radiation Oncology, Klinikum rechts der Isar, TU München, Ismaninger Str. 22, 81675 Munich, Germany
                [2 ]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Institute for innovative Radiotherapy (iRT), , Helmholtz Zentrum München, ; Ingolstädter Landstr. 1, Neuherberg, Germany
                [3 ]ISNI 0000000123222966, GRID grid.6936.a, Department of Nuclear Medicine, Klinikum rechts der Isar, , TU München, ; Ismaninger Str. 22, 81675 Munich, Germany
                [4 ]Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany
                Article
                5970
                10.1186/s12885-019-5970-0
                6664500
                31357959
                © The Author(s). 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Research Article
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                © The Author(s) 2019

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