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A Concise Review of Pelvic Radiation Therapy (RT) for Rectal Cancer with Synchronous Liver Metastases

A Concise Review of Pelvic Radiation Therapy (RT) for Rectal Cancer with Synchronous Liver... Hindawi International Journal of Surgical Oncology Volume 2019, Article ID 5239042, 11 pages https://doi.org/10.1155/2019/5239042 Review Article A Concise Review of Pelvic Radiation Therapy (RT) for Rectal Cancer with Synchronous Liver Metastases Omer Sager , Ferrat Dincoglan, Selcuk Demiral, Bora Uysal, Hakan Gamsiz, Bahar Dirican, and Murat Beyzadeoglu Department of Radiation Oncology, University of Health Sciences, Gulhane Medical Faculty, Ankara, Turkey Correspondence should be addressed to Omer Sager; omersager@gmail.com Received 30 November 2018; Accepted 3 April 2019; Published 21 April 2019 Academic Editor:C.H.Yip Copyright © 2019 Omer Sager et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background and Objective. Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer- related mortality worldwide. eTh liver is a very common site of metastatic spread for colorectal cancers, and, while nearly half of the patients develop metastases during the course of their disease, synchronous liver metastases are detected in 15% to 25% of cases. There is no standardized treatment in this setting and no consensus exists on optimal sequencing of multimodality management for rectal cancer with synchronous liver metastases. Methods. Herein, we review the use of pelvic radiation therapy (RT) as part of potentially curative or palliative management of rectal cancer with synchronous liver metastases. Results. er Th e is accumulating evidence on the utility of pelvic RT for facilitating subsequent surgery, improving local tumor control, and achieving palliation of symptoms in patients with stage IV rectal cancer. Introduction of superior imaging capabilities and contemporary RT approaches such as Intensity Modulated Radiation era Th py (IMRT) and Image Guided Radiation Therapy (IGRT) oer ff improved precision and toxicity profile of radiation delivery in the modern era. Conclusion. Even in the setting of stage IV rectal cancer with synchronous liver metastases, there may be potential for extended survival and cure by aggressive management of primary tumor and metastases in selected patients. Despite lack of consensus on sequencing of treatment modalities, pelvic RT may serve as a critical component of multidisciplinary management. Resectability of primary rectal tumor and liver metastases, patient preferences, comorbidities, symptomatology, and logistical issues should be thoroughly considered in decision making for optimal management of patients. 1. Background and Introduction has been shown to achieve survival rates exceeding 70% at 5 years for selected patients with limited disease burden [13– Colorectal cancer is a major health concern as a very 47]. common cancer and a leading cause of cancer-related mor- The role of radiation therapy (RT) in the management tality worldwide [1–4]. Cancers of the rectum account for a of nonmetastatic locally advanced rectal cancers is well considerable proportion of all large intestine cancers and are established; however, its utility in the setting of synchronous typically included within the group of colorectal cancers in liver metastases needs elucidation. Herein, we address the epidemiological studies [5]. The liver is a very common site of utility of pelvic RT as part of potentially curative or palliative metastatic spread for colorectal cancers, and, while nearly half management of rectal cancer with synchronous liver metas- of the patients develop metastases during the course of their tases in light of the literature. disease, synchronous liver metastases are detected in 15% to 25% of cases [6–12]. With ever-increasing advances in both surgical and clinical oncology disciplines, multimodality 2. Rationale for Pelvic RT in the Setting of management has substantially improved outcomes of rectal Rectal Cancer with Liver Metastases cancer with oligometastases. If feasible, surgical removal of the primary rectal tumor along with resection/ablation of The utility of RT has been well established in nonmetastatic livermetastasesasapotentiallycurativetherapeuticapproach locally advanced rectal cancer, and preoperative sequencing 2 International Journal of Surgical Oncology of pelvic irradiation rather than postoperative administration (with or without other distant metastases) as a palliative has been shown to reduce the risk of local recurrence and therapeutic strategy are summarized in Table 1. Pelvic RT achieves effective palliation of symptoms due cancer related mortality [48–50]. In terms of dose and to primary tumor in stage IV rectal cancer. Two reviews fractionation for preoperative pelvic irradiation, 2 main RT focusing on studies conducted in different time periods schemes include short course RT (SCRT) to deliver a total (1949-1999 and 2011-2016) confirmed the palliative efficacy radiation dose of 25 Gy with 5 daily treatment fractions ofRT formanagementofprimary rectal tumorrelated of 5Gyeachover1week andlongcourseRT(LCRT)to symptoms [94, 95]. deliver a total radiation dose of 45-50.4 Gy (with or without InthesystematicreviewbyCameron et al.based on an additional boost of 5.4 Gy delivered in 3 fractions if 27 studies, pooled overall symptomatic response rate was circumferential resection margin is threatened) over 5 to 6 75%, while response rates were 78%, 81%, 71%, and 72% for weeks with conventional fractionation (1.8-2 Gy per each symptoms of pain, bleeding and discharge, mass effect, and fraction). While assessment of local failure, disease free other pelvic symptoms, respectively [94]. survival (DFS), overall survival (OS), sphincter preserva- Buwenge et al. reviewed more recently published series tion, late toxicity, and quality of life revealed comparable and reported response rates of 79%, 87%, and 78% for outcomes with both preoperative RT approaches in several symptoms of pain, bleeding, and obstruction, respectively studies, practice patterns vary widely around the globe [51– [95]. In addition to 2 retrospective and 2 prospective series 58]. Surgery with total mesorectal excision (TME) has been in our review (Table 1), these 2 reviews with different study traditionally scheduled within 1 week (immediate surgery) or periodsrevealedeeff ctivepalliationofpelvicsymptomsby 6to8weeksaeft rcompletionofSCRTorLCRT,respectively using RT [94, 95]. Similar response rates in both earlier and [48,49,59].However,consideringthe increasedpathological more recent RT series suggest that the palliative efficacy of RT response rates achieved with a longer time interval between may not be neglected in the modern era and persists despite preoperative RT and surgery, delayed rather than immediate the availability of newer effective systemic treatments. surgery aer ft preoperative SCRT has been suggested as a viable therapeutic approach to improve treatment outcomes [60–69]. While incorporation of RT in multimodality treat- 4. Pelvic RT as Part of Potentially Curative ment of nonmetastatic rectal cancers is widely accepted, its Multimodality Management of utility for management of rectal cancer is debated in the Rectal Cancer with Synchronously setting of synchronously detected liver metastases. Detected Liver Metastases Given the increased life expectancy of patients with metastatic stage IV rectal cancer treated in the modern era Synchronous liver metastases have been variably defined in using more effective local and systemic therapies, addressing the literature. Most common definition includes metastases oftheprimary diseasebecomes more critical to improve detected at or before diagnosis of primary rectal cancer; patient comfort and quality of life with contemporary RT however, metastases detected within 3 to 6 months of diag- techniques allowing improved toxicity profile. Indeed, 7% of nosis have also been included in the “synchronous” group thestudy population consistedofpatientswithstage IV rectal in several studies [96–101]. Compared to metachronous liver cancer in the landmark Dutch trial assessing preoperative metastases, synchronously detected liver metastases may be RT followed by TME, and reported rates of 2-year local associated with poorer prognosis and survival [96, 102– recurrence were 10.1% and 23.8% for patients treated with 104].Eveninthissetting,thereremainsthe potentialfor or without preoperative RT, respectively [70]. Other studies cure with multimodality management. Outcomes of selected focusing on management of stage IV rectal cancer have series incorporating RT in multimodality management of also incorporated RT as part of multimodality management rectal cancer with synchronously detected liver metastases with several purposes including symptomatic palliation of are summarized in Table 2. symptoms, local control of primary disease, and facilitating Despite heterogeneity in patient and treatment character- subsequent TME surgery [71–87]. istics in these studies, several conclusions may be drawn. Several studies investigating the omission of RT in the Although with a very limited sample size, the study setting of nonmetastatic or metastatic disease consistently by Shin et al. using SCRT in multimodality management reported inferior outcomes, substantiating the utility of reported a high rate (84%) of R0 resection with no LR during RT in multimodality management of rectal cancer [88–91]. the follow-up period [73]. Moreover, in the setting of metastatic rectal cancer, improved In the study by Fossum et al. including 93 patients, primary tumor control by use of local therapy has been LR was not observed in patients receiving neoadjuvant associated with improved prognosis and survival as well [92, RT, and omission of neoadjuvant RT was associated with 93]. development of subsequent LR [91]. Overall, outcomes of 8 retrospective and 4 prospective 3. Review of Studies Including Pelvic RT with studies reveal that pelvic RT may serve as a critical com- ponent of multidisciplinary management (Table 2). Con- Palliative Intent temporary RT techniques including Intensity Modulated Selected series incorporating pelvic RT in multimodality Radiation era Th py (IMRT) and Image Guided Radiation management of stage IV rectal cancer with liver metastases Therapy (IGRT) along with timely management of radiation International Journal of Surgical Oncology 3 ft Table 1: Selected series incorporating pelvic RT in multimodality management of stage IV rectal cancer with liver metastases (with or without other d istant metastases) as a palliative therapeutic strategy. Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to palliative RT (Reference) fractionation (range) Symptoms due to rectal Stage IV rectal 30 Gy/6 fx (50%) tumor resolved in 94% cancer with 45 Gy/25 fx (16%) Overall 1-year actuarial Crane et al. [85] 2001 Retrospective 80 52 (3-444) weeks synchronous 35 Gy/14 fx (14%) symptom control rate 85% distant metastases Other (20%) Overall 2-year actuarial symptom control rate 82% Median total RT Overall symptomatic dose 36 Gy (range: palliation rate 80% Metastatic stage IV 8-60 Gy) Bae et al. [86] 2011 Retrospective 80 5(1-44)months Median symptom control colorectal cancer Median dose per duration 5 months (range: fraction 2.5 Gy 1-44 months) (range: 1.8-8 Gy) Complete resolution of pelvic symptoms during the whole course of disease in Stage IV rectal 12 patients (30%) Tyc-Szczepaniak et Prospective phase cancer with 25 Gy/5 fx (97.5%) 2013 40 26 (19-34) months Significant improvement in al. [87] II study synchronous 30 Gy/6 fx (2.5%) 14 patients (35%) distant metastases 67% probability of a sustained good palliative effect at 2 years Complete response (i.e., complete resolution of symptoms) at 4 weeks after treatment in 7 patients Stage IV rectal (38.9%) Prospective phase cancer with Partial response at 4 weeks Picardi et al. [72] 2016 18 25 Gy/5 fx 11.5 (3-36) months II study synchronous aer treatment in 9 patients distant metastases (50%) Reduction or resolution of pain 87.5% Reduction or resolution of bleeding 100% 4 International Journal of Surgical Oncology Table 2: Selected series incorporating pelvic RT as part of potentially cur ative multimodality management of rectal cancer with synchronously detected liver metastases (with or without other distant metastases). Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to RT (Reference) fractionation (range) No local recurrence during Stage IV LARC 16.7 (15.5-23.5) follow-up period Shin et al. [73] 2011 Retrospective 6 with synchronous 25 Gy/5 fx months R0 resection accomplished distant metastases in 5 patients (84%) 1-year OS 95% 2-year OS 70% Mean survival time 40.5 Stage IV LARC months 45±5.4 Gy/25-28 Salgado et al. [74] 2014 Retrospective 26 with synchronous - 1-year PFS 91% fx distant metastases 2-year PFS 36% Mean PFS time 23.1 months 1-year LC 91% 2-year LC 66% Median PFS 16 months Stage IV LARC 2-year PFS 34.8% Yoon et al. [83] 2016 Retrospective 50 with synchronous 25 Gy/5 fx 22 (9-59) months 2-year OS 73.9% distant metastases 5-year OS 55.1% Overall R0 resection rate for both the primary tumor and liver metastases was 77.8% in arm A (induction Prospective Stage IV rectal CapeOx + CapeOx-RT) multicenter cancer with 45±5.4 Gy/25-28 and 70% in arm B Cho et al. [82] 2016 38 - fx (CapeOx-RT alone) randomized phase synchronous liver 2study metastases Median PFS14.2monthsin arm A and 15.1 months in arm B 3-year OS 75% in arm A and 88.8% in arm B Surgical resection of rectum and liver accomplished in 25 patients Stage IV rectal (78%) Prospective phase cancer with R0 resection in 20 Kim et al. [81] 2016 32 25 Gy/5 fx - 2study synchronous liver patients(63%) metastases Rectal tumor downstaging in 54% of patients Median OS 38 months Median PFS 9 months International Journal of Surgical Oncology 5 Table 2: Continued. Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to RT (Reference) fractionation (range) Radiological complete or partial response for local disease 90% Radiological complete or partial response for metastatic disease 66% Median OS in patients having unresectable Stage IV rectal metastatic disease at cancer with 50.4 Gy/28 fx (split Bird et al. [80] 2017 Retrospective 78 6.2 years baseline 23 (19-28) months synchronous liver course RT) Estimated 3-year OS 62% metastases for the 12 patients treated with radical surgery for both rectum and liver Forpatientsnot receiving rectal surgery, palliative re-irradiation or surgery at a later date needed in only 7% LR was not observed in patients receiving neoadjuvant RT Median 50.4 Gy/28 12 patients (26%) receiving fx for LCRT no RT had LR Stage IV rectal Median 25 Gy/5 fx Omission of neoadjuvant cancer with Fossum et al. [91] 2017 Retrospective 93 for SCRT 43 (16-67) months RT was associated with synchronous (±intraoperative development of subsequent distant metastases RT to median dose LR of 12.5 Gy) 5-year OS 43.3% for no RT group 5-year OS 58.3% for the RT group 6 International Journal of Surgical Oncology Table 2: Continued. Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to RT (Reference) fractionation (range) 1-year OS 97% Stage IV rectal 2-year OS 86.2% cancer with 25 (14.75-42.25) 3-year OS 76% Holliday et al. [76] 2017 Retrospective 38 25 Gy/5 fx synchronous months 1-year PFS 52.1% distant metastases 2-year PFS 22.7% 3-year PFS 17% Median OS 3.8 ( 0.5–9.4) years for all patients 2-year OS 74% Stage IV rectal 5-year OS 38% Prospective, cancer with For36of50patients(72%) Bisschop et al. [79] 2017 multicenter phase 50 25 Gy/5 fx 8.1 (6-9.8) years synchronous with radical (R0) primary 2study distant metastases tumor and metastatic site treatment, median OS 4.4 years, LR 5.6%, distant recurrence 80.6% 3 patients died and 10 patients had tumor Stage IV rectal progression during the Retrospective cancer with 20.5 (3.6–63.1) D'Hondt et al. [105] 2017 18 - follow-up period multicenter study synchronous liver months Median time to progression metastases after liver surgery 4.2 (2.8–9.2) months Median OS 48.4 (43.3-54.8) months for all patients Stage IV rectal For the 40 patients cancer with 50 Gy/25 fx (53%) completing the treatment Labori et al. [84] 2017 Retrospective 45 48 (6-85) months synchronous liver or 25 Gy/5 fx (47%) sequence, median OS 49.7 metastases (45.2-57.1) months and recurrence free survival 13 (16-30.3) months Median disease free survival 26 (23–28) months Median OS 53 (36-69) Stage IV rectal months for patients Salvador-Roses ´ et cancer with completing treatment 2018 Prospective 35 50.4 Gy 38 (11-64) months al. [75] synchronous liver strategy Median OS 25 (7-42) metastases months for patients not completing treatment strategy International Journal of Surgical Oncology 7 induced toxicity by use of nutritional supplementation may in study conception and design, data collection, and data improve patient compliance and quality of life [106]. analysis and interpretation. 5. Conclusion References [1] F. Bray, J. Ferlay, I. 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A Concise Review of Pelvic Radiation Therapy (RT) for Rectal Cancer with Synchronous Liver Metastases

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Copyright © 2019 Omer Sager et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi International Journal of Surgical Oncology Volume 2019, Article ID 5239042, 11 pages https://doi.org/10.1155/2019/5239042 Review Article A Concise Review of Pelvic Radiation Therapy (RT) for Rectal Cancer with Synchronous Liver Metastases Omer Sager , Ferrat Dincoglan, Selcuk Demiral, Bora Uysal, Hakan Gamsiz, Bahar Dirican, and Murat Beyzadeoglu Department of Radiation Oncology, University of Health Sciences, Gulhane Medical Faculty, Ankara, Turkey Correspondence should be addressed to Omer Sager; omersager@gmail.com Received 30 November 2018; Accepted 3 April 2019; Published 21 April 2019 Academic Editor:C.H.Yip Copyright © 2019 Omer Sager et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background and Objective. Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer- related mortality worldwide. eTh liver is a very common site of metastatic spread for colorectal cancers, and, while nearly half of the patients develop metastases during the course of their disease, synchronous liver metastases are detected in 15% to 25% of cases. There is no standardized treatment in this setting and no consensus exists on optimal sequencing of multimodality management for rectal cancer with synchronous liver metastases. Methods. Herein, we review the use of pelvic radiation therapy (RT) as part of potentially curative or palliative management of rectal cancer with synchronous liver metastases. Results. er Th e is accumulating evidence on the utility of pelvic RT for facilitating subsequent surgery, improving local tumor control, and achieving palliation of symptoms in patients with stage IV rectal cancer. Introduction of superior imaging capabilities and contemporary RT approaches such as Intensity Modulated Radiation era Th py (IMRT) and Image Guided Radiation Therapy (IGRT) oer ff improved precision and toxicity profile of radiation delivery in the modern era. Conclusion. Even in the setting of stage IV rectal cancer with synchronous liver metastases, there may be potential for extended survival and cure by aggressive management of primary tumor and metastases in selected patients. Despite lack of consensus on sequencing of treatment modalities, pelvic RT may serve as a critical component of multidisciplinary management. Resectability of primary rectal tumor and liver metastases, patient preferences, comorbidities, symptomatology, and logistical issues should be thoroughly considered in decision making for optimal management of patients. 1. Background and Introduction has been shown to achieve survival rates exceeding 70% at 5 years for selected patients with limited disease burden [13– Colorectal cancer is a major health concern as a very 47]. common cancer and a leading cause of cancer-related mor- The role of radiation therapy (RT) in the management tality worldwide [1–4]. Cancers of the rectum account for a of nonmetastatic locally advanced rectal cancers is well considerable proportion of all large intestine cancers and are established; however, its utility in the setting of synchronous typically included within the group of colorectal cancers in liver metastases needs elucidation. Herein, we address the epidemiological studies [5]. The liver is a very common site of utility of pelvic RT as part of potentially curative or palliative metastatic spread for colorectal cancers, and, while nearly half management of rectal cancer with synchronous liver metas- of the patients develop metastases during the course of their tases in light of the literature. disease, synchronous liver metastases are detected in 15% to 25% of cases [6–12]. With ever-increasing advances in both surgical and clinical oncology disciplines, multimodality 2. Rationale for Pelvic RT in the Setting of management has substantially improved outcomes of rectal Rectal Cancer with Liver Metastases cancer with oligometastases. If feasible, surgical removal of the primary rectal tumor along with resection/ablation of The utility of RT has been well established in nonmetastatic livermetastasesasapotentiallycurativetherapeuticapproach locally advanced rectal cancer, and preoperative sequencing 2 International Journal of Surgical Oncology of pelvic irradiation rather than postoperative administration (with or without other distant metastases) as a palliative has been shown to reduce the risk of local recurrence and therapeutic strategy are summarized in Table 1. Pelvic RT achieves effective palliation of symptoms due cancer related mortality [48–50]. In terms of dose and to primary tumor in stage IV rectal cancer. Two reviews fractionation for preoperative pelvic irradiation, 2 main RT focusing on studies conducted in different time periods schemes include short course RT (SCRT) to deliver a total (1949-1999 and 2011-2016) confirmed the palliative efficacy radiation dose of 25 Gy with 5 daily treatment fractions ofRT formanagementofprimary rectal tumorrelated of 5Gyeachover1week andlongcourseRT(LCRT)to symptoms [94, 95]. deliver a total radiation dose of 45-50.4 Gy (with or without InthesystematicreviewbyCameron et al.based on an additional boost of 5.4 Gy delivered in 3 fractions if 27 studies, pooled overall symptomatic response rate was circumferential resection margin is threatened) over 5 to 6 75%, while response rates were 78%, 81%, 71%, and 72% for weeks with conventional fractionation (1.8-2 Gy per each symptoms of pain, bleeding and discharge, mass effect, and fraction). While assessment of local failure, disease free other pelvic symptoms, respectively [94]. survival (DFS), overall survival (OS), sphincter preserva- Buwenge et al. reviewed more recently published series tion, late toxicity, and quality of life revealed comparable and reported response rates of 79%, 87%, and 78% for outcomes with both preoperative RT approaches in several symptoms of pain, bleeding, and obstruction, respectively studies, practice patterns vary widely around the globe [51– [95]. In addition to 2 retrospective and 2 prospective series 58]. Surgery with total mesorectal excision (TME) has been in our review (Table 1), these 2 reviews with different study traditionally scheduled within 1 week (immediate surgery) or periodsrevealedeeff ctivepalliationofpelvicsymptomsby 6to8weeksaeft rcompletionofSCRTorLCRT,respectively using RT [94, 95]. Similar response rates in both earlier and [48,49,59].However,consideringthe increasedpathological more recent RT series suggest that the palliative efficacy of RT response rates achieved with a longer time interval between may not be neglected in the modern era and persists despite preoperative RT and surgery, delayed rather than immediate the availability of newer effective systemic treatments. surgery aer ft preoperative SCRT has been suggested as a viable therapeutic approach to improve treatment outcomes [60–69]. While incorporation of RT in multimodality treat- 4. Pelvic RT as Part of Potentially Curative ment of nonmetastatic rectal cancers is widely accepted, its Multimodality Management of utility for management of rectal cancer is debated in the Rectal Cancer with Synchronously setting of synchronously detected liver metastases. Detected Liver Metastases Given the increased life expectancy of patients with metastatic stage IV rectal cancer treated in the modern era Synchronous liver metastases have been variably defined in using more effective local and systemic therapies, addressing the literature. Most common definition includes metastases oftheprimary diseasebecomes more critical to improve detected at or before diagnosis of primary rectal cancer; patient comfort and quality of life with contemporary RT however, metastases detected within 3 to 6 months of diag- techniques allowing improved toxicity profile. Indeed, 7% of nosis have also been included in the “synchronous” group thestudy population consistedofpatientswithstage IV rectal in several studies [96–101]. Compared to metachronous liver cancer in the landmark Dutch trial assessing preoperative metastases, synchronously detected liver metastases may be RT followed by TME, and reported rates of 2-year local associated with poorer prognosis and survival [96, 102– recurrence were 10.1% and 23.8% for patients treated with 104].Eveninthissetting,thereremainsthe potentialfor or without preoperative RT, respectively [70]. Other studies cure with multimodality management. Outcomes of selected focusing on management of stage IV rectal cancer have series incorporating RT in multimodality management of also incorporated RT as part of multimodality management rectal cancer with synchronously detected liver metastases with several purposes including symptomatic palliation of are summarized in Table 2. symptoms, local control of primary disease, and facilitating Despite heterogeneity in patient and treatment character- subsequent TME surgery [71–87]. istics in these studies, several conclusions may be drawn. Several studies investigating the omission of RT in the Although with a very limited sample size, the study setting of nonmetastatic or metastatic disease consistently by Shin et al. using SCRT in multimodality management reported inferior outcomes, substantiating the utility of reported a high rate (84%) of R0 resection with no LR during RT in multimodality management of rectal cancer [88–91]. the follow-up period [73]. Moreover, in the setting of metastatic rectal cancer, improved In the study by Fossum et al. including 93 patients, primary tumor control by use of local therapy has been LR was not observed in patients receiving neoadjuvant associated with improved prognosis and survival as well [92, RT, and omission of neoadjuvant RT was associated with 93]. development of subsequent LR [91]. Overall, outcomes of 8 retrospective and 4 prospective 3. Review of Studies Including Pelvic RT with studies reveal that pelvic RT may serve as a critical com- ponent of multidisciplinary management (Table 2). Con- Palliative Intent temporary RT techniques including Intensity Modulated Selected series incorporating pelvic RT in multimodality Radiation era Th py (IMRT) and Image Guided Radiation management of stage IV rectal cancer with liver metastases Therapy (IGRT) along with timely management of radiation International Journal of Surgical Oncology 3 ft Table 1: Selected series incorporating pelvic RT in multimodality management of stage IV rectal cancer with liver metastases (with or without other d istant metastases) as a palliative therapeutic strategy. Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to palliative RT (Reference) fractionation (range) Symptoms due to rectal Stage IV rectal 30 Gy/6 fx (50%) tumor resolved in 94% cancer with 45 Gy/25 fx (16%) Overall 1-year actuarial Crane et al. [85] 2001 Retrospective 80 52 (3-444) weeks synchronous 35 Gy/14 fx (14%) symptom control rate 85% distant metastases Other (20%) Overall 2-year actuarial symptom control rate 82% Median total RT Overall symptomatic dose 36 Gy (range: palliation rate 80% Metastatic stage IV 8-60 Gy) Bae et al. [86] 2011 Retrospective 80 5(1-44)months Median symptom control colorectal cancer Median dose per duration 5 months (range: fraction 2.5 Gy 1-44 months) (range: 1.8-8 Gy) Complete resolution of pelvic symptoms during the whole course of disease in Stage IV rectal 12 patients (30%) Tyc-Szczepaniak et Prospective phase cancer with 25 Gy/5 fx (97.5%) 2013 40 26 (19-34) months Significant improvement in al. [87] II study synchronous 30 Gy/6 fx (2.5%) 14 patients (35%) distant metastases 67% probability of a sustained good palliative effect at 2 years Complete response (i.e., complete resolution of symptoms) at 4 weeks after treatment in 7 patients Stage IV rectal (38.9%) Prospective phase cancer with Partial response at 4 weeks Picardi et al. [72] 2016 18 25 Gy/5 fx 11.5 (3-36) months II study synchronous aer treatment in 9 patients distant metastases (50%) Reduction or resolution of pain 87.5% Reduction or resolution of bleeding 100% 4 International Journal of Surgical Oncology Table 2: Selected series incorporating pelvic RT as part of potentially cur ative multimodality management of rectal cancer with synchronously detected liver metastases (with or without other distant metastases). Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to RT (Reference) fractionation (range) No local recurrence during Stage IV LARC 16.7 (15.5-23.5) follow-up period Shin et al. [73] 2011 Retrospective 6 with synchronous 25 Gy/5 fx months R0 resection accomplished distant metastases in 5 patients (84%) 1-year OS 95% 2-year OS 70% Mean survival time 40.5 Stage IV LARC months 45±5.4 Gy/25-28 Salgado et al. [74] 2014 Retrospective 26 with synchronous - 1-year PFS 91% fx distant metastases 2-year PFS 36% Mean PFS time 23.1 months 1-year LC 91% 2-year LC 66% Median PFS 16 months Stage IV LARC 2-year PFS 34.8% Yoon et al. [83] 2016 Retrospective 50 with synchronous 25 Gy/5 fx 22 (9-59) months 2-year OS 73.9% distant metastases 5-year OS 55.1% Overall R0 resection rate for both the primary tumor and liver metastases was 77.8% in arm A (induction Prospective Stage IV rectal CapeOx + CapeOx-RT) multicenter cancer with 45±5.4 Gy/25-28 and 70% in arm B Cho et al. [82] 2016 38 - fx (CapeOx-RT alone) randomized phase synchronous liver 2study metastases Median PFS14.2monthsin arm A and 15.1 months in arm B 3-year OS 75% in arm A and 88.8% in arm B Surgical resection of rectum and liver accomplished in 25 patients Stage IV rectal (78%) Prospective phase cancer with R0 resection in 20 Kim et al. [81] 2016 32 25 Gy/5 fx - 2study synchronous liver patients(63%) metastases Rectal tumor downstaging in 54% of patients Median OS 38 months Median PFS 9 months International Journal of Surgical Oncology 5 Table 2: Continued. Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to RT (Reference) fractionation (range) Radiological complete or partial response for local disease 90% Radiological complete or partial response for metastatic disease 66% Median OS in patients having unresectable Stage IV rectal metastatic disease at cancer with 50.4 Gy/28 fx (split Bird et al. [80] 2017 Retrospective 78 6.2 years baseline 23 (19-28) months synchronous liver course RT) Estimated 3-year OS 62% metastases for the 12 patients treated with radical surgery for both rectum and liver Forpatientsnot receiving rectal surgery, palliative re-irradiation or surgery at a later date needed in only 7% LR was not observed in patients receiving neoadjuvant RT Median 50.4 Gy/28 12 patients (26%) receiving fx for LCRT no RT had LR Stage IV rectal Median 25 Gy/5 fx Omission of neoadjuvant cancer with Fossum et al. [91] 2017 Retrospective 93 for SCRT 43 (16-67) months RT was associated with synchronous (±intraoperative development of subsequent distant metastases RT to median dose LR of 12.5 Gy) 5-year OS 43.3% for no RT group 5-year OS 58.3% for the RT group 6 International Journal of Surgical Oncology Table 2: Continued. Authors RT dose and Median follow-up Study year Study design Number of patients Disease status Response to RT (Reference) fractionation (range) 1-year OS 97% Stage IV rectal 2-year OS 86.2% cancer with 25 (14.75-42.25) 3-year OS 76% Holliday et al. [76] 2017 Retrospective 38 25 Gy/5 fx synchronous months 1-year PFS 52.1% distant metastases 2-year PFS 22.7% 3-year PFS 17% Median OS 3.8 ( 0.5–9.4) years for all patients 2-year OS 74% Stage IV rectal 5-year OS 38% Prospective, cancer with For36of50patients(72%) Bisschop et al. [79] 2017 multicenter phase 50 25 Gy/5 fx 8.1 (6-9.8) years synchronous with radical (R0) primary 2study distant metastases tumor and metastatic site treatment, median OS 4.4 years, LR 5.6%, distant recurrence 80.6% 3 patients died and 10 patients had tumor Stage IV rectal progression during the Retrospective cancer with 20.5 (3.6–63.1) D'Hondt et al. [105] 2017 18 - follow-up period multicenter study synchronous liver months Median time to progression metastases after liver surgery 4.2 (2.8–9.2) months Median OS 48.4 (43.3-54.8) months for all patients Stage IV rectal For the 40 patients cancer with 50 Gy/25 fx (53%) completing the treatment Labori et al. [84] 2017 Retrospective 45 48 (6-85) months synchronous liver or 25 Gy/5 fx (47%) sequence, median OS 49.7 metastases (45.2-57.1) months and recurrence free survival 13 (16-30.3) months Median disease free survival 26 (23–28) months Median OS 53 (36-69) Stage IV rectal months for patients Salvador-Roses ´ et cancer with completing treatment 2018 Prospective 35 50.4 Gy 38 (11-64) months al. [75] synchronous liver strategy Median OS 25 (7-42) metastases months for patients not completing treatment strategy International Journal of Surgical Oncology 7 induced toxicity by use of nutritional supplementation may in study conception and design, data collection, and data improve patient compliance and quality of life [106]. analysis and interpretation. 5. Conclusion References [1] F. Bray, J. Ferlay, I. 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