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

Background and Objective Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer-related mortality worldwide. The 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 There 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 Therapy (IMRT) and Image Guided Radiation Therapy (IGRT) offer 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.


Background and Introduction
Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer-related mortality worldwide [1][2][3][4]. Cancers of the rectum account for a considerable proportion of all large intestine cancers and are typically included within the group of colorectal cancers in epidemiological studies [5]. The 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 [6][7][8][9][10][11][12]. With ever-increasing advances in both surgical and clinical oncology disciplines, multimodality management has substantially improved outcomes of rectal cancer with oligometastases. If feasible, surgical removal of the primary rectal tumor along with resection/ablation of liver metastases as a potentially curative therapeutic approach has been shown to achieve survival rates exceeding 70% at 5 years for selected patients with limited disease burden .
The role of radiation therapy (RT) in the management of nonmetastatic locally advanced rectal cancers is well established; however, its utility in the setting of synchronous liver metastases needs elucidation. Herein, we address the utility of pelvic RT as part of potentially curative or palliative management of rectal cancer with synchronous liver metastases in light of the literature.

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International Journal of Surgical Oncology of pelvic irradiation rather than postoperative administration has been shown to reduce the risk of local recurrence and cancer related mortality [48][49][50]. In terms of dose and fractionation for preoperative pelvic irradiation, 2 main RT schemes include short course RT (SCRT) to deliver a total radiation dose of 25 Gy with 5 daily treatment fractions of 5 Gy each over 1 week and long course RT (LCRT) to deliver a total radiation dose of 45-50.4 Gy (with or without an additional boost of 5.4 Gy delivered in 3 fractions if circumferential resection margin is threatened) over 5 to 6 weeks with conventional fractionation (1.8-2 Gy per each fraction). While assessment of local failure, disease free survival (DFS), overall survival (OS), sphincter preservation, late toxicity, and quality of life revealed comparable outcomes with both preoperative RT approaches in several studies, practice patterns vary widely around the globe [51][52][53][54][55][56][57][58]. Surgery with total mesorectal excision (TME) has been traditionally scheduled within 1 week (immediate surgery) or 6 to 8 weeks after completion of SCRT or LCRT, respectively [48,49,59]. However, considering the increased pathological response rates achieved with a longer time interval between preoperative RT and surgery, delayed rather than immediate surgery after preoperative SCRT has been suggested as a viable therapeutic approach to improve treatment outcomes [60][61][62][63][64][65][66][67][68][69]. While incorporation of RT in multimodality treatment of nonmetastatic rectal cancers is widely accepted, its utility for management of rectal cancer is debated in the setting of synchronously detected liver metastases.
Given the increased life expectancy of patients with metastatic stage IV rectal cancer treated in the modern era using more effective local and systemic therapies, addressing of the primary disease becomes more critical to improve patient comfort and quality of life with contemporary RT techniques allowing improved toxicity profile. Indeed, 7% of the study population consisted of patients with stage IV rectal cancer in the landmark Dutch trial assessing preoperative RT followed by TME, and reported rates of 2-year local recurrence were 10.1% and 23.8% for patients treated with or without preoperative RT, respectively [70]. Other studies focusing on management of stage IV rectal cancer have also incorporated RT as part of multimodality management with several purposes including symptomatic palliation of symptoms, local control of primary disease, and facilitating subsequent TME surgery [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87].
Several studies investigating the omission of RT in the setting of nonmetastatic or metastatic disease consistently reported inferior outcomes, substantiating the utility of RT in multimodality management of rectal cancer [88][89][90][91]. Moreover, in the setting of metastatic rectal cancer, improved primary tumor control by use of local therapy has been associated with improved prognosis and survival as well [92,93].

Review of Studies Including Pelvic RT with Palliative Intent
Selected series incorporating pelvic RT in multimodality management of stage IV rectal cancer with liver metastases (with or without other distant metastases) as a palliative therapeutic strategy are summarized in Table 1. Pelvic RT achieves effective palliation of symptoms due to primary tumor in stage IV rectal cancer. Two reviews focusing on studies conducted in different time periods (1949-1999 and 2011-2016) confirmed the palliative efficacy of RT for management of primary rectal tumor related symptoms [94,95].
In the systematic review by Cameron et al. based on 27 studies, pooled overall symptomatic response rate was 75%, while response rates were 78%, 81%, 71%, and 72% for symptoms of pain, bleeding and discharge, mass effect, and other pelvic symptoms, respectively [94].
Buwenge et al. reviewed more recently published series and reported response rates of 79%, 87%, and 78% for symptoms of pain, bleeding, and obstruction, respectively [95]. In addition to 2 retrospective and 2 prospective series in our review (Table 1), these 2 reviews with different study periods revealed effective palliation of pelvic symptoms by using RT [94,95]. Similar response rates in both earlier and more recent RT series suggest that the palliative efficacy of RT may not be neglected in the modern era and persists despite the availability of newer effective systemic treatments.

Pelvic RT as Part of Potentially Curative Multimodality Management of Rectal Cancer with Synchronously Detected Liver Metastases
Synchronous liver metastases have been variably defined in the literature. Most common definition includes metastases detected at or before diagnosis of primary rectal cancer; however, metastases detected within 3 to 6 months of diagnosis have also been included in the "synchronous" group in several studies [96][97][98][99][100][101]. Compared to metachronous liver metastases, synchronously detected liver metastases may be associated with poorer prognosis and survival [96,[102][103][104]. Even in this setting, there remains the potential for cure with multimodality management. Outcomes of selected series incorporating RT in multimodality management of rectal cancer with synchronously detected liver metastases are summarized in Table 2.
Despite heterogeneity in patient and treatment characteristics in these studies, several conclusions may be drawn.
Although with a very limited sample size, the study by Shin et al. using SCRT in multimodality management reported a high rate (84%) of R0 resection with no LR during the follow-up period [73].
In the study by Fossum et al. including 93 patients, LR was not observed in patients receiving neoadjuvant RT, and omission of neoadjuvant RT was associated with development of subsequent LR [91].
Overall, outcomes of 8 retrospective and 4 prospective studies reveal that pelvic RT may serve as a critical component of multidisciplinary management (Table 2). Contemporary RT techniques including Intensity Modulated Radiation Therapy (IMRT) and Image Guided Radiation Therapy (IGRT) along with timely management of radiation   International Journal of Surgical Oncology

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. Similar response rates in earlier and more recent palliative RT series suggest that the palliative efficacy of RT may not be neglected in the modern era and persists despite the availability of newer effective systemic treatments. Given the increased life expectancy of patients with rectal cancer and synchronous liver metastases, addressing of the primary tumor with pelvic RT may have utility as part of potentially curative management. SCRT may be preferred in this setting to avoid delaying of systemic treatment, and improving distant as well as local control may be attempted by use of intensified chemoradiotherapy regimens. Modern RT techniques offer excellent precision and accuracy with an improved toxicity profile.
Backdating of liver surgery to be performed in the interval between RT and rectal surgery may be a viable therapeutic approach to shorten the overall treatment time and liver first strategies may be thoroughly investigated to avoid progression of liver metastases during the disease course.
Intensification of systemic treatment with or without biological agents, immunotherapy, optimal dose and fractionation for RT, optimal sequencing, and combination of treatment modalities warrant further extensive research.

Conflicts of Interest
The authors declare no conflicts of interest, financial or otherwise.

Authors' Contributions
Omer Sager contributed to study conception and design, data collection, data analysis and interpretation, and manuscript drafting. Ferrat Dincoglan took part in the study conception and design, data collection, and manuscript drafting. Selcuk Demiral participated in study conception and design, data collection, and data analysis and interpretation. Bora Uysal partook in data collection, data analysis and interpretation, and manuscript drafting. Hakan Gamsiz contributed to study conception and design, data analysis and interpretation, and manuscript drafting. Bahar Dirican took part in study conception and design, data analysis and interpretation, and manuscript drafting. Murat Beyzadeoglu participated in study conception and design, data collection, and data analysis and interpretation.