Survival Benefits of Asymptomatic Primary Tumor Resection After Bevacizumab Plus FOLFIRI as First-Line Therapy for Patients with Metastatic Colorectal Cancer with Synchronous Unresectable Metastasis

Survival Benefits of Asymptomatic Primary Tumor Resection After Bevacizumab Plus FOLFIRI as First-Line Therapy for Patients with Metastatic Colorectal Cancer with Synchronous Unresectable Metastasis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Survival Benefits of Asymptomatic Primary Tumor Resection After Bevacizumab Plus FOLFIRI as First-Line Therapy for Patients with Metastatic Colorectal Cancer with Synchronous Unresectable Metastasis Yen-Cheng Chen, Tsung-Kun Chang, Wei-Chih Su, Yung-Sung Yeh, Po-Jung Chen, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4516245/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Metastatic colorectal cancer (mCRC) poses a clinical challenge and requires a combination of systemic therapy and conversion surgery. Although first-line chemotherapy and targeted therapy are considered the standard treatments for mCRC, the role of primary tumor resection (PTR) in asymptomatic synchronous mCRC with unresectable metastatic lesion after initial therapy remains relatively underexplored. Materials A retrospective review was conducted from January 2015 to January 2021, involving 74 patients with synchronous mCRC who received bevacizumab plus FOFIRI as first-line systemic therapy. All 74 patients had unresectable metastatic lesions confirmed through multidisciplinary team discussion. Patient characteristics, PTR data, and radiotherapy (RT) and overall survival (OS) outcomes were analyzed. The patients were categorized into a “PTR” group and a “No PTR” group and then further stratified into “4A,” “4B,” and “4C” subgroups based on the initial mCRC stage. Additionally, four subgroups—namely “PTR(+)/RT(+),” “PTR(+)/RT(−),” “PTR(−)/RT(+),” and “PTR(−)/RT(−)”—were formed to assess the combined effects of PTR and RT. Results The median OS for all the patients was 23.8 months (20.5–27.1 months). The “PTR” group exhibited a significantly higher median OS of 25.9 months (21.3–30.5 months) compared with 21.4 months (15.8–27.1 months) in the “No PTR” group ( p = 0.048). Subgroup analyses revealed a trend of improved survival with PTR in patients with stage IVA and IVB; however, the results were not statistically significant ( p = 0.116 and 0.493, respectively). A subgroup analysis of PTR and RT combinations revealed no significant difference in median OS rates. Conclusion For asymptomatic mCRC with synchronous unresectable distant metastasis, PTR following first-line therapy with bevacizumab plus FOLFIRI can provide a survival benefit, particularly in stage IVA/IVB patients compared with stage IVC patients. Additionally, RT for primary tumor did not provide an additional OS benefit in mCRC with unresectable metastasis. A prospective randomized trial with a larger sample size is essential to further elucidate the role of PTR in this context. Colorectal cancer asymptomatic unresectable metastasis primary tumor resection first-line bevacizumab plus FOLFIRI Figures Figure 1 Figure 2 Figure 3 Background Globally, colorectal cancer (CRC) ranks as the third most commonly diagnosed type of malignant cancer worldwide.[ 1 ] The highest annual number of CRC cases was reported in Asia, and the annual incidence rate continues to increase, considerably affecting public health.[ 1 ] Although early-stage CRC can be effectively treated with curative surgical resection, managing metastatic CRC (mCRC) poses a considerable clinical challenge that necessitates a combination of systemic therapy and surgery.[ 2 – 4 ] The standard approach to mCRC treatment involves precise first-line systemic therapy tailored on the basis of the RAS, BRAF gene type, and microsatellite instability status.[ 5 – 7 ] Surgical resection, including primary tumor resection (PTR) and metastasectomy, is often recommended after neoadjuvant systemic therapy and is believed to provide survival benefits for patients with mCRC.[ 7 – 9 ] The combination of PTR and metastasectomy is considered the most favorable scenario following neoadjuvant therapy for curative resection in such patients.[ 8 ] However, the role of PTR in the treatment of mCRC with unresectable distant metastasis after first-line therapy remains a topic of controversy. Randomized controlled trial (RCT) JCOG1007 investigated the role of PTR in asymptomatic synchronous unresectable CRC metastasis.[ 10 ] The findings of that study revealed that PTR conducted prior to systemic chemotherapy provided no survival benefit.[ 10 ] Consequently, the primary treatment approach for asymptomatic mCRC with synchronous unresectable metastasis shifted toward systemic therapy.[ 5 , 6 ] Although the application of standard targeted therapy plus chemotherapy yielded response rates of 55–60% for mCRC,[ 11 ] this success raises a clinical question: In a scenario where an asymptomatic synchronous mCRC patient receives standard systemic therapy and exhibits tumor shrinkage in both the primary tumor and metastasis but where the distant metastatic lesion remains unresectable, should PTR be performed? PTR is imperative in cases of symptomatic primary tumors to address complications such as bleeding and bowel obstruction.[ 12 ] However, for patients with asymptomatic mCRC who have undergone systemic therapy, the decision to undergo PTR involves weighing the potential advantages and disadvantages of such resection. The potential advantages of PTR as described as follows: 1) Prevention of imminent tumor-related complications such as bowel obstruction, tumor bleeding, and bowel perforation; 2) removal of radiotherapy (RT)- or chemotherapy-resistant tumor cells; and 3) reduction of the tumor burden.[ 13 , 14 ] Conversely, the potential major disadvantages of PTR lie in the interruption of systemic therapy. During PTR, chemotherapy is usually delayed for approximately 2 weeks before and after the surgery to avoid immune compromise,[ 15 , 16 ] and the administration of antivascular endothelial growth factor monoclonal antibodies, such as bevacizumab, is often postponed for at least 28 days before and after colorectal surgery.[ 17 , 18 ] Additionally, PTR may contribute to the progression of distant metastatic lesion growth due to the release of wound-healing factors and the removal of a source of angiostatin from the primary tumor.[ 19 , 20 ] Several meta-analyses and systemic review articles have explored the effect of PTR on mCRC with unresectable metastasis, with the majority suggesting that PTR contributes to survival benefits.[ 21 – 23 ] However, many of these analyses have included studies where PTR was followed by either intensive or palliative chemotherapy.[ 13 , 14 , 24 ] Moreover, systemic therapy typically involves chemotherapy without targeted therapy.[ 13 , 14 , 24 ] Notably, survival outcome data for mCRC with synchronous unresectable distant metastasis following neoadjuvant chemotherapy and targeted therapy are lacking. In the present single-institution study, we retrospectively evaluated 74 patients with mCRC with synchronous unresectable distant metastasis who received bevacizumab plus FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan). Real-world data—including those related to the effects of PTR, RT, and survival outcomes—were analyzed. Materials and methods Patients Patient selection From the database of a single medical center, we enrolled 106 patients with mCRC who received bevacizumab plus FOLFIRI as first-line systemic therapy from January 2015 to January 2021. Six of these patients with metachronous mCRC were then excluded. One colorectal surgeon and one radiologist reviewed initial diagnostic computed tomography (CT) images or magnetic resonance images to determine the resectability of the metastatic lesions. Twenty-three patients with mCRC with resectable metastasis were subsequently excluded. Additionally, based on medical records, three patients with mCRC who underwent metastasectomy following systemic therapy were excluded. Thus, the final analysis included 74 patients with mCRC with asymptomatic synchronous unresectable metastasis and no history of metastasectomy. A patient selection flowchart is presented in Fig. 1 . The present study protocol was approved by the Institutional Ethics Committee of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20230267). Treatment of mCRC A treatment plan was discussed by a multidisciplinary committee comprising colorectal surgeons, radiologists, gastroenterologists, medical oncologists, radiation oncologists, and pathologists. The first-line therapy principle was established according to the National Comprehensive Cancer Network guidelines and the consensus regarding mCRC treatment in Taiwan.[ 6 , 25 ] The chemotherapy regimen involved FOLFIRI, and RAS and BRAF gene mutation statuses were examined.[ 26 , 27 ] The treatment regimen comprised a 120-minute intravenous (IV) infusion of bevacizumab (5 mg/kg) on day 1, followed by a 4-hour IV infusion of irinotecan (180 mg/m 2 ) plus 500 mL of normal saline and leucovorin (200 mg/m 2 ) plus 5-FU (2800 mg/m 2 ) plus 500 mL of normal saline for 42–48 hours. This regimen was then repeated once every 2 weeks. Irinotecan dosage adjustments were made based on UGT1A1 genotyping.[ 7 ] RT could be applied to the primary tumor site after multidisciplinary team discussion, as described in our previous studies.[ 16 , 28 ] Response Evaluation Criteria in Solid Tumors version 1.1, coupled with CT image and magnetic resonance image studies, were used to assess treatment responses.[ 29 ] Following first-line therapy, on the basis of the response of the primary tumor and the control of distant metastasis, PTR was considered after multidisciplinary team discussion. PTR could take the form of either conventional laparotomy or minimally invasive surgery.[ 28 ] Colostomy was performed for patients experiencing bowel obstruction, malnutrition, post-intersphincteric resection, or anastomosis leakage.[ 28 ] Statistical analysis On the basis of medical records, patients undergoing PTR after systemic therapy were designated as the “PTR” group. Conversely, those who did not receive PTR throughout the entire course of mCRC treatment were designated as the “No PTR” group. These patients were further classified into the aforementioned “4A,” “4B,” and “4C” subgroups based on their initially clinically diagnosed mCRC stages (Fig. 1 ). The patients with mCRC who received RT for primary tumor were classified into the “RT” group, whereas those who did not receive RT were classified into the “No RT” group. Furthermore, the patients with mCRC were subdivided into four groups—namely “PTR(+)/RT(+),” “PTR(+)/RT(−),” “PTR(−)/RT(+),” and “PTR(−)/RT(−)”—depending on whether they received PTR or RT. Descriptive statistics—including medians, means, and proportions—were employed to characterize patient characteristics and gene alterations. The endpoint of the follow-up period was determined by the patient’s date of death, their date of final follow-up, or December 31, 2023. Overall survival (OS) was defined as the time from the date of diagnosis of mCRC to the date of death from any cause, the date of final follow-up, or the study endpoint. Median OS was calculated using the Kaplan–Meier method, and the time-to-event distributions were compared using the log-rank test. A P value of < 0.05 was considered statistically significant. Statistical analysis was conducted using the Statistical Package for the Social Sciences software package (version 20; International Business Machines Corporation Inc., Armonk, NY, USA), as in our previous study.[ 16 , 30 ] Results Patient characteristics Of the 74 patients with mCRC analyzed in this study, the liver was the most common metastatic site (68.9%), followed by the lung (31.1%) and then the peritoneum (21.6%). Among the 74 patients, 37 were classified into each of the “PTR” and “No PTR” groups. The median time interval between the initiation of FOLFIRI plus bevacizumab treatment and PTR was 8.1 months (3.9–15.8 months). No significant difference in age, sex, or body mass index was noted between the two groups. All the enrolled patients with mCRC exhibited adequate general condition for first-line systemic therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. No significant difference in ECOG performance status was identified between the two groups ( P = 0.288). In the “PTR” group, 18 (48.6%), 15 (40.6%), and 4 (10.8%) patients were classified as stage IVA, stage IVB, and stage IVC, respectively. In the “No PTR” group, 15 (40.6%), 11 (29.7%), and 11 (29.7%) patients were classified as stage IVA, stage IVB, and stage IVC, respectively. No significant difference in the distribution of mCRC stages was noted between the groups ( P = 0.193). All the enrolled mCRC cases were adenocarcinomas, with the majority being well or moderately differentiated types (“PTR” group: 91.9%; “No PTR” group: 97.3%; P = 0.919). Five (13.5%) and 11 patients (29.7%) in the “PTR” and “No PTR” groups, respectively, had carcinoembryonic antigen levels exceeding 5 ng/dL at the initial diagnosis ( P = 0.295). In the “PTR” group, 24 patients (64.9%) received RT on the primary tumor, whereas in the “No PTR” group, 12 patients (32.4%) received RT on the primary tumor ( P = 0.587). All the enrolled patients received elective PTR because of the asymptomatic nature of the primary tumor. The characteristics of the enrolled patients are outlined in Table 1 . Table 1 Patients Characteristics of PTR and No PTR groups (n = 74). Location of metastasis (n = 74) a Liver 51 (68.9%) Lung 23 (31.1%) Peritoneum 16 (21.6%) Para-aortic lymph node 12 (16.2%) Adrenal gland 6 (8.1%) Bone 4 (5.4%) Ovary 3 (4.1%) Characteristic PTR (n = 37) No PTR (n = 37) P value Age (years, median) (range) 59 (36–82) 56 (26–79) 0.188 Gender Male 23 (62.2%) 21 (56.8%) 0.733 Female 14 (37.8%) 16 (43.2%) BMI kg/m 2 (mean) (range) b 23.5 (16.7–31.0) 25.0(16.0-34.4) 0.074 ECOG c 0 20 (54.1%) 10 (27.0%) 0.288 1 17 (45.9%) 27 (73.0%) Clinical stage IVA 18 (48.6%) 15 (40.6%) 0.193 IVB 15 (40.6%) 11 (29.7%) IVC 4 (10.8%) 11 (29.7%) Histology (adenocarcinoma) Well or moderately differentiated 34 (91.9%) 36 (97.3%) 0.919 Poorly differentiated 3 (8.1%) 1 (2.7%) Sidedness Left colon 30 (81.1%) 30 (81.1%) 1.000 Right colon 7 (18.9%) 7 (18.9%) Pretreatment CEA d ≦ 5 ng/dL 32 (86.5%) 26 (70.3%) 0.295 > 5 ng/dL 5 (13.5%) 11 (29.7%) Radiotherapy on primary tumor Yes 24 (64.9%) 12 (32.4%) 0.587 No 13 (35.1%) 25 (67.6%) Nature of PTR Elective 37 (100%) 37 (100%) 1.000 Emergency 0 (0%) 0 (0%) a Because of multiple organ metastasis, the sum of the percentage exceeds 100%. b BMI: body mass index c ECOG: Eastern Cooperative Oncology Group performance status d CEA: carcinoembryonic antigen Gene alterations In the “PTR” group, 12 patients (32.4%) exhibited wild-type KRAS , and 15 patients (40.5%) had KRAS mutation. In the “No PTR” group, 20 patients (56.8%) exhibited wild-type KRAS , and 13 patients (43.2%) exhibited KRAS mutation ( P = 0.713). In the “PTR” group, 12 patients (32.4%) exhibited wild-type NRAS , and one patient (2.7%) had NRAS mutation. In the “No PTR” group, 18 patients (48.6%) had wild-type NRAS , and no patients exhibited NRAS mutation ( P = 0.615). Regarding BRAF status, 27 patients (73.0%) were diagnosed as having wild-type BRAF in the “PTR” group. In the “No PTR” group, 31 patients (83.8%) exhibited wild-type BRAF ( P = 0.475). Regarding UGT1A1 presentation, in the “PTR” group, 19 patients (51.4%) had the TA6/TA6 type, and six patients (16.2%) had the TA6/TA7 type. In the “No PTR” group, 27 patients (73.0%) had the TA6/TA6 type, and three patients (8.1%) had the TA6/TA7 type. No statistical significance in terms of UGT1A1 presentation was observed between the two groups ( P = 0.929). Further details of gene alterations are presented in Table 2 . Table 2 Gene alteration status (patients, N = 74) Gene alteration PTR (n = 37) No PTR (n = 37) P value KRAS mutation Wild type 12 (32.4%) 20 (56.8%) 0.713 Mutation 15 (40.5%) 13 (43.2%) N/A 10 (27.0%) 4 (10.8%) NRAS mutation Wild type 12 (32.4%) 18 (48.6%) 0.615 Mutation 1 (2.7%) 0 (0.0%) N/A 24 (64.9%) 19 (51.4%) BRAF mutation Wild type 27 (73.0%) 31 (83.8%) 0.475 Mutation 0 (0.0%) 0 (0.0%) N/A 10 (27.0%) 6 (16.2%) UGT1A1 TA6/TA6 19 (51.4%) 27 (73.0%) 0.929 TA6/TA7 6 (16.2%) 3 (8.1%) TA7/TA7 0 (0.0%) 0 (0.0%) N/A 12 (32.4%) 7 (18.9%) Survival and treatment outcome Primary tumor resection Overall, the median OS period for all the enrolled patients was 23.8 months (20.5–27.1 months). The estimated 3-year OS rate was 23.0%, and the estimated 5-year OS rate was 5.7% (Fig. 2 A). In the group analysis of survival outcomes, the “PTR” group exhibited a median OS period of 25.9 months (21.3–30.5 months), with estimated 3-year and 5-year OS rates of 32.4% and 8.9%, respectively. By contrast, in the “No PTR” group, the median OS period was 21.4 months (15.8–27.1 months), with estimated 3-year and 5-year OS rates of 13.5% and 2.7%, respectively. The OS outcome in the “PTR” group was significantly superior to that in the “No PTR” group ( P = 0.048; Fig. 2 B). In the subgroup analysis, we compared the survival outcomes across multiple mCRC stages. For stage IVA, the “PTR-4A” group demonstrated a median OS period of 28.8 months (13.9–43.7 months). The estimated 3-year OS rate was 33.3%, and the estimated 5-year OS rate was 11.1%. By contrast, in the “No PTR-4A” group, the median OS period was 21.0 months (14.4–27.6 months), with an estimated 3-year OS rate of 13.3% and an estimated 5-year OS rate of 6.7%. Although the “PTR-4A” group exhibited a trend of a longer OS period than did the “No PTR-4A” group, the difference was not statistically significant ( P = 0.116; Fig. 2 C). In the stage IVB analysis, the “PTR-4B” group demonstrated a median OS period of 24.3 months (18.7–29.9 months), with an estimated 3-year OS rate of 40.0% and an estimated 5-year OS rate of 8.0%. In the “No PTR-4B” group, the estimated median OS period was 25.1 months (15.6–34.6 months), with an estimated 3-year OS rate of 18.2% and an estimated 5-year OS rate of 0.0%. Although the “No PTR-4B” group exhibited a slightly longer OS period than did the “PTR-4B” group, the “PTR-4B” group revealed superior 3-year and 5-year OS rates. No significant difference was noted between the OS outcomes of these two subgroups ( P = 0.493; Fig. 2 D). In the stage IVC analysis, the “PTR-4C” group demonstrated a median OS period of 22.9 months (16.4–29.4 months), with an estimated 2-year OS rate of 50.0% and an estimated 3-year OS rate of 0.0%. In the “No PTR-4C” group, the estimated median OS period was 16.6 months (10.1–23.0 months), with an estimated 2-year OS rate of 27.3% and an estimated 3-year OS rate of 9.1%. No significant difference in OS outcomes was observed between the stage IVC subgroups ( P = 0.760; Fig. 2 E). Radiotherapy In the “RT” group, the estimated median OS period was 22.9 months (18.6–27.2 months), with an estimated 3-year OS rate of 19.4% and an estimated 5-year OS rate of 6.5%. Conversely, in the “No RT” group, the estimated median OS survival period was 24.8 months (21.1–28.5 months), with an estimated 3-year OS rate of 26.3% and an estimated 5-year OS rate of 5.3%. No significant difference was noted between the OS outcomes of the two groups ( P = 0.650; Fig. 3 A). In the subgroup analysis, the median OS period for the “PTR(+)/RT(+)” group was 23.3 months (20.3–26.4 months), with an estimated 3-year OS rate of 25.0% and an estimated 5-year OS rate of 10.0%. In the “PTR(+)/RT(−)” group, the estimated median OS period was 36.1 months (19.4–52.7 months), with an estimated 3-year OS rate of 46.2% and an estimated 5-year OS rate of 7.7%. The median OS period for the “PTR(−)/RT(+)” was 15.4 months (1.7–29.1 months), with estimated 3-year and 5-year OS rates of 8.3% and 0.0%, respectively. In the “PTR(−)/RT(−)” group, the estimated median OS period was 21.9 months (15.6–28.2 months), with estimated 3-year and 5-year OS rates of 16.0% and 4.0%, respectively. Overall, no significant differences were observed among the OS outcomes of these four subgroups ( P = 0.174; Fig. 3 B). Discussion Many studies have investigated the therapeutic impact of PTR on asymptomatic synchronous mCRC with unresectable distant metastasis. Furthermore, many studies have indicated that PTR may offer some survival benefits. However, most PTRs discussed in previous studies refer to procedures conducted before chemotherapy.[ 31 , 32 ] Accordingly, some RCTs have been initiated subsequently. The JCOG1007 study, involving 165 patients, concluded that PTR followed by chemotherapy provided no survival benefit compared with chemotherapy alone.[ 10 ] The CAIRO4 Phase 3 trial reported that PTR followed by systemic therapy resulted in higher 60-day mortality than systemic therapy alone; however, all the OS outcomes are still pending.[ 33 ] The SYNCHRONOUS trial, comprising 393 patients, reported that PTR prior to chemotherapy did not extend the OS period for synchronous unresectable mCRC.[ 34 , 35 ] The ongoing GRECCAR 8 trial, which aimed to include 290 patients, has yet to yield available results.[ 36 ] Among all these RCTs, the JCOG1007 study has presented the most robust evidence indicating that PTR followed by chemotherapy does not yield a survival benefit compared with chemotherapy alone.[ 10 ] Nevertheless, the present study focused on the role of PTR after neoadjuvant systemic therapy and aimed to address the question outlined in the Background section of this paper, namely whether PTR should be performed for patients with mCRC with synchronous unresectable distant metastasis after neoadjuvant systemic therapy. The standard first-line targeted therapy comprises an antiepidermal growth factor receptor agent (cetuximab or panitumumab) and an antivascular endothelial growth factor agent (bevacizumab).[ 37 ] Although the antiepidermal growth factor receptor agent is effective, it can be administered only to patients with wild-type RAS .[ 38 ] To ensure homogeneity and avoid potential confounding factors in OS outcomes, this study enrolled patients with mCRC who received a single systemic regimen—namely FOLFIRI chemotherapy plus bevacizumab targeted therapy—regardless of whether wild-type RAS or RAS mutation was present. The comparisons of basic patient characteristics in Tables 1 and 2 reveal no statistical significance in each variable between the “PTR” and “No PTR” groups. Consequently, the composition of patients with mCRC in both groups was similar; this feature enhances the credibility of the study results. In the present study, the median OS period for the “PTR” group was 25.9 months, which was significantly longer than 21.4 months observed in the “No PTR” group ( P = 0.048). However, the “No PTR” group had more stage IVC patients (11 patients, 29.7%) than the “PTR” group (4 patients, 10.8%) (Table 1 ). To mitigate the potential prognostic impact of different cancer stages on OS, we conducted subgroup analyses according to clinical stages. The median OS period in the “PTR-4A” subgroup was longer than that in the “No PTR-4A” subgroup (28.8 and 21.0 months, respectively), and the OS curves exhibited clear separation (Fig. 2 C). However, the OS difference was less evident between the “PTR-4B” and “No PTR-4B” subgroups (24.3 and 25.1 months, respectively); the “PTR-4B” group exhibited a higher survival rate, but the OS curve exhibited many crossover points (Fig. 2 D). Regarding stage IVC, the OS curve for the “PTR-4C” group appeared chaotic because of the limited number of patients. These results indicate that PTR may play a relatively pivotal role in mCRC cases with single-organ involvement. For multiorgan or peritoneal carcinomatosis mCRC, systemic therapy remains the primary treatment approach.[ 9 ] A possible reason behind the observed survival benefit in patients who underwent PTR may be an advantage such as the removal of chemotherapy-resistant tumor cells or the reduction of tumor burden, as mentioned in the Background section of this paper. However, selection bias may have influenced these results given the retrospective study design and the nonrandomized grouping method.[ 39 ] For example, we failed to clarify detailed “T” and “N” stages for each patient; consequently, advanced primary tumor (ex: T4N2M1a) and localized primary tumor (ex: T2N0M1a) may have been categorized as the same stage (stage IVA). Many studies have reported that T4 tumors exhibit inferior survival prognoses compared with T1, T2, and T3 tumors in patients with mCRC.[ 24 , 40 , 41 ] Furthermore, T4 primary tumors pose a greater challenge for curative surgical resection,[ 42 ] potentially leading to a higher likelihood of their being classified into the “No PTR” group. Lau et al . conducted a single-institution retrospective review to investigate the role of PTR in mCRC treatment. Their results revealed that treatment with PTR plus chemotherapy led to a significantly longer OS period compared with chemotherapy alone.[ 13 ] By contrast, JCOG1007, an RCT, reported that treatment with PTR plus chemotherapy yielded an OS period of 25.9 months, which was similar to that obtained with chemotherapy alone (26.7 months).[ 10 ] Despite their similar study designs in terms of patient grouping, these two studies yielded divergent results. Both studies focused on the role of PTR before systemic therapy for mCRC, which differs from the aim of the present study. However, this instance serves as an illustrative example of how selection bias can affect study outcomes and underscores the importance of RCTs in accurately interpreting clinical dilemmas. Compared with our treatment experience, the median OS period for patients with mCRC who received bevacizumab plus FOLFIRI as first-line therapy was 30 months.[ 26 ] For patients with mCRC with peritoneal carcinomatosis who received the same first-line therapy, the median OS period was 24.6 months.[ 9 ] In the present study, all the enrolled patients had unresectable metastasis, and the median OS period in the “PTR” group was 25.9 months. This similarity in survival outcomes suggests that our enrolled patients did not belong to a specific outlier group. In the OS analysis, regarding PTR and RT, the “No RT” group exhibited a longer median OS period than the “RT” group (22.9 months vs. 24.8 months, P = 0.650, Fig. 3 A). Moreover, the estimated 3-year and 5-year OS rates in the “No RT” group were superior to those in the “RT” group (Fig. 3 A). In our four-subgroup OS analysis based on PTR and RT, among the patients with mCRC who underwent PTR, those who did not receive RT had a longer OS period than those who received RT (23.3 months vs. 36.1 months, P = 0.271, Supplementary Fig. 1A). Similarly, for patients with mCRC who did not undergo PTR, those who did not receive RT on the primary tumor had a longer OS period than those who received RT on the primary tumor (15.4 months vs. 21.9 months, P = 0.737, Supplementary Fig. 1B). These results indicate the advanced T/N stage of the primary tumor. In our clinical practice, RT is typically administered to treat advanced CRC with local invasion or lymphadenopathy.[ 16 , 28 ] Thus, RT indirectly reflects a more advanced T/N stage of the primary tumor, contributing to a shorter OS period.[ 24 , 40 , 41 ] Conversely, a comparison of the OS outcomes based on RT revealed a trend toward a longer OS period for patients with mCRC who received RT and underwent PTR compared with those who underwent RT without PTR (23.3 months vs. 15.4 months, P = 0.226, Supplementary Fig. 2A). Similarly, for patients with mCRC who did not receive RT, a longer OS period was observed for those who underwent PTR than for those who did not (36.1 months vs. 21.9 months, P = 0.049, Supplementary Fig. 2B). These results suggest that under similar primary tumor T/N stage conditions, PTR can provide a survival benefit to patients with mCRC with unresectable metastasis after first-line systemic therapy. Because the tumor burden of metastatic lesions is a crucial factor influencing poor prognosis,[ 43 , 44 ] a reduction in tumor burden due to PTR is unlikely to be the primary reason for the observed differences in OS outcomes. Although selection bias may contribute to a portion of the survival benefit, it is insufficient to account for all the differences in the present results given the analysis of OS periods based on PTR and RT, as described previously. Because systemic therapy is the gold standard for the treatment of mCRC,[ 6 ] the OS outcome in mCRC is expected to have the strongest relationship with this type of therapy. One plausible explanation for the observed differences could be chemotherapy-induced psychological distress. In the context of mCRC treatment, psychological distress often accompanies chemotherapy and serves as a hidden detrimental factor affecting quality of life and the treatment course.[ 45 , 46 ] Some studies have introduced psychological support and care to alleviate anxiety and depression in patients with mCRC.[ 47 , 48 ] On the basis of our clinical observations, patients with mCRC may experience psychological exhaustion after a prolonged course of systemic therapy. The perception of an endless need for treatment can lead to a sense of despair, potentially causing patients to contemplate discontinuing their treatment. PTR may act as a treatment milestone and strengthen patients’ confidence in the treatment plan. Such a psychological boost could motivate patients to persevere through subsequent long-term treatment, thereby indirectly contributing to the prolonged OS period. However, in this retrospective study, we were unable to collect psychological assessment data to validate this hypothesis. Several studies have explored the therapeutic efficacy of metastasis-directed RT and have reported promising outcomes.[ 49 , 50 ] However, the effect of RT on primary tumor in mCRC treatment has not been studied extensively. In the present study, we analyzed the survival outcomes associated with RT intervention in patients with mCRC. The findings of our study indicated that RT applied to the primary tumor did not confer additional benefits to OS in patients with mCRC (Fig. 3 A). This result aligns with our previous treatment results observed in cases of locally advanced rectal cancer with synchronous metastasis.[ 28 ] Compared with systemic therapy alone, the combination of RT and systemic therapy led to prolonged local recurrence-free survival and progression-free survival but no significant difference in OS.[ 28 ] The present data reveals that similar survival outcomes can be observed in the treatment of metastatic colon cancer as well as in that of rectal cancer. This study was a retrospective analysis conducted at a single center; such a study design is associated with limitations, such as a small patient sample. Therefore, the sample size may not have been sufficient for robust subgroup analyses. General patient condition was assessed solely on the basis of performance status, and essential laboratory data—such as those related to liver function, renal function, and underlying disease—were not included. Some details regarding primary tumor, such as T/N stage, were not available, and although RT was used as an indirect measure for evaluating primary tumor T/N stage, it cannot precisely reflect the primary tumor condition. The absence of an assessment of the patients’ psychological status, along with a lack of a questionnaire to evaluate the scale of psychological exhaustion, weakens the hypothesis related to psychological stress. Additionally, selection bias due to the aforementioned limitations and the retrospective nature of this study could not be ruled out. Conclusion The present study provides real-world insights into the treatment impact of PTR on patients with mCRC undergoing first-line therapy. In cases of mCRC with synchronous unresectable metastasis, PTR demonstrates a survival benefit following neoadjuvant chemotherapy and targeted therapy. This therapeutic effect of PTR is especially pronounced in stages IVA and IVB. Furthermore, our findings indicate that RT on the primary tumor does not provide additional benefits to OS in the context of mCRC with unresectable metastasis. To establish a clearer understanding of the genuine effects of PTR following systematic therapy, larger-scale prospective, randomized trials are needed. Abbreviations BMI: body mass index CEA: carcinoembryonic antigen CRC : colorectal cancer. mCRC : metastatic colorectal cancer. CT : computed tomography. ECOG : Eastern Cooperative Oncology Group. FOLFIRI : folinic acid, 5-fluorouracil, and irinotecan. IV : intravenous. OS : overall survival. PTR : primary tumor resection. RCT : randomized controlled trial. RT : radiotherapy. Declarations Ethics approval and consent to participate The present study protocol was approved by the Institutional Ethics Committee of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20230267). Consent to participate is not applicable due to retrospective study design. Consent for publication On behalf of all co-authors, the corresponding author has obtained the consent for publication. Availability of data and materials All relevant data and information can be obtained from the corresponding author upon reasonable request. Competing interests The authors declare no competing interests. Funding This research did not receive any specific grants from public, commercial, or not-for-profit sector funding agencies. Authors' contributions YCC, JYW, and CWH designed the study. YCC, TKC, WCS, YSY, PJC, YTC, PJH, PHY, HLT, JYW and CWH extracted and collected data. YCC, TKC, WCS, YSY, PJC, YTC, HLT, JYW, and CWH analyzed and interpreted the data. YCC, JYW, and CWH drafted the manuscript. YCC, JYW, and CWH critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgments This work was supported by grants through funding from the National Science and Technology Council (MOST 111-2314-B-037-070-MY3, NSTC 112-2314-B-037-090, NSTC 112-2314-B-037-050-MY3) and the Ministry of Health and Welfare (12D1-IVMOHW02) and funded by the health and welfare surcharge of on tobacco products, and the Kaohsiung Medical University Hospital (KMUH112-2R37, KMUH112-2R38, KMUH112-2R39, KMUH112-2M27, KMUH112-2M28, KMUH112-2M29, KMUH-SH11207) and Kaohsiung Medical University Research Center Grant (KMU-TC112A04). In addition, this study was supported by the Grant of Taiwan Precision Medicine Initiative and Taiwan Biobank, Academia Sinica, Taiwan, R.O.C. References Li N, Lu B, Luo C, Cai J, Lu M, Zhang Y, Chen H, Dai M: Incidence, mortality, survival, risk factor and screening of colorectal cancer: A comparison among China, Europe, and northern America . Cancer letters 2021, 522 :255-268. 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Additional Declarations No competing interests reported. Supplementary Files NewSupplementaryfigure1.jpg NewSupplementaryfigure2.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4516245","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":316246536,"identity":"005be52e-1dde-4dbe-b22b-62d7d81cddeb","order_by":0,"name":"Yen-Cheng Chen","email":"","orcid":"","institution":"Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yen-Cheng","middleName":"","lastName":"Chen","suffix":""},{"id":316246541,"identity":"f11946f4-c3ee-4b5e-a05b-4e1115920a02","order_by":1,"name":"Tsung-Kun Chang","email":"","orcid":"","institution":"Kaohsiung Medical 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2","display":"","copyAsset":false,"role":"figure","size":66284,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003eOverall survival curve. \u003cstrong\u003e(B) \u003c/strong\u003eOverall survival curve for “PTR” and “No PTR.” \u003cstrong\u003e(C) \u003c/strong\u003eOverall survival curve for “PTR-4A” and “No PTR-4A.” \u003cstrong\u003e(D)\u003c/strong\u003e Overall survival curve for “PTR-4B” and “No PTR-4B.” \u003cstrong\u003e(D)\u003c/strong\u003e Overall survival curve for “PTR-4C” and “No PTR-4C.”\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4516245/v1/bde1b6ba696e7f2643f01f35.jpg"},{"id":60427388,"identity":"15554b88-944b-42a4-9718-f6e234101ec7","added_by":"auto","created_at":"2024-07-16 15:51:07","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":70890,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003eOverall survival curve for “RT” and “No RT.” \u003cstrong\u003e(B) \u003c/strong\u003eOverall survival curve for “PTR(+)/RT(+),” “PTR(+)/RT(−),” “PTR(−)/RT(+),” and “PTR(−)/RT(−).”\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4516245/v1/e8d48dbdf7fe55c9ac296d26.jpg"},{"id":60429716,"identity":"cc4004b7-e2f5-42df-87bb-e4f7411723b2","added_by":"auto","created_at":"2024-07-16 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15:51:10","extension":"jpg","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":188050,"visible":true,"origin":"","legend":"","description":"","filename":"NewSupplementaryfigure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4516245/v1/0f5eda8f5904c76ef53ec51e.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Survival Benefits of Asymptomatic Primary Tumor Resection After Bevacizumab Plus FOLFIRI as First-Line Therapy for Patients with Metastatic Colorectal Cancer with Synchronous Unresectable Metastasis","fulltext":[{"header":"Background","content":"\u003cp\u003eGlobally, colorectal cancer (CRC) ranks as the third most commonly diagnosed type of malignant cancer worldwide.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The highest annual number of CRC cases was reported in Asia, and the annual incidence rate continues to increase, considerably affecting public health.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Although early-stage CRC can be effectively treated with curative surgical resection, managing metastatic CRC (mCRC) poses a considerable clinical challenge that necessitates a combination of systemic therapy and surgery.[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] The standard approach to mCRC treatment involves precise first-line systemic therapy tailored on the basis of the \u003cem\u003eRAS, BRAF\u003c/em\u003e gene type, and microsatellite instability status.[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Surgical resection, including primary tumor resection (PTR) and metastasectomy, is often recommended after neoadjuvant systemic therapy and is believed to provide survival benefits for patients with mCRC.[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] The combination of PTR and metastasectomy is considered the most favorable scenario following neoadjuvant therapy for curative resection in such patients.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] However, the role of PTR in the treatment of mCRC with unresectable distant metastasis after first-line therapy remains a topic of controversy.\u003c/p\u003e \u003cp\u003eRandomized controlled trial (RCT) JCOG1007 investigated the role of PTR in asymptomatic synchronous unresectable CRC metastasis.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] The findings of that study revealed that PTR conducted prior to systemic chemotherapy provided no survival benefit.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Consequently, the primary treatment approach for asymptomatic mCRC with synchronous unresectable metastasis shifted toward systemic therapy.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Although the application of standard targeted therapy plus chemotherapy yielded response rates of 55\u0026ndash;60% for mCRC,[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] this success raises a clinical question: In a scenario where an asymptomatic synchronous mCRC patient receives standard systemic therapy and exhibits tumor shrinkage in both the primary tumor and metastasis but where the distant metastatic lesion remains unresectable, should PTR be performed?\u003c/p\u003e \u003cp\u003ePTR is imperative in cases of symptomatic primary tumors to address complications such as bleeding and bowel obstruction.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] However, for patients with asymptomatic mCRC who have undergone systemic therapy, the decision to undergo PTR involves weighing the potential advantages and disadvantages of such resection. The potential advantages of PTR as described as follows: 1) Prevention of imminent tumor-related complications such as bowel obstruction, tumor bleeding, and bowel perforation; 2) removal of radiotherapy (RT)- or chemotherapy-resistant tumor cells; and 3) reduction of the tumor burden.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Conversely, the potential major disadvantages of PTR lie in the interruption of systemic therapy. During PTR, chemotherapy is usually delayed for approximately 2 weeks before and after the surgery to avoid immune compromise,[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and the administration of antivascular endothelial growth factor monoclonal antibodies, such as bevacizumab, is often postponed for at least 28 days before and after colorectal surgery.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Additionally, PTR may contribute to the progression of distant metastatic lesion growth due to the release of wound-healing factors and the removal of a source of angiostatin from the primary tumor.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSeveral meta-analyses and systemic review articles have explored the effect of PTR on mCRC with unresectable metastasis, with the majority suggesting that PTR contributes to survival benefits.[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] However, many of these analyses have included studies where PTR was followed by either intensive or palliative chemotherapy.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Moreover, systemic therapy typically involves chemotherapy without targeted therapy.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Notably, survival outcome data for mCRC with synchronous unresectable distant metastasis following neoadjuvant chemotherapy and targeted therapy are lacking. In the present single-institution study, we retrospectively evaluated 74 patients with mCRC with synchronous unresectable distant metastasis who received bevacizumab plus FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan). Real-world data\u0026mdash;including those related to the effects of PTR, RT, and survival outcomes\u0026mdash;were analyzed.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eFrom the database of a single medical center, we enrolled 106 patients with mCRC who received bevacizumab plus FOLFIRI as first-line systemic therapy from January 2015 to January 2021. Six of these patients with metachronous mCRC were then excluded. One colorectal surgeon and one radiologist reviewed initial diagnostic computed tomography (CT) images or magnetic resonance images to determine the resectability of the metastatic lesions. Twenty-three patients with mCRC with resectable metastasis were subsequently excluded. Additionally, based on medical records, three patients with mCRC who underwent metastasectomy following systemic therapy were excluded. Thus, the final analysis included 74 patients with mCRC with asymptomatic synchronous unresectable metastasis and no history of metastasectomy. A patient selection flowchart is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The present study protocol was approved by the Institutional Ethics Committee of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20230267).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment of mCRC\u003c/h2\u003e \u003cp\u003eA treatment plan was discussed by a multidisciplinary committee comprising colorectal surgeons, radiologists, gastroenterologists, medical oncologists, radiation oncologists, and pathologists. The first-line therapy principle was established according to the National Comprehensive Cancer Network guidelines and the consensus regarding mCRC treatment in Taiwan.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] The chemotherapy regimen involved FOLFIRI, and \u003cem\u003eRAS\u003c/em\u003e and \u003cem\u003eBRAF\u003c/em\u003e gene mutation statuses were examined.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] The treatment regimen comprised a 120-minute intravenous (IV) infusion of bevacizumab (5 mg/kg) on day 1, followed by a 4-hour IV infusion of irinotecan (180 mg/m\u003csup\u003e2\u003c/sup\u003e) plus 500 mL of normal saline and leucovorin (200 mg/m\u003csup\u003e2\u003c/sup\u003e) plus 5-FU (2800 mg/m\u003csup\u003e2\u003c/sup\u003e) plus 500 mL of normal saline for 42\u0026ndash;48 hours. This regimen was then repeated once every 2 weeks. Irinotecan dosage adjustments were made based on \u003cem\u003eUGT1A1\u003c/em\u003e genotyping.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] RT could be applied to the primary tumor site after multidisciplinary team discussion, as described in our previous studies.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Response Evaluation Criteria in Solid Tumors version 1.1, coupled with CT image and magnetic resonance image studies, were used to assess treatment responses.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] Following first-line therapy, on the basis of the response of the primary tumor and the control of distant metastasis, PTR was considered after multidisciplinary team discussion. PTR could take the form of either conventional laparotomy or minimally invasive surgery.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Colostomy was performed for patients experiencing bowel obstruction, malnutrition, post-intersphincteric resection, or anastomosis leakage.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eOn the basis of medical records, patients undergoing PTR after systemic therapy were designated as the \u0026ldquo;PTR\u0026rdquo; group. Conversely, those who did not receive PTR throughout the entire course of mCRC treatment were designated as the \u0026ldquo;No PTR\u0026rdquo; group. These patients were further classified into the aforementioned \u0026ldquo;4A,\u0026rdquo; \u0026ldquo;4B,\u0026rdquo; and \u0026ldquo;4C\u0026rdquo; subgroups based on their initially clinically diagnosed mCRC stages (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The patients with mCRC who received RT for primary tumor were classified into the \u0026ldquo;RT\u0026rdquo; group, whereas those who did not receive RT were classified into the \u0026ldquo;No RT\u0026rdquo; group. Furthermore, the patients with mCRC were subdivided into four groups\u0026mdash;namely \u0026ldquo;PTR(+)/RT(+),\u0026rdquo; \u0026ldquo;PTR(+)/RT(\u0026minus;),\u0026rdquo; \u0026ldquo;PTR(\u0026minus;)/RT(+),\u0026rdquo; and \u0026ldquo;PTR(\u0026minus;)/RT(\u0026minus;)\u0026rdquo;\u0026mdash;depending on whether they received PTR or RT.\u003c/p\u003e \u003cp\u003eDescriptive statistics\u0026mdash;including medians, means, and proportions\u0026mdash;were employed to characterize patient characteristics and gene alterations. The endpoint of the follow-up period was determined by the patient\u0026rsquo;s date of death, their date of final follow-up, or December 31, 2023. Overall survival (OS) was defined as the time from the date of diagnosis of mCRC to the date of death from any cause, the date of final follow-up, or the study endpoint. Median OS was calculated using the Kaplan\u0026ndash;Meier method, and the time-to-event distributions were compared using the log-rank test. A \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analysis was conducted using the Statistical Package for the Social Sciences software package (version 20; International Business Machines Corporation Inc., Armonk, NY, USA), as in our previous study.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eOf the 74 patients with mCRC analyzed in this study, the liver was the most common metastatic site (68.9%), followed by the lung (31.1%) and then the peritoneum (21.6%). Among the 74 patients, 37 were classified into each of the \u0026ldquo;PTR\u0026rdquo; and \u0026ldquo;No PTR\u0026rdquo; groups. The median time interval between the initiation of FOLFIRI plus bevacizumab treatment and PTR was 8.1 months (3.9\u0026ndash;15.8 months). No significant difference in age, sex, or body mass index was noted between the two groups. All the enrolled patients with mCRC exhibited adequate general condition for first-line systemic therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0\u0026ndash;1. No significant difference in ECOG performance status was identified between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.288). In the \u0026ldquo;PTR\u0026rdquo; group, 18 (48.6%), 15 (40.6%), and 4 (10.8%) patients were classified as stage IVA, stage IVB, and stage IVC, respectively. In the \u0026ldquo;No PTR\u0026rdquo; group, 15 (40.6%), 11 (29.7%), and 11 (29.7%) patients were classified as stage IVA, stage IVB, and stage IVC, respectively. No significant difference in the distribution of mCRC stages was noted between the groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.193).\u003c/p\u003e \u003cp\u003eAll the enrolled mCRC cases were adenocarcinomas, with the majority being well or moderately differentiated types (\u0026ldquo;PTR\u0026rdquo; group: 91.9%; \u0026ldquo;No PTR\u0026rdquo; group: 97.3%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.919). Five (13.5%) and 11 patients (29.7%) in the \u0026ldquo;PTR\u0026rdquo; and \u0026ldquo;No PTR\u0026rdquo; groups, respectively, had carcinoembryonic antigen levels exceeding 5 ng/dL at the initial diagnosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.295). In the \u0026ldquo;PTR\u0026rdquo; group, 24 patients (64.9%) received RT on the primary tumor, whereas in the \u0026ldquo;No PTR\u0026rdquo; group, 12 patients (32.4%) received RT on the primary tumor (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.587). All the enrolled patients received elective PTR because of the asymptomatic nature of the primary tumor. The characteristics of the enrolled patients are outlined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003ePatients Characteristics of PTR and No PTR groups (n\u0026thinsp;=\u0026thinsp;74).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLocation of metastasis (n\u0026thinsp;=\u0026thinsp;74)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e51 (68.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e23 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16 (21.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePara-aortic lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e12 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdrenal gland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e6 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCharacteristic\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTR (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo PTR (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years, median) (range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (36\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (26\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (62.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (56.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.733\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (37.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e(mean) (range)\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.5 (16.7\u0026ndash;31.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.0(16.0-34.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG\u003c/b\u003e\u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (54.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.288\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (45.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (73.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eIVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (48.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (40.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eIVB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (40.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eIVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistology (adenocarcinoma)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWell or moderately differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (91.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (97.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoorly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSidedness\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft colon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (81.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (81.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight colon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePretreatment CEA\u003c/b\u003e\u003csup\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;5 ng/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (86.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5 ng/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRadiotherapy on primary tumor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (64.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (32.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (67.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNature of PTR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e Because of multiple organ metastasis, the sum of the percentage exceeds 100%.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e BMI: body mass index\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ec\u003c/sup\u003e ECOG: Eastern Cooperative Oncology Group performance status\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ed\u003c/sup\u003e CEA: carcinoembryonic antigen\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGene alterations\u003c/h2\u003e \u003cp\u003eIn the \u0026ldquo;PTR\u0026rdquo; group, 12 patients (32.4%) exhibited wild-type \u003cem\u003eKRAS\u003c/em\u003e, and 15 patients (40.5%) had \u003cem\u003eKRAS\u003c/em\u003e mutation. In the \u0026ldquo;No PTR\u0026rdquo; group, 20 patients (56.8%) exhibited wild-type \u003cem\u003eKRAS\u003c/em\u003e, and 13 patients (43.2%) exhibited \u003cem\u003eKRAS\u003c/em\u003e mutation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.713). In the \u0026ldquo;PTR\u0026rdquo; group, 12 patients (32.4%) exhibited wild-type \u003cem\u003eNRAS\u003c/em\u003e, and one patient (2.7%) had \u003cem\u003eNRAS\u003c/em\u003e mutation. In the \u0026ldquo;No PTR\u0026rdquo; group, 18 patients (48.6%) had wild-type \u003cem\u003eNRAS\u003c/em\u003e, and no patients exhibited \u003cem\u003eNRAS\u003c/em\u003e mutation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.615). Regarding \u003cem\u003eBRAF\u003c/em\u003e status, 27 patients (73.0%) were diagnosed as having wild-type \u003cem\u003eBRAF\u003c/em\u003e in the \u0026ldquo;PTR\u0026rdquo; group. In the \u0026ldquo;No PTR\u0026rdquo; group, 31 patients (83.8%) exhibited wild-type \u003cem\u003eBRAF\u003c/em\u003e (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.475). Regarding \u003cem\u003eUGT1A1\u003c/em\u003e presentation, in the \u0026ldquo;PTR\u0026rdquo; group, 19 patients (51.4%) had the TA6/TA6 type, and six patients (16.2%) had the TA6/TA7 type. In the \u0026ldquo;No PTR\u0026rdquo; group, 27 patients (73.0%) had the TA6/TA6 type, and three patients (8.1%) had the TA6/TA7 type. No statistical significance in terms of \u003cem\u003eUGT1A1\u003c/em\u003e presentation was observed between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.929). Further details of gene alterations are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGene alteration status (patients, N\u0026thinsp;=\u0026thinsp;74)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene alteration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTR (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo PTR (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e mutation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (32.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20 (56.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.713\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNRAS\u003c/b\u003e \u003cb\u003emutation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (32.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (48.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.615\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24 (64.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (51.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBRAF\u003c/b\u003e \u003cb\u003emutation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (73.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (83.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.475\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUGT1A1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTA6/TA6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (51.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27 (73.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTA6/TA7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTA7/TA7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (32.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSurvival and treatment outcome\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003ePrimary tumor resection\u003c/h2\u003e \u003cp\u003eOverall, the median OS period for all the enrolled patients was 23.8 months (20.5\u0026ndash;27.1 months). The estimated 3-year OS rate was 23.0%, and the estimated 5-year OS rate was 5.7% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In the group analysis of survival outcomes, the \u0026ldquo;PTR\u0026rdquo; group exhibited a median OS period of 25.9 months (21.3\u0026ndash;30.5 months), with estimated 3-year and 5-year OS rates of 32.4% and 8.9%, respectively. By contrast, in the \u0026ldquo;No PTR\u0026rdquo; group, the median OS period was 21.4 months (15.8\u0026ndash;27.1 months), with estimated 3-year and 5-year OS rates of 13.5% and 2.7%, respectively. The OS outcome in the \u0026ldquo;PTR\u0026rdquo; group was significantly superior to that in the \u0026ldquo;No PTR\u0026rdquo; group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eIn the subgroup analysis, we compared the survival outcomes across multiple mCRC stages. For stage IVA, the \u0026ldquo;PTR-4A\u0026rdquo; group demonstrated a median OS period of 28.8 months (13.9\u0026ndash;43.7 months). The estimated 3-year OS rate was 33.3%, and the estimated 5-year OS rate was 11.1%. By contrast, in the \u0026ldquo;No PTR-4A\u0026rdquo; group, the median OS period was 21.0 months (14.4\u0026ndash;27.6 months), with an estimated 3-year OS rate of 13.3% and an estimated 5-year OS rate of 6.7%. Although the \u0026ldquo;PTR-4A\u0026rdquo; group exhibited a trend of a longer OS period than did the \u0026ldquo;No PTR-4A\u0026rdquo; group, the difference was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.116; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eIn the stage IVB analysis, the \u0026ldquo;PTR-4B\u0026rdquo; group demonstrated a median OS period of 24.3 months (18.7\u0026ndash;29.9 months), with an estimated 3-year OS rate of 40.0% and an estimated 5-year OS rate of 8.0%. In the \u0026ldquo;No PTR-4B\u0026rdquo; group, the estimated median OS period was 25.1 months (15.6\u0026ndash;34.6 months), with an estimated 3-year OS rate of 18.2% and an estimated 5-year OS rate of 0.0%. Although the \u0026ldquo;No PTR-4B\u0026rdquo; group exhibited a slightly longer OS period than did the \u0026ldquo;PTR-4B\u0026rdquo; group, the \u0026ldquo;PTR-4B\u0026rdquo; group revealed superior 3-year and 5-year OS rates. No significant difference was noted between the OS outcomes of these two subgroups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.493; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003eIn the stage IVC analysis, the \u0026ldquo;PTR-4C\u0026rdquo; group demonstrated a median OS period of 22.9 months (16.4\u0026ndash;29.4 months), with an estimated 2-year OS rate of 50.0% and an estimated 3-year OS rate of 0.0%. In the \u0026ldquo;No PTR-4C\u0026rdquo; group, the estimated median OS period was 16.6 months (10.1\u0026ndash;23.0 months), with an estimated 2-year OS rate of 27.3% and an estimated 3-year OS rate of 9.1%. No significant difference in OS outcomes was observed between the stage IVC subgroups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.760; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRadiotherapy\u003c/h2\u003e \u003cp\u003eIn the \u0026ldquo;RT\u0026rdquo; group, the estimated median OS period was 22.9 months (18.6\u0026ndash;27.2 months), with an estimated 3-year OS rate of 19.4% and an estimated 5-year OS rate of 6.5%. Conversely, in the \u0026ldquo;No RT\u0026rdquo; group, the estimated median OS survival period was 24.8 months (21.1\u0026ndash;28.5 months), with an estimated 3-year OS rate of 26.3% and an estimated 5-year OS rate of 5.3%. No significant difference was noted between the OS outcomes of the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.650; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003eIn the subgroup analysis, the median OS period for the \u0026ldquo;PTR(+)/RT(+)\u0026rdquo; group was 23.3 months (20.3\u0026ndash;26.4 months), with an estimated 3-year OS rate of 25.0% and an estimated 5-year OS rate of 10.0%. In the \u0026ldquo;PTR(+)/RT(\u0026minus;)\u0026rdquo; group, the estimated median OS period was 36.1 months (19.4\u0026ndash;52.7 months), with an estimated 3-year OS rate of 46.2% and an estimated 5-year OS rate of 7.7%. The median OS period for the \u0026ldquo;PTR(\u0026minus;)/RT(+)\u0026rdquo; was 15.4 months (1.7\u0026ndash;29.1 months), with estimated 3-year and 5-year OS rates of 8.3% and 0.0%, respectively. In the \u0026ldquo;PTR(\u0026minus;)/RT(\u0026minus;)\u0026rdquo; group, the estimated median OS period was 21.9 months (15.6\u0026ndash;28.2 months), with estimated 3-year and 5-year OS rates of 16.0% and 4.0%, respectively. Overall, no significant differences were observed among the OS outcomes of these four subgroups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.174; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eMany studies have investigated the therapeutic impact of PTR on asymptomatic synchronous mCRC with unresectable distant metastasis. Furthermore, many studies have indicated that PTR may offer some survival benefits. However, most PTRs discussed in previous studies refer to procedures conducted before chemotherapy.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] Accordingly, some RCTs have been initiated subsequently. The JCOG1007 study, involving 165 patients, concluded that PTR followed by chemotherapy provided no survival benefit compared with chemotherapy alone.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] The CAIRO4 Phase 3 trial reported that PTR followed by systemic therapy resulted in higher 60-day mortality than systemic therapy alone; however, all the OS outcomes are still pending.[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] The SYNCHRONOUS trial, comprising 393 patients, reported that PTR prior to chemotherapy did not extend the OS period for synchronous unresectable mCRC.[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] The ongoing GRECCAR 8 trial, which aimed to include 290 patients, has yet to yield available results.[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAmong all these RCTs, the JCOG1007 study has presented the most robust evidence indicating that PTR followed by chemotherapy does not yield a survival benefit compared with chemotherapy alone.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Nevertheless, the present study focused on the role of PTR after neoadjuvant systemic therapy and aimed to address the question outlined in the \u003cspan refid=\"Sec1\" class=\"InternalRef\"\u003eBackground\u003c/span\u003e section of this paper, namely whether PTR should be performed for patients with mCRC with synchronous unresectable distant metastasis after neoadjuvant systemic therapy. The standard first-line targeted therapy comprises an antiepidermal growth factor receptor agent (cetuximab or panitumumab) and an antivascular endothelial growth factor agent (bevacizumab).[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] Although the antiepidermal growth factor receptor agent is effective, it can be administered only to patients with wild-type \u003cem\u003eRAS\u003c/em\u003e.[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] To ensure homogeneity and avoid potential confounding factors in OS outcomes, this study enrolled patients with mCRC who received a single systemic regimen\u0026mdash;namely FOLFIRI chemotherapy plus bevacizumab targeted therapy\u0026mdash;regardless of whether wild-type \u003cem\u003eRAS\u003c/em\u003e or \u003cem\u003eRAS\u003c/em\u003e mutation was present. The comparisons of basic patient characteristics in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e reveal no statistical significance in each variable between the \u0026ldquo;PTR\u0026rdquo; and \u0026ldquo;No PTR\u0026rdquo; groups. Consequently, the composition of patients with mCRC in both groups was similar; this feature enhances the credibility of the study results.\u003c/p\u003e \u003cp\u003eIn the present study, the median OS period for the \u0026ldquo;PTR\u0026rdquo; group was 25.9 months, which was significantly longer than 21.4 months observed in the \u0026ldquo;No PTR\u0026rdquo; group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048). However, the \u0026ldquo;No PTR\u0026rdquo; group had more stage IVC patients (11 patients, 29.7%) than the \u0026ldquo;PTR\u0026rdquo; group (4 patients, 10.8%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). To mitigate the potential prognostic impact of different cancer stages on OS, we conducted subgroup analyses according to clinical stages. The median OS period in the \u0026ldquo;PTR-4A\u0026rdquo; subgroup was longer than that in the \u0026ldquo;No PTR-4A\u0026rdquo; subgroup (28.8 and 21.0 months, respectively), and the OS curves exhibited clear separation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). However, the OS difference was less evident between the \u0026ldquo;PTR-4B\u0026rdquo; and \u0026ldquo;No PTR-4B\u0026rdquo; subgroups (24.3 and 25.1 months, respectively); the \u0026ldquo;PTR-4B\u0026rdquo; group exhibited a higher survival rate, but the OS curve exhibited many crossover points (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Regarding stage IVC, the OS curve for the \u0026ldquo;PTR-4C\u0026rdquo; group appeared chaotic because of the limited number of patients. These results indicate that PTR may play a relatively pivotal role in mCRC cases with single-organ involvement. For multiorgan or peritoneal carcinomatosis mCRC, systemic therapy remains the primary treatment approach.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eA possible reason behind the observed survival benefit in patients who underwent PTR may be an advantage such as the removal of chemotherapy-resistant tumor cells or the reduction of tumor burden, as mentioned in the \u003cspan refid=\"Sec1\" class=\"InternalRef\"\u003eBackground\u003c/span\u003e section of this paper. However, selection bias may have influenced these results given the retrospective study design and the nonrandomized grouping method.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] For example, we failed to clarify detailed \u0026ldquo;T\u0026rdquo; and \u0026ldquo;N\u0026rdquo; stages for each patient; consequently, advanced primary tumor (ex: T4N2M1a) and localized primary tumor (ex: T2N0M1a) may have been categorized as the same stage (stage IVA). Many studies have reported that T4 tumors exhibit inferior survival prognoses compared with T1, T2, and T3 tumors in patients with mCRC.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] Furthermore, T4 primary tumors pose a greater challenge for curative surgical resection,[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] potentially leading to a higher likelihood of their being classified into the \u0026ldquo;No PTR\u0026rdquo; group.\u003c/p\u003e \u003cp\u003eLau \u003cem\u003eet al\u003c/em\u003e. conducted a single-institution retrospective review to investigate the role of PTR in mCRC treatment. Their results revealed that treatment with PTR plus chemotherapy led to a significantly longer OS period compared with chemotherapy alone.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] By contrast, JCOG1007, an RCT, reported that treatment with PTR plus chemotherapy yielded an OS period of 25.9 months, which was similar to that obtained with chemotherapy alone (26.7 months).[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Despite their similar study designs in terms of patient grouping, these two studies yielded divergent results. Both studies focused on the role of PTR before systemic therapy for mCRC, which differs from the aim of the present study. However, this instance serves as an illustrative example of how selection bias can affect study outcomes and underscores the importance of RCTs in accurately interpreting clinical dilemmas. Compared with our treatment experience, the median OS period for patients with mCRC who received bevacizumab plus FOLFIRI as first-line therapy was 30 months.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] For patients with mCRC with peritoneal carcinomatosis who received the same first-line therapy, the median OS period was 24.6 months.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] In the present study, all the enrolled patients had unresectable metastasis, and the median OS period in the \u0026ldquo;PTR\u0026rdquo; group was 25.9 months. This similarity in survival outcomes suggests that our enrolled patients did not belong to a specific outlier group.\u003c/p\u003e \u003cp\u003eIn the OS analysis, regarding PTR and RT, the \u0026ldquo;No RT\u0026rdquo; group exhibited a longer median OS period than the \u0026ldquo;RT\u0026rdquo; group (22.9 months vs. 24.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.650, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Moreover, the estimated 3-year and 5-year OS rates in the \u0026ldquo;No RT\u0026rdquo; group were superior to those in the \u0026ldquo;RT\u0026rdquo; group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). In our four-subgroup OS analysis based on PTR and RT, among the patients with mCRC who underwent PTR, those who did not receive RT had a longer OS period than those who received RT (23.3 months vs. 36.1 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.271, Supplementary Fig.\u0026nbsp;1A). Similarly, for patients with mCRC who did not undergo PTR, those who did not receive RT on the primary tumor had a longer OS period than those who received RT on the primary tumor (15.4 months vs. 21.9 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.737, Supplementary Fig.\u0026nbsp;1B). These results indicate the advanced T/N stage of the primary tumor. In our clinical practice, RT is typically administered to treat advanced CRC with local invasion or lymphadenopathy.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Thus, RT indirectly reflects a more advanced T/N stage of the primary tumor, contributing to a shorter OS period.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eConversely, a comparison of the OS outcomes based on RT revealed a trend toward a longer OS period for patients with mCRC who received RT and underwent PTR compared with those who underwent RT without PTR (23.3 months vs. 15.4 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.226, Supplementary Fig.\u0026nbsp;2A). Similarly, for patients with mCRC who did not receive RT, a longer OS period was observed for those who underwent PTR than for those who did not (36.1 months vs. 21.9 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049, Supplementary Fig.\u0026nbsp;2B). These results suggest that under similar primary tumor T/N stage conditions, PTR can provide a survival benefit to patients with mCRC with unresectable metastasis after first-line systemic therapy.\u003c/p\u003e \u003cp\u003eBecause the tumor burden of metastatic lesions is a crucial factor influencing poor prognosis,[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] a reduction in tumor burden due to PTR is unlikely to be the primary reason for the observed differences in OS outcomes. Although selection bias may contribute to a portion of the survival benefit, it is insufficient to account for all the differences in the present results given the analysis of OS periods based on PTR and RT, as described previously. Because systemic therapy is the gold standard for the treatment of mCRC,[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] the OS outcome in mCRC is expected to have the strongest relationship with this type of therapy. One plausible explanation for the observed differences could be chemotherapy-induced psychological distress. In the context of mCRC treatment, psychological distress often accompanies chemotherapy and serves as a hidden detrimental factor affecting quality of life and the treatment course.[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] Some studies have introduced psychological support and care to alleviate anxiety and depression in patients with mCRC.[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] On the basis of our clinical observations, patients with mCRC may experience psychological exhaustion after a prolonged course of systemic therapy. The perception of an endless need for treatment can lead to a sense of despair, potentially causing patients to contemplate discontinuing their treatment. PTR may act as a treatment milestone and strengthen patients\u0026rsquo; confidence in the treatment plan. Such a psychological boost could motivate patients to persevere through subsequent long-term treatment, thereby indirectly contributing to the prolonged OS period. However, in this retrospective study, we were unable to collect psychological assessment data to validate this hypothesis.\u003c/p\u003e \u003cp\u003eSeveral studies have explored the therapeutic efficacy of metastasis-directed RT and have reported promising outcomes.[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] However, the effect of RT on primary tumor in mCRC treatment has not been studied extensively. In the present study, we analyzed the survival outcomes associated with RT intervention in patients with mCRC. The findings of our study indicated that RT applied to the primary tumor did not confer additional benefits to OS in patients with mCRC (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). This result aligns with our previous treatment results observed in cases of locally advanced rectal cancer with synchronous metastasis.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Compared with systemic therapy alone, the combination of RT and systemic therapy led to prolonged local recurrence-free survival and progression-free survival but no significant difference in OS.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] The present data reveals that similar survival outcomes can be observed in the treatment of metastatic colon cancer as well as in that of rectal cancer.\u003c/p\u003e \u003cp\u003eThis study was a retrospective analysis conducted at a single center; such a study design is associated with limitations, such as a small patient sample. Therefore, the sample size may not have been sufficient for robust subgroup analyses. General patient condition was assessed solely on the basis of performance status, and essential laboratory data\u0026mdash;such as those related to liver function, renal function, and underlying disease\u0026mdash;were not included. Some details regarding primary tumor, such as T/N stage, were not available, and although RT was used as an indirect measure for evaluating primary tumor T/N stage, it cannot precisely reflect the primary tumor condition. The absence of an assessment of the patients\u0026rsquo; psychological status, along with a lack of a questionnaire to evaluate the scale of psychological exhaustion, weakens the hypothesis related to psychological stress. Additionally, selection bias due to the aforementioned limitations and the retrospective nature of this study could not be ruled out.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study provides real-world insights into the treatment impact of PTR on patients with mCRC undergoing first-line therapy. In cases of mCRC with synchronous unresectable metastasis, PTR demonstrates a survival benefit following neoadjuvant chemotherapy and targeted therapy. This therapeutic effect of PTR is especially pronounced in stages IVA and IVB. Furthermore, our findings indicate that RT on the primary tumor does not provide additional benefits to OS in the context of mCRC with unresectable metastasis. To establish a clearer understanding of the genuine effects of PTR following systematic therapy, larger-scale prospective, randomized trials are needed.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eBMI:\u0026nbsp;\u003c/strong\u003ebody mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCEA:\u0026nbsp;\u003c/strong\u003ecarcinoembryonic antigen\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRC\u003c/strong\u003e: colorectal cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emCRC\u003c/strong\u003e: metastatic colorectal cancer.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCT\u003c/strong\u003e: computed tomography.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECOG\u003c/strong\u003e: Eastern Cooperative Oncology Group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFOLFIRI\u003c/strong\u003e: folinic acid, 5-fluorouracil, and irinotecan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIV\u003c/strong\u003e: intravenous.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e: overall survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePTR\u003c/strong\u003e: primary tumor resection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRCT\u003c/strong\u003e: randomized controlled trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRT\u003c/strong\u003e: radiotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study protocol was approved by the Institutional Ethics Committee of Kaohsiung Medical University Hospital\u0026nbsp;(KMUHIRB-E(I)-20230267). Consent to participate is not applicable due to retrospective study design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn behalf of all co-authors, the corresponding author has obtained the consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data and information can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grants from public, commercial, or not-for-profit sector funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYCC, JYW, and CWH designed the study. YCC, TKC, WCS, YSY, PJC, YTC, PJH, PHY, HLT, JYW and CWH extracted and collected data. YCC, TKC, WCS, YSY, PJC, YTC, HLT, JYW, and CWH analyzed and interpreted the data. YCC, JYW, and CWH drafted the manuscript. YCC, JYW, and CWH critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants through funding from the National Science and Technology Council (MOST 111-2314-B-037-070-MY3, NSTC 112-2314-B-037-090, NSTC 112-2314-B-037-050-MY3) and the Ministry of Health and Welfare (12D1-IVMOHW02) and funded by the health and welfare surcharge of on tobacco products, and the Kaohsiung Medical University Hospital (KMUH112-2R37, KMUH112-2R38, KMUH112-2R39, KMUH112-2M27, KMUH112-2M28, KMUH112-2M29, KMUH-SH11207) and Kaohsiung Medical University Research Center Grant (KMU-TC112A04). In addition, this study was supported by the Grant of Taiwan Precision Medicine Initiative and Taiwan Biobank, Academia Sinica, Taiwan, R.O.C.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLi N, Lu B, Luo C, Cai J, Lu M, Zhang Y, Chen H, Dai M: \u003cstrong\u003eIncidence, mortality, survival, risk factor and screening of colorectal cancer: A comparison among China, Europe, and northern America\u003c/strong\u003e. \u003cem\u003eCancer letters \u003c/em\u003e2021, \u003cstrong\u003e522\u003c/strong\u003e:255-268.\u003c/li\u003e\n\u003cli\u003eBiller LH, Schrag D: \u003cstrong\u003eDiagnosis and Treatment of Metastatic Colorectal Cancer: A Review\u003c/strong\u003e. \u003cem\u003eJama \u003c/em\u003e2021, \u003cstrong\u003e325\u003c/strong\u003e(7):669-685.\u003c/li\u003e\n\u003cli\u003eShin AE, Giancotti FG, Rustgi AK: \u003cstrong\u003eMetastatic colorectal cancer: mechanisms and emerging therapeutics\u003c/strong\u003e. \u003cem\u003eTrends in pharmacological sciences \u003c/em\u003e2023, \u003cstrong\u003e44\u003c/strong\u003e(4):222-236.\u003c/li\u003e\n\u003cli\u003eTsai HL, Shi HY, Chen YC, Huang CW, Su WC, Chang TK, Li CC, Chen PJ, Yeh YS, Yin TC\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eClinical and cost-effectiveness analysis of mFOLOFX6 with or without a targeted drug among patients with metastatic colorectal cancer: inverse probability of treatment weighting\u003c/strong\u003e. \u003cem\u003eAmerican journal of cancer research \u003c/em\u003e2023, \u003cstrong\u003e13\u003c/strong\u003e(9):4039-4056.\u003c/li\u003e\n\u003cli\u003eNetwork NCC: \u003cstrong\u003eNCCN Guidelines for Colon Cancer and Rectal Cancer V.1.2023\u003c/strong\u003e. 2023.\u003c/li\u003e\n\u003cli\u003eChen HH, Ke TW, Huang CW, Jiang JK, Chen CC, Hsieh YY, Teng HW, Lin BW, Liang YH, Su YL\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eTaiwan Society of Colon and Rectal Surgeons Consensus on mCRC Treatment\u003c/strong\u003e. \u003cem\u003eFrontiers in oncology \u003c/em\u003e2021, \u003cstrong\u003e11\u003c/strong\u003e:764912.\u003c/li\u003e\n\u003cli\u003eTsai HL, Huang CW, Lin YW, Wang JH, Wu CC, Sung YC, Chen TL, Wang HM, Tang HC, Chen JB\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDetermination of the UGT1A1 polymorphism as guidance for irinotecan dose escalation in metastatic colorectal cancer treated with first-line bevacizumab and FOLFIRI (PURE FIST)\u003c/strong\u003e. \u003cem\u003eEuropean journal of cancer (Oxford, England : 1990) \u003c/em\u003e2020, \u003cstrong\u003e138\u003c/strong\u003e:19-29.\u003c/li\u003e\n\u003cli\u003eHernandez Dominguez O, Yilmaz S, Steele SR: \u003cstrong\u003eStage IV Colorectal Cancer Management and Treatment\u003c/strong\u003e. \u003cem\u003eJournal of clinical medicine \u003c/em\u003e2023, \u003cstrong\u003e12\u003c/strong\u003e(5).\u003c/li\u003e\n\u003cli\u003eLi CC, Chang TK, Chen YC, Tsai HL, Huang CW, Su WC, Ma CJ, Yin TC, Chen PJ, Wang JY: \u003cstrong\u003eClinical Outcomes of Patients with Peritoneal Metastasis-Only Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI Through Irinotecan Dose Escalation According to UGT1A1 Polymorphism: Compared to Liver Metastasis-Only, and Lung Metastasis-Only\u003c/strong\u003e. \u003cem\u003eCancer management and research \u003c/em\u003e2022, \u003cstrong\u003e14\u003c/strong\u003e:1541-1549.\u003c/li\u003e\n\u003cli\u003eKanemitsu Y, Shitara K, Mizusawa J, Hamaguchi T, Shida D, Komori K, Ikeda S, Ojima H, Ike H, Shiomi A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePrimary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; 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Wang J: \u003cstrong\u003eStereotactic ablative radiotherapy for colorectal cancer liver metastasis\u003c/strong\u003e. \u003cem\u003eSeminars in cancer biology \u003c/em\u003e2021, \u003cstrong\u003e71\u003c/strong\u003e:21-32.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Colorectal cancer, asymptomatic, unresectable metastasis, primary tumor resection, first-line bevacizumab plus FOLFIRI","lastPublishedDoi":"10.21203/rs.3.rs-4516245/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4516245/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMetastatic colorectal cancer (mCRC) poses a clinical challenge and requires a combination of systemic therapy and conversion surgery. Although first-line chemotherapy and targeted therapy are considered the standard treatments for mCRC, the role of primary tumor resection (PTR) in asymptomatic synchronous mCRC with unresectable metastatic lesion after initial therapy remains relatively underexplored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective review was conducted from January 2015 to January 2021, involving 74 patients with synchronous mCRC who received bevacizumab plus FOFIRI as first-line systemic therapy. All 74 patients had unresectable metastatic lesions confirmed through multidisciplinary team discussion. Patient characteristics, PTR data, and radiotherapy (RT) and overall survival (OS) outcomes were analyzed. The patients were categorized into a “PTR” group and a “No PTR” group and then further stratified into “4A,” “4B,” and “4C” subgroups based on the initial mCRC stage. Additionally, four subgroups—namely “PTR(+)/RT(+),” “PTR(+)/RT(−),” “PTR(−)/RT(+),” and “PTR(−)/RT(−)”—were formed to assess the combined effects of PTR and RT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median OS for all the patients was 23.8 months (20.5–27.1 months). The “PTR” group exhibited a significantly higher median OS of 25.9 months (21.3–30.5 months) compared with 21.4 months (15.8–27.1 months) in the “No PTR” group (\u003cem\u003ep\u003c/em\u003e = 0.048). Subgroup analyses revealed a trend of improved survival with PTR in patients with stage IVA and IVB; however, the results were not statistically significant (\u003cem\u003ep\u003c/em\u003e = 0.116 and 0.493, respectively). A subgroup analysis of PTR and RT combinations revealed no significant difference in median OS rates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor asymptomatic mCRC with synchronous unresectable distant metastasis, PTR following first-line therapy with bevacizumab plus FOLFIRI can provide a survival benefit, particularly in stage IVA/IVB patients compared with stage IVC patients. Additionally, RT for primary tumor did not provide an additional OS benefit in mCRC with unresectable metastasis. A prospective randomized trial with a larger sample size is essential to further elucidate the role of PTR in this context.\u003c/p\u003e","manuscriptTitle":"Survival Benefits of Asymptomatic Primary Tumor Resection After Bevacizumab Plus FOLFIRI as First-Line Therapy for Patients with Metastatic Colorectal Cancer with Synchronous Unresectable Metastasis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 15:51:01","doi":"10.21203/rs.3.rs-4516245/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5dd2d4df-501e-4f2d-8d14-96a5fc157b03","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-18T23:51:26+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-16 15:51:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4516245","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4516245","identity":"rs-4516245","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}