Impact of combined resection of the internal iliac artery on loss of volume of the gluteus muscles after pelvic exenteration.

PURPOSE: To clarify the influence of additional internal iliac artery (IIA) resection on the loss of the gluteus muscle volume after pelvic exenteration (PE). METHODS: The subjects of this retrospective analysis were 78 patients who underwent PE with or without IIA resection (n = 44 and n = 34, respectively) between 2006 and 2018. The areas of gluteal muscles (GMs) and psoas muscles (PSMs) were calculated using CT images before and 6 months after PE, and the difference was compared. RESULTS: The volumes of the GMs and PSMs were significantly reduced after PE (P < 0.001 and P = 0.005, respectively). In the IIA resection group, the GMs were significantly reduced after surgery, but the PSMs were not. The maximum GM (Gmax) was the most atrophied among the GMs. Multivariable analysis revealed that complete IIA resection was an independent promotor of the loss of volume of the Gmax (P = 0.044). In 18 patients with unilateral IIA resection, the downsizing rate of the Gmax was significantly greater on the resected side than on the non-resected side (P = 0.008). CONCLUSIONS: The GMs and PSMs were significantly smaller after PE. Complete IIA resection reduced the Gmax area remarkably. Preservation of the superior gluteus artery is likely to help maintain Gmax size, suggesting a potential preventative measure against secondary sarcopenia.

Current status of transanal total mesorectal excision for rectal cancer and the expanding indications of the transanal approach for extended pelvic surgeries.

Transanal total mesorectal excision (taTME) has been rapidly accepted as a promising surgical approach to the distal rectum. The benefits include ease of access to the bottom of the deep pelvis linearly over a short distance in order to easily visualize the important anatomy. Furthermore, the distal resection margins can be secured under direct vision. Additionally, a two-team approach combining taTME with a transabdominal approach could decrease the operative time and conversion rate. Although taTME was expected to become more rapidly popularized worldwide, enthusiasm for it has stalled due to unfamiliar intraoperative complications, a lack of oncologic evidence from randomized trials, and the widespread use of robotic surgery. While international registries have reported favorable short- and medium-term outcomes from taTME, a Norwegian national study reported a high local recurrence rate of 9.5%. The characteristics of the recurrences included rapid, multifocal growth in the pelvis, which was quite different from recurrences following traditional transabdominal TME; thus, the Norwegian Colorectal Cancer Group reached a consensus for a temporary moratorium on the performance of taTME. To ensure acceptable baseline quality and patient safety, taTME should be performed by well-trained colorectal surgeons. Although the appropriate indications for taTME remain controversial, the transanal approach is extremely important as a means of goal setting in difficult TME cases and as an aid to the transabdominal approach in various types of extended pelvic surgeries. The benefits in transanal lateral lymph node dissection and pelvic exenteration are presented herein.

Role of resection for extrahepatopulmonary metastases of colon cancer.

BACKGROUND: Although surgical resection for liver or lung metastases of colorectal cancer has been widely accepted, the use of this approach for extrahepatopulmonary metastases remains debatable due to the systemic nature of the disease. The aim of this study was to clarify the utility of resection along with perioperative chemotherapy for patients with extrahepatopulmonary metastases of colon cancer. METHODS: This is a retrospective single-arm study at a single institution. Forty-two patients with resectable extrahepatopulmonary metastases who underwent metastasectomy with curative intent between 2009 and 2018 at Nagoya University Hospital were retrospectively analyzed. The primary outcomes measured were overall and relapse-free survival. RESULTS: The most common metastatic site was the peritoneum (n = 31), followed by the distant lymph nodes (n = 10), ovary (n = 1) and spleen (n = 1), with overlaps. Preoperative and postoperative chemotherapies were administered to 22 and 8 patients, respectively; the remaining 14 patients received surgery alone. R0 resection was achieved in 36 patients (85.7%). The 5-year overall survival and 3-year relapse-free survival rates were 58.6% and 33.8%, respectively. In the univariate analysis, R1 resection was associated with a poor relapse-free survival rate (P = 0.02). In the multivariate analysis, the absence of perioperative chemotherapy was an independent risk factor for poor overall survival rates (P = 0.02). CONCLUSIONS: Surgical resection benefited selected patients with extrahepatopulmonary metastases with favorable long-term survival outcomes. Surgery alone without systemic chemotherapy is likely to bring poor outcome; therefore, preoperative induction might be promising to keep up with chemotherapy.

Stoma creation is associated with a low incidence of midline incisional hernia after colorectal surgery: the "fighting over the fascia" theory concerning the incision and stoma hole.

PURPOSE: Parastomal hernia (PH) develops more frequently than incisional hernia (IH) after colorectal surgery with stoma. This study evaluated our hypothesis that inward traction of the fascia when closing a midline incision widens the stoma hole and increases the incidence of PH. METHODS: A total of 795 patients who underwent colorectal resection between 2006 and 2016 were retrospectively analyzed. The risk classification was constructed from IH risk factors extracted from the non-stoma group. Then, the classification was extrapolated to the stoma group for predicting midline IH and PH. RESULTS: The incidence of IH was 5.3% in the stoma group and 12.5% in the non-stoma group (p = 0.005). PH developed in 19.6% of 97 patients with permanent stoma. The risk classification was able to predict PH without a significant difference but was well balanced in patients with permanent stoma; however, it failed to predict IH in the stoma group. CONCLUSION: The risk classification constructed from the non-stoma group was useful for predicting not midline IH but PH, suggesting that the stoma site was the most vulnerable for herniation. The "fighting over the fascia" theory between the midline incision and stoma hole may explain the causal relationship between the midline IH and PH.

The significance of the time to arterial perfusion in intraoperative ICG angiography during colorectal surgery.

BACKGROUND: Intraoperative indocyanine green angiography (ICG-A) is a promising tool to confirm blood supply; however, the assessment is difficult without clear demarcation. In this study, the clinical impact of the time to arterial perfusion (TAP) on anastomotic leakage (AL) was evaluated, especially in patients without ICG demarcation. METHODS: The TAP was assessed using ICG-A during colorectal surgery in 110 patients. ICG demarcation required changing the transection line, and the TAP was measured at the new stump. The patients were divided into marginal flow (MF) and direct flow (DF) groups according to the arterial route. Delayed TAP was defined as the third quartile or slower TAP in each group. RESULTS: Sixty-six patients (60%) were classified into the MF group, including 64 patients who underwent rectal or sigmoid resection with high ligation of the inferior mesenteric artery. The cut-off value of the delayed TAP in the MF group was significantly slower than that in the DF group (30 and 22 s, respectively, p < 0.001). In the entire cohort, the transection line was changed in 2 patients, resulting in no AL. Nevertheless, AL still developed in 6 patients (5.4%), 5 of whom were in the MF group, and delayed TAP was found in 5 of 6 patients. Delayed TAP was significantly associated with AL in the MF group (p = 0.046). CONCLUSIONS: In patients without ICG demarcation, delayed TAP might be helpful for predicting the high-risk patients with AL in the MF group; however, performing diverting stoma or strictly careful observation might be a realistic reaction.

The survival benefit of neoadjuvant chemotherapy for resectable colorectal liver metastases with high tumor burden score.

BACKGROUND: The indications for neoadjuvant chemotherapy (NAC) in resectable colorectal liver metastases (CRLMs) remain unclear. Tumor burden score (TBS) is a prognostic tool based on tumor size and number of tumors. However, its utility in the NAC setting for initially resectable CRLM has never been investigated. METHODS: TBS is a distance from the origin on a Cartesian plane to the coordinates (x, y) = (tumor size in centimeter, number of tumors). TBS < 3 was defined as "TBS-low", whereas TBS ≥ 3 as "TBS-high". Between 2008 and 2018, 102 patients who underwent hepatectomy for resectable CRLM were retrospectively analyzed using the Kaplan-Meier method and Cox proportional hazards regression models. RESULTS: Among the TBS-low (n = 46) and TBS-high (n = 56) groups, baseline patient characteristics were mostly similar except for TBS-related parameters. NAC was more frequently administered in the TBS-high group (p = 0.038). The overall survival (OS) rates were similar between the two groups. Subgroup analysis showed that NAC was associated with non-significantly improved 5-year OS in the TBS-high group [76.1% with NAC and 54.9% without NAC (p = 0.093)]. In multivariate analysis, NAC was an independent prognostic factor for favorable OS only in the TBS-high group, while adjuvant chemotherapy (AC) was associated with improved OS only in the TBS-low group. CONCLUSION: In patients with resectable CRLM, the TBS-high population had a survival benefit from NAC, while the TBS-low population benefited from AC. TBS may serve as an indicator for patients who will benefit from NAC.

The carcinoembryonic antigen ratio is a potential predictor of survival in recurrent colorectal cancer.

BACKGROUND: The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. METHODS: This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. RESULTS: Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor. CONCLUSION: The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.

What is the impact of systemic chemotherapy for lateral lymph nodes in patients with locally advanced low rectal cancer?

PURPOSE: Systemic chemotherapy (SC) before surgery is a potential treatment to improve survival in patients with advanced rectal cancer. However, the impact of SC on lateral lymph nodes (LLNs) remains unclear. METHODS: A total of 78 patients with stage II/III low rectal cancer, who received 3-month oxaliplatin-based SC followed by LLN dissection (LLND) in principle, were analysed retrospectively. "Total lateral lymph node metastases (tLLNMs)" was defined as having either pathological LLNMs (pLLNMs) or lateral local recurrences (LLRs). Patients with the maximum short-axis size of LLNs ≥ 7 mm were classified into the swollen group (n = 21). RESULTS: In the total cohort, tLLNMs included 6 pLLNMs (7.7%) and 2 LLRs (2.6%). In the non-swollen group, no patients had pLLNMs, but one had LLR (1.8%). In the swollen group, pLLNMs and LLRs were detected in 6 (28.6%) and 1 (4.8%), respectively. The swollen group was an independent risk factor for tLLNMs (P < 0.001), leading to the significantly worse 5-year relapse-free survival (RFS) of 52.4% than the others. CONCLUSION: For patients without swollen LLNs, SC could allow for omission both of lateral irradiation and LLND. For patients with swollen LLNs, the lateral local control was favourable after SC and LLND without chemoradiotherapy (CRT); however, oxaliplatin-based SC might be insufficient to improve survival, requiring more intensive chemotherapy. CRT should be indicated according to the other risk factors of central local recurrence, although the swollen LLNs should be removed.

Phase II study of capecitabine plus oxaliplatin (CapOX) as adjuvant chemotherapy for locally advanced rectal cancer (CORONA II).

OBJECTIVE: This multicenter, single-arm phase II study (UMIN000008429) aimed to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapOX) as postoperative adjuvant chemotherapy for patients with locally advanced rectal cancer. METHODS: Patients with resectable clinical Stage II or III rectal cancer were enrolled to receive eight cycles of CapOX therapy (130 mg/m2 oxaliplatin on day 1 and 2000 mg/m2 oral capecitabine on days 1-14, every 3 weeks) after curative surgical resection. The primary endpoint was 3-year relapse-free survival (RFS) rate, and secondary endpoints were 3-year overall survival (OS) rate, treatment compliance, and safety. RESULTS: A total of 40 patients (Stage II, 21; Stage III, 19) were enrolled between September 2012 and November 2015 from seven institutions. Thirty-nine patients (97%) received R0 resection, and 32 patients (84%) received postoperative CapOX therapy. The completion rate of all eight cycles of CapOX therapy was 66%. Relative dose intensities were 87% for oxaliplatin and 84% for capecitabine. At a median follow-up period of 46 months, disease recurrence was observed in nine patients, including three with local recurrence. Three-year RFS and OS rates were 75% (95% CI 57-86%) and 96% (95% CI 80-99%), respectively. Frequencies of Grade ≥ 3 hematological and non-hematologic adverse events were 19% and 38%, respectively. CONCLUSION: CapOX therapy is feasible as adjuvant chemotherapy for locally advanced rectal cancer.

Pelvic exenteration associated with future renal dysfunction.

PURPOSE: This study aimed to clarify the long-term change in the renal function after pelvic exenteration (PE) and to evaluate the risk factors for any future dysfunction. METHODS: This study comprised 40 patients. A greater than 25% decline in the estimated glomerular filtration rate (eGFR) at 3 years was defined as early renal function disorder (ERFD), possibly predicting future chronic kidney disease (CKD). RESULTS: In the entire cohort, the median eGFR decreased by 23% at 3 years, and CKD developed in 50%. The patients were divided into the ERFD (n = 16) and non-ERFD (n = 24) groups. In the ERFD group, the eGFR significantly decreased by 28% during the first 1.5 years and continued to decline after that, resulting in 81.3% of patients reaching CKD, whereas it was 4% and 37.5%, respectively, in the non-ERFD group. In a growth model analysis, late urinary tract complications (UTC) and small bowel obstruction were shown to be risk factors for ERFD. CONCLUSION: Although PE was associated with a high incidence of future CKD, ERFD could predict it. Close observation of the eGFR decline over 1.5 years might be beneficial to identify ERFD patients. High-risk patients with late UTC and small bowel obstruction should, therefore, be observed carefully.

Importance of the neoadjuvant rectal (NAR) score to the outcome of neoadjuvant chemotherapy alone for locally advanced rectal cancer.

PURPOSE: The neoadjuvant rectal (NAR) score is a promising indicator of survival after preoperative chemoradiotherapy for rectal cancer. However, its effectiveness after neoadjuvant chemotherapy (NAC) alone has not been fully investigated. METHODS: We analyzed data retrospectively on 61 patients with rectal cancer, who received NAC followed by surgical resection between 2010 and 2015, and evaluated the impact of the NAR score on survival. RESULTS: The median NAR score was 14.9. Of the 61 patients, 13, 35, and 13 were classified as having NAR-low (< 8), NAR-intermediate (8-16), and NAR-high (> 16) scores, respectively. The median observation period was 49.0 months. According to the NAR score, the 3-year DFS in the NAR-low group was 100%, which was significantly better than that in the NAR-intermediate (64.8%, p = 0.041), and NAR-high (61.5%, p = 0.018) groups. When the NAR-intermediate and NAR-high groups were investigated as a single high-risk group, the 3-year DFS of the patients who received adjuvant chemotherapy was 88.7%, which was significantly better than that of the patients who did not receive adjuvant chemotherapy (53.3%, p = 0.042). CONCLUSIONS: The NAR score may predict the DFS and could serve as a favorable indicator of adjuvant chemotherapy after NAC alone.

Neoadjuvant CAPOX and bevacizumab alone for locally advanced rectal cancer: long-term results from the N-SOG 03 trial.

BACKGROUND: Neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains an experimental treatment, and the efficacy in terms of long-term outcome has not been fully elucidated. The N-SOG 03 trial examined the safety and efficacy of neoadjuvant CAPOX and bevacizumab (Bev) without radiotherapy in patients with poor-risk LARC. METHODS: Thirty-two patients with MRI-defined LARC received neoadjuvant CAPOX and Bev followed by curative resection between 2010 and 2011. The overall survival (OS), progression-free survival (PFS), and local-relapse rate (LRR) were calculated using the Kaplan-Meier method, and the risk factors were evaluated by multivariate analysis using the Cox proportional hazard models. This trial is registered with UMIN, number 000003507. RESULTS: In the entire cohort, the 5-year OS was 81.3%. Because of disease progression during chemotherapy, 3 patients ultimately did not undergo curative surgery. As a result, 29 patients underwent R0/1 resection. Among these 29 patients, the 5-year OS, PFS, and LRR were 89.7%, 72.4% and 13.9%, respectively. In multivariate analysis, cT4b tumor was an independent poor prognostic factor for OS and LRR, and ypT4b tumor and absence of N down-staging were independent poor prognostic factors for PFS. CONCLUSIONS: Patients with cT4b tumor were not suitable for NAC alone. However, the long-term outcomes of the other patients were satisfactory, and NAC alone might be an option for treatment of LARC. N down-staging was likely to bring favorable PFS, even in patients with cStage III.

Impact of RAS/BRAF mutation status in locally advanced rectal cancer treated with preoperative chemotherapy.

PURPOSE: Our sincere hope is to establish the predictive factors of neoadjuvant chemotherapy (NAC) response and provide patients with greater certainty regarding treatment outcomes. The aim of this study was to assess the response to NAC and survival in patients with locally advanced rectal cancer (LARC) according to their RAS/BRAF mutation status. METHODS: Data on 57 patients with LARC who received NAC between 2009 and 2016 were analyzed retrospectively. The patients were classified into two groups based on their mutation status: wild-type in both RAS and BRAF (WT) or mutant-type in either RAS or BRAF (MT). RESULTS: Twenty-three patients were classified as WT, and the remaining 34 patients were MT. Histological response to NAC was similar in both groups. In responders, the 3-year relapse-free survival (RFS) was better compared with the non-responders (92 and 66%, respectively). In the WT group, the 3-year RFS was 95% which was significantly better than that in the MT group (59%, p = 0.011). The MT group was further subdivided into the following 2 groups by the pathological response; the MT responders (n = 10) and MT non-responders (n = 24). The 3-year RFS was 50% in the MT non-responders, which was significantly worse compared to that in the remaining patients (92%, p = 0.001). CONCLUSION: RAS/BRAF mutations did not affect the response to NAC. However, the RFS was likely to be poor for those in the MT group who did not achieve favorable pathological response. In contrast, the RFS was favorable in the WT group regardless of the pathological response.

Role of bevacizumab in neoadjuvant chemotherapy and its influence on microvessel density in rectal cancer.

BACKGROUND: The role of bevacizumab (Bev) in neoadjuvant chemotherapy (NAC) without radiotherapy for rectal cancer has not been fully discussed. The purpose of this study is to assess the clinicopathological benefit of Bev in NAC for rectal cancer and to investigate its influence on microvessel status in cancerous tissue. METHODS: Data on 47 patients with rectal cancer, who received NAC with or without Bev between August 2008 and November 2012, were analyzed retrospectively. The objective response was evaluated using the maximum tumor diameter. Tumor regression grade 3/4 was classified as a pathological response. RESULTS: Thirty-one patients (66 %) received NAC that included Bev and the other 16 patients were treated without Bev. The objective response rate was significantly higher in the Bev group than in the non-Bev group (64.5 vs. 25.0 %, p = 0.015). The rate of pathological response was much higher in the Bev group (41.9 %) than in the non-Bev group (12.5 %), but did not reach significant difference (p = 0.052). Microvessel density (MVD) in the resected cancerous tissue was significantly lower in the Bev group than in the non-Bev group. CONCLUSIONS: We have confirmed that objective and pathological responses were better in patients treated with NAC that included Bev than in those who received NAC without Bev. Additionally, MVD in tumor tissues was inhibited in the patients treated with Bev. To investigate the impact of Bev in NAC on long-term survival, further follow-up is required.

MRI and FDG-PET for assessment of response to neoadjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND: The purpose of this study was to assess the value of magnetic resonance imaging (MRI) and additional (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced rectal cancer (LARC). METHODS: Data on 40 patients with LARC, who were treated with NAC and underwent MRI and FDG-PET/CT before and after NAC, were analyzed retrospectively. Surgery was performed at a median of 6 weeks after NAC and the images were compared with the histological findings. The tumor regression grade 3/4 was classified as a responder. RESULTS: Sixteen patients were pathological responders. Receiver operating characteristic (ROC) analysis revealed that MRI total volume after NAC (MRI-TV2) and ΔMRI-TV had the highest performance to assess responders (area under the ROC curve [AUC] 0.849 and AUC 0.853, respectively). The reduction rate of the maximum standardized uptake value (ΔSUVmax) was also an informative factor (AUC 0.719). There seems no added value of adding FDG-PET/CT to MRI-TV2 and ΔMRI-TV in assessment of NAC responders judging from changes in AUC (AUC of ΔSUVmax and MRI-TV2 was 0.844, and AUC of ΔSUVmax and ΔMRI-TV was 0.846). CONCLUSIONS: MRI-TV2 and ΔMRI-TV were the most accurate factors to assess pathological response to NAC. Although ΔSUVmax by itself was also informative, the addition of FDG-PET/CT to MRI did not improve performance. Patients with LARC who were treated by induction chemotherapy should receive an MRI examination before and after NAC to assess treatment response. A more than 70 % volume reduction shown by MRI volumetry may justify the omission of subsequent radiotherapy.

Minimum radial margin in pelvic exenteration for locally advanced or recurrent rectal cancer.

PURPOSE: The aim of this study was to clarify the suitable radial margin (RM) for favourable outcomes after pelvic exenteration (PE), focusing on the discrepancy between the concepts of circumferential resection margin (CRM) and traditional R status. METHODS: Seventy-three patients with locally advanced (LARC, n = 24) or locally recurrent rectal cancer (LRRC, n = 49) who underwent PE between 2006 and 2018 were retrospectively analysed. Patients were histologically classified into the following 3 groups; wide RM (≥1 mm, n = 45), narrow RM (0-1 mm, n = 10), and exposed RM (n = 18). The analysis was performed not only in the entire cohort but also in each disease group separately. RESULTS: The rates of traditional R0 (RM > 0 mm) and wide RM were 75.3% and 61.6%, respectively, resulting in the discrepancy rate of 13.7% between the two concepts. Preoperative radiotherapy was given in 12.3%. In the entire cohort, the local recurrence and overall survival (OS) rates for narrow RMs were significantly worse than those for wide RMs (p < 0.001 and p = 0.002), but were similar to those for exposed RMs. In both LARC and LRRC, RM < 1 mm resulted in significantly worse local recurrence and OS rates compared to the wide RMs. Multivariate analysis showed that RM < 1 mm was an independent risk factor for local recurrence in both LARC (HR 15.850, p = 0.015) and LRRC (HR 4.874, p = 0.005). CONCLUSIONS: Narrow and exposed RMs had an almost equal impact on local recurrence and poor OS after PE. Preoperative radiotherapy might have a key role to ensure a wide RM.

Indications for neoadjuvant treatment based on risk factors for poor prognosis before and after neoadjuvant chemotherapy alone in patients with locally advanced rectal cancer.

INTRODUCTION: The oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC. MATERIALS AND METHODS: We examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed. RESULTS: In the median follow-up duration after surgery of 60 months (3-120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32-28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27-27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01-6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06-29.93, P = 0.043). CONCLUSION: NAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.

Randomised phase II trial of capecitabine plus oxaliplatin with continuous versus intermittent use of oxaliplatin as adjuvant chemotherapy for stage II/III colon cancer (CCOG-1302 study).

BACKGROUND: Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer. PATIENTS AND METHODS: Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS). RESULTS: Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p < 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p < 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66). CONCLUSION: CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN. TRIAL IDENTIFIER: UMIN000012535.

The role of surgery for locally recurrent and second recurrent rectal cancer with metastatic disease.

BACKGROUND: The role of surgery for locally recurrent rectal cancer (LRRC) with resectable distant metastases or second LRRC remains unclear. This study aimed to clarify the influence of synchronous distant metastases (SDMs), a history of distant metastasis resection (HDMR), and a second LRRC on the outcome. METHODS: The long-term outcomes of 70 surgically treated patients with LRRC between 2006 and 2018 were compared by SDM (n = 10), HDMR (n = 17), and second LRRC (n = 7). RESULTS: Among the 10 patients with SDM, 4 patients underwent simultaneous resection, whereas the other 6 underwent staged resection with distant first approach. Recurrence developed in 9 patients, of which 2 patients with liver re-resection achieved long-term survival without cancer. The patients with and without SDM had equivalent 5-year overall survival rate (40.5% vs. 53.3%, p = 0.519); however, patients with SDM had a worse 3-year recurrence-free survival rate than those without SDM (10.0% vs. 37.5%, p = 0.031). Multivariate analysis showed that primary non-sphincter-preserving surgery, second LRRC, and R1 resection were independent risk factors for overall survival. Similarly, primary non-sphincter-preserving surgery, second LRRC, SDM, and R1 resection were risk factors for recurrence-free survival. CONCLUSIONS: Patients with SDM might still be suitable to undergo salvage surgery and achieve favourable overall survival. Distant metastasectomy should be performed first, followed by a sufficient interval to avoid unnecessary LRRC resection in uncurable patients. An HDMR should not be taken into consideration when making surgical plans. Surgical indication of second LRRC should be strict, especially in referred patients.

Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan.

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.