Yong Sang Hong

Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial

BACKGROUND The safety and short-term efficacy of laparoscopic surgery for rectal cancer after preoperative chemoradiotherapy has not been demonstrated. The aim of the randomised Comparison of Open versus laparoscopic surgery for mid and low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was to compare open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy. METHODS Between April 4, 2006, and Aug 26, 2009, patients with cT3N0-2 mid or low rectal cancer without distant metastasis after preoperative chemoradiotherapy were enrolled at three tertiary-referral hospitals. Patients were randomised 1:1 to receive either open surgery (n=170) or laparoscopic surgery (n=170), stratified according to sex and preoperative chemotherapy regimen. Short-term outcomes assessed were involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, recovery of bowel function, perioperative morbidity, postoperative pain, and quality of life. Analyses were based on the intention-to-treat population. Patients continue to be followed up for the primary outcome (3-year disease-free survival). This study is registered with ClinicalTrials.gov, number NCT00470951. FINDINGS Two patients (1.2%) in the laparoscopic group were converted to open surgery, but were included in the laparoscopic group for analyses. Estimated blood loss was less in the laparoscopic group than in the open group (median 217.5 mL [150.0-400.0] in the open group vs 200.0 mL [100.0-300.0] in the laparoscopic group, p=0.006), although surgery time was longer in the laparoscopic group (mean 244.9 min [SD 75.4] vs 197.0 min [62.9], p<0.0001). Involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, and perioperative morbidity did not differ between the two groups. The laparoscopic surgery group showed earlier recovery of bowel function than the open surgery group (time to pass first flatus, median 38.5 h [23.0-53.0] vs 60.0 h [43.0-73.0], p<0.0001; time to resume a normal diet, 85.0 h [66.0-95.0] vs 93.0 h [86.0-121.0], p<0.0001; time to first defecation, 96.5 h [70.0-125.0] vs 123 h [94.0-156.0], p<0.0001). The total amount of morphine used was less in the laparoscopic group than in the open group (median 107.2 mg [80.0-150.0] vs 156.9 mg [117.0-185.2], p<0.0001). 3 months after proctectomy or ileostomy takedown, the laparoscopic group showed better physical functioning score than the open group (0.501 [n=122] vs -4.970 [n=128], p=0.0073), less fatigue (-5.659 [n=122] vs 0.098 [n=129], p=0.0206), and fewer micturition (-2.583 [n=122] vs 4.725 [n=129], p=0.0002), gastrointestinal (-0.400 [n=122] vs 4.331 [n=129], p=0.0102), and defecation problems (0.535 [n=103] vs 5.327 [n=99], p=0.0184) in repeated measures analysis of covariance, adjusted for baseline values. INTERPRETATION Laparoscopic surgery after preoperative chemoradiotherapy for mid or low rectal cancer is safe and has short-term benefits compared with open surgery; the quality of oncological resection was equivalent.

Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.

BACKGROUND The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. METHODS In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911. FINDINGS Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]). INTERPRETATION Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. FUNDING Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Optimal surgery time after preoperative chemoradiotherapy for locally advanced rectal cancers.

Objective:To evaluate the effect of the time interval between chemoradiotherapy (CRT) and surgery on CRT response and surgical outcomes. Summary Background Data:Although preoperative CRT is a standard component of multimodal treatment for locally advanced rectal cancers, the optimal time for surgery after CRT has yet to be established. This study analyzed outcomes in 397 prospectively enrolled patients with locally advanced rectal cancer who underwent fractionated CRT involving 50.4 Gy radiotherapy followed by surgical resection between 4 and 8 weeks later. Methods:Patients were divided into 2 groups according to the time that elapsed between CRT and surgery: group A (28–41 day interval) and group B (42–56 day interval). CRT responses and surgical outcomes were analyzed. Results:Of the 397 patients, 217 (54.7%) were in group A and 180 (45.3%) in group B. The 2 groups were similar in terms of pretreatment characteristics other than a slight difference in mean age (A: 55.3 years vs. B: 57.5 years, P = 0.042). Analysis of CRT responses showed that the 2 groups were similar in terms of T-level downstaging rate (A: 47.5% vs. B: 44.4%, P = 0.548), volume reduction rate (A: 34.6% vs. B: 34.2%, P = 0.870) and complete response rate (A: 13.8% vs. B: 15.0%, P = 0.740). Analysis of surgical outcomes showed that the 2 groups were also similar in terms of sphincter-preservation rate (A: 83.9% vs. B: 82.2%, P = 0.688) and anastomosis-related complication rate (A: 5.5% vs. B: 3.9%, P = 0.453). The median follow-up period was 31 months (range, 5–63), and both groups showed similar local recurrence-free survival rates (P = 0.1165). Conclusion:The present findings suggest that compared with a 4 to 6 week interval, delaying surgery for 6 to 8 weeks after completion of fractionated radiotherapy with concurrent chemotherapy does not improve CRT response or the sphincter-preservation rate, and does not decrease morbidity or local recurrence.

Influence of preoperative chemoradiotherapy on the number of lymph nodes retrieved in rectal cancer.

Objective:To evaluate the relation of preoperative chemoradiotherapy to the number of lymph nodes retrieved in curative intent surgery for rectal cancer. Summary Background Data:Current guidelines recommend evaluation of least 12 to 14 lymph nodes in rectal cancer. It is well known that lymph nodes retrieval is affected by many factors. Methods:This was a retrospective study of 615 patients who underwent curative intent surgery for primary rectal cancer. Preoperative chemoradiotherapy involving 50.4 Gy fractionated radiotherapy and concurrent chemotherapy was performed in patients with locally advanced rectal cancer (clinically T3 or T4). We explored associations between the number of lymph nodes retrieved in the pathologic specimen and patient demographics (age, gender, body mass index [BMI]), treatment (surgeon, sphincter-saving, preoperative chemoradiotherapy), and tumor-related variables (location, stage, histology). After adjustment for other factors, we compared the mean number of obtained lymph nodes between patients treated with preoperative chemoradiotherapy and those treated without preoperative chemoradiotherapy. Results:Univariate analysis demonstrated that age, BMI, preoperative chemoradiotherapy, location, and stage significantly related the number of lymph nodes retrieved. Multivariate analysis revealed age, BMI, preoperative chemoradiotherapy, and stage as independent factors influencing the number of lymph nodes retrieved. The mean number of lymph nodes adjusted for age, BMI, and stage was significantly lower in patients treated with preoperative chemoradiotherapy than in those treated without preoperative chemoradiotherapy (14.5 vs. 21.5, P < 0.001). The reduction rate by preoperative chemoradiotherapy was 32.6% (7/21.5). In patients who underwent preoperative chemoradiotherapy, advanced age (P < 0.001) and high BMI (P = 0.037) were associated with decreased number of retrieved lymph nodes. Conclusions:Preoperative chemoradiotherapy significantly decreased the number of retrieved lymph nodes by approximately 33%. Therefore, the recommended number of retrieved lymph nodes should be adjusted when rectal cancer is treated with preoperative chemoradiotherapy.

Pathologic Nodal Classification Is the Most Discriminating Prognostic Factor for Disease-Free Survival in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy and Curative Resection

PURPOSE We retrospectively evaluated the effects of clinical and pathologic factors on disease-free survival (DFS) with the aim of identifying the most discriminating factor predicting DFS in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and curative resection. METHODS AND MATERIALS The study involved 420 patients who underwent preoperative CRT and curative resection between August 2001 and October 2006. Gender, age, distance from the anal verge, histologic type, histologic grade, pretreatment carcinoembryonic antigen (CEA) level, cT, cN, cStage, circumferential resection margin, type of surgery, preoperative chemotherapy, adjuvant chemotherapy, ypT, ypN, ypStage, and tumor regression grade (TRG) were analyzed to identify prognostic factors associated with DFS. To compare the discriminatory prognostic ability of four tumor response-related pathologic factors (ypT, ypN, ypStage, and TRG), the Akaike information criteria were calculated. RESULTS The 5-year DFS rate was 75.4%. On univariate analysis, distance from the anal verge, histologic type, histologic grade, pretreatment CEA level, cT, circumferential resection margin, type of surgery, preoperative chemotherapeutic regimen, ypT, ypN, ypStage, and TRG were significantly associated with DFS. Multivariate analysis showed that the four parameters ypT, ypN, ypStage, and TRG were, consistently, significant prognostic factors for DFS. The ypN showed the lowest Akaike information criteria value for DFS, followed by ypStage, ypT, and TRG, in that order. CONCLUSION In our study, ypT, ypN, ypStage, and TRG were important prognostic factors for DFS, and ypN was the most discriminating factor.

Tumor Volume Reduction Rate Measured by Magnetic Resonance Volumetry Correlated With Pathologic Tumor Response of Preoperative Chemoradiotherapy for Rectal Cancer

PURPOSE To determine whether the tumor volume reduction rate (TVRR) measured using three-dimensional region-of-interest magnetic resonance volumetry correlates with the pathologic tumor response after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS AND MATERIALS The study included 405 patients with locally advanced rectal cancer (cT3-T4) who had undergone preoperative CRT and radical proctectomy. The tumor volume was measured using three-dimensional region-of-interest magnetic resonance volumetry before and after CRT but before surgery. We analyzed the correlation between the TVRR and the pathologic tumor response in terms of downstaging and tumor regression grade (TRG). Downstaging was defined as ypStage 0-I (ypT0-T2N0M0), and the TRG proposed by Dworak et al. was used. RESULTS The mean TVRR was 65.0% +/- 22.3%. Downstaging and complete regression occurred in 167 (41.2%) and 58 (14.3%) patients, respectively. The TVRRs according to ypT classification (ypT0-T2 vs. ypT3-T4), ypN classification (ypN0 vs. ypN1-N2), downstaging (ypStage 0-I vs. ypStage II-III), good regression (TRG 3-4 vs. TRG 1-2), and complete regression (TRG 4 vs. TRG 1-3) were all significantly different (p <.05). When the TVRR was categorized into three groups (<60%, 60-80%, and >80%), the rates of ypT0-T2, ypN0, downstaging, and good regression were all significantly greater for patients with a TVRR of >or=60%, as was the complete regression rate for patients with a TVRR >80% (p <.05). CONCLUSION The TVRR measured using three-dimensional region-of-interest magnetic resonance volumetry correlated significantly with the pathologic tumor response in terms of downstaging and TRG after preoperative CRT for locally advanced rectal cancer.

S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial

BACKGROUND Capecitabine plus oxaliplatin (CapeOX) is one of the reference doublet cytotoxic chemotherapy treatments for patients with metastatic colorectal cancer. We aimed to compare the efficacy and safety of CapeOX with that of S-1 plus oxaliplatin (SOX), a promising alternative treatment for patients with metastatic colorectal cancer. METHODS In this open-label, multicentre, randomised phase 3 trial, we randomly assigned patients (1:1) from 11 institutions in South Korea to receive either CapeOX (capecitabine 1000 mg/m(2) twice daily on days 1-14 and oxaliplatin 130 mg/m(2) on day 1) or SOX (S-1 40 mg/m(2) twice daily on days 1-14 and oxaliplatin 130 mg/m(2) on day 1). Treatment was repeated every 3 weeks and continued for as many as nine cycles of oxaliplatin-containing chemotherapy, except in instances of disease progression, unacceptable toxicity, or a patients refusal. Maintenance chemotherapy with S-1 or capecitabine was allowed after discontinuation of oxaliplatin. Randomisation was done with a computer-generated sequence (stratified by primary sites, previous adjuvant or neoadjuvant treatment, and the presence of measurable lesions). The primary endpoint was to show non-inferiority of SOX relative to CapeOX in terms of progression-free survival (PFS). The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00677443. FINDINGS Between May 14, 2008, and Sept 23, 2009, we randomly assigned 168 patients to receive SOX and 172 to receive CapeOX. Median PFS was 8·5 months (95% CI 7·6-9·3) in the SOX group and 6·7 months (6·2-7·1) in the CapeOX group (hazard ratio, 0·79 [95% CI 0·60-1·04]; p(non-inferiority)<0·0001, p(log-rank)=0·09). The upper limit of the CI was below the predefined margin of 1·43, showing the non-inferiority of SOX to CapeOX. We recorded a higher incidence of grade 3-4 neutropenia (49 [29%] vs 24 [15%]), thrombocytopenia (37 [22%] vs 11 [7%]), and diarrhoea (16 [10%] vs seven [4%]) in the SOX group than in the CapeOX group. The frequency of any grade of hand-foot syndrome was greater in the CapeOX group than it was in the SOX group (51 [31%] vs 23 [14%]). INTERPRETATION The SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. Further investigation is needed to explore its potential when used together with other targeted agents or as adjuvant chemotherapy. FUNDING Korea Healthcare Technology Research and Development Project, Ministry of Health and Welfare, South Korea.

Carcinoembryonic antigen as a predictor of pathologic response and a prognostic factor in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and surgery.

PURPOSE To evaluate the role of serum carcinoembryonic antigen (CEA) as a predictor of response to preoperative chemoradiotherapy (CRT) and prognostic factor for rectal cancer. MATERIALS AND METHODS The study retrospectively evaluated 352 locally advanced rectal cancer patients who underwent preoperative CRT followed by surgery. Serum CEA levels were determined before CRT administration (pre-CRT CEA) and before surgery (post-CRT CEA). Correlations between pre-CRT CEA levels and rates of good response (Tumor regression grade 3/4) were explored. Patients were categorized into three CEA groups according to their pre-/post-CRT CEA levels (ng/mL) (Group A: pre-CRT CEA <or= 3; B: pre-CRT CEA >3, post-CRT CEA <or=3; C: pre- and post-CRT CEA >3 ng/mL), and their oncologic outcomes were compared. RESULTS Of 352 patients, good responses were achieved in 94 patients (26.7%). The rates of good response decreased significantly as the pre-CRT CEA levels became more elevated (CEA [ng/mL]: <or=3, 36.4%; 3-6, 23.6%; 6-9, 15.6%; >9, 7.8%; p < 0.001). The rates of good response were significantly higher in Group A than in Groups B and C (36.4% vs. 17.3% and 14.3%, respectively; p < 0.001). The 3-year disease-free survival rate was significantly better in Groups A and B than in Group C (82% and 79% vs. 57%, respectively; p = 0.005); the CEA grouping was identified as an independent prognostic factor (p = 0.025). CONCLUSIONS In locally advanced rectal cancer patients, CEA levels could be of clinical value as a predictor of response to preoperative CRT and as an independent prognostic factor after preoperative CRT and curative surgery.

Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with locally advanced resectable rectal cancer: a multicenter Phase II study.

PURPOSE To evaluate the efficacy and safety of preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with rectal cancer. METHODS AND MATERIALS Forty patients with locally advanced, nonmetastatic, and mid- to lower rectal cancer were enrolled. Radiotherapy was delivered at a dose of 50.4 Gy/28 fractions. Concurrent chemotherapy consisted of an initial dose of cetuximab of 400 mg/m(2) 1 week before radiotherapy, and then cetuximab 250 mg/m(2)/week, irinotecan 40 mg/m(2)/week for 5 consecutive weeks and capecitabine 1,650 mg/m(2)/day for 5 days a week (weekdays only) from the first day during radiotherapy. Total mesorectal excision was performed within 6 ± 2 weeks. The pathologic responses and survival outcomes were evaluated as study endpoints, and an additional KRAS mutation analysis was performed. RESULTS In total, 39 patients completed their planned preoperative chemoradiation and underwent R0 resection. The pathologic complete response rate was 23.1% (9/39), and 3 patients (7.7%) showed near total regression of tumor. The 3-year disease-free and overall survival rates were 80.0% and 94.7%, respectively. Grade 3/4 toxicities included leukopenia (4, 10.3%), neutropenia (2, 5.1%), anemia (1, 2.6%), diarrhea (2, 5.1%), fatigue (1, 2.6%), skin rash (1, 2.6%), and ileus (1, 2.6%). KRAS mutations were found in 5 (13.2%) of 38 patients who had available tissue for testing. Clinical outcomes were not significantly correlated with KRAS mutation status. CONCLUSIONS Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine was active and well tolerated. KRAS mutation status was not a predictive factor for pathologic response in this study.

Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistance

5‐Fluorouracil (5‐FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5‐FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5‐FU resistance, we isolated secreted proteins that were up‐ or downregulated in a 5‐FU‐resistant cancer cell line, compared with the parent cell line (SNU‐C4), using a stable isotope‐coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5‐FU. In total, 238 proteins with molecular weights ranging from 50 to 75 kDa were identified. Among these, 45 and 35 secreted proteins were up‐ and downregulated in the 5‐FU‐resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde‐3‐phosphate dehydrogenase, pyruvate kinase M2 (PK‐M2), transketolase, and NADP(+)‐dependent malic enzyme 1. In particular, the level of PK‐M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5‐FU‐based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5‐FU‐based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK‐M2 observed with 5‐FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5‐FU‐based chemotherapy suggest the relevance of dysregulated glycolysis and 5‐FU‐resistant CRC.