Jong Lyul Lee

RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial

BACKGROUND The standard sunitinib schedule, 4 weeks on, followed by 2 weeks off (4/2 schedule), is associated with troublesome toxicities, and maintenance of adequate sunitinib dosing and drug levels, which are essential for achieving an optimal treatment outcome, is challenging. The objective of this study was to investigate the efficacy and safety of an alternative sunitinib dosing schedule of 2 weeks on and 1 week off (2/1 schedule) compared with the standard sunitinib schedule of 4 weeks on and 2 weeks off (4/2 schedule). PATIENTS AND METHODS In this multicenter, randomized, open-label, phase II trial, treatment-naïve patients with clear-cell type metastatic renal cell carcinoma (mRCC) were randomly assigned to 4/2 or 2/1 schedules after stratification by Memorial Sloan Kettering Cancer Center risk group and the presence or absence of measurable lesions. The primary end point was the 6-month failure-free survival (FFS) rate, determined by intention-to-treat analysis. RESULTS From November 2007 to February 2014, 76 patients were accrued, and 74 were eligible. FFS rates at 6 months were 44% with the 4/2 schedule (N = 36) and 63% with the 2/1 schedule (N = 38). Neutropenia (all grades, 61% versus 37%; grade 3-4, 28% versus 11%) and fatigue (all grades, 83% versus 58%) were more frequently observed with schedule 4/2. There was a strong tendency toward a lower incidence of stomatitis, hand-foot syndrome, and rash with schedule 2/1. Objective response rates (ORRs) were 47% in schedule 2/1 and 36% in schedule 4/2. With a median follow-up of 30.0 months, the median time to progression (TTP) was 12.1 months in schedule 2/1 and 10.1 months in schedule 4/2. CONCLUSION Sunitinib administered with a 2/1 schedule is associated with less toxicity and higher FFS at 6 months than a 4/2 schedule, without compromising the efficacy in terms of ORR and TTP (NCT00570882).

The Role of Diverting Stoma After an Ultra-low Anterior Resection for Rectal Cancer.

Purpose A diverting stoma is known to reduce the consequences of distal anastomotic failure following colorectal surgery. The aim of this study was to evaluate the efficacy of a diverting stoma after an ultra-low anterior resection (uLAR) for rectal cancer. Methods Between 2000 and 2007, 836 patients who underwent an uLAR were divided into two groups, depending on the fecal diversion: 246 received fecal diversion, and 590 had no diversion. Patient- and disease-related variables were compared between the two groups. Results Thirty-two of the 836 patients (3.8%) had immediate anastomosis-related complications and required reoperation. Anastomosis leakage comprised 72% of the complications (23/32). The overall immediate complication rate was significantly lower in patients with a diverting stoma (0.8%, 2/246) compared to those without a diverting stoma (5.1%, 30/590; P = 0.005). The fecal diversion group had lower tumor location, lower anastomosis level, and more preoperative chemo-radiation therapy (P < 0.001). In total, 12% of patients in the diverting stoma group had complications either in making or reversing the stoma (30/246). Conclusion The diverting stoma decreased the rate of immediate anastomosis-related complications. However, the rate of complications associated with the diverting stoma was non-negligible, so strict criteria should be applied when deciding whether to use a diverting stoma.

3′-Deoxy-3′-18F-Fluorothymidine PET for the Early Prediction of Response to Leucovorin, 5-Fluorouracil, and Oxaliplatin Therapy in Patients with Metastatic Colorectal Cancer

The aim of this study was to evaluate 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX). Methods: The main eligibility criteria included histologically confirmed mCRC, ≥1 extrahepatic measurable lesions, and no prior chemotherapy in a metastatic setting. Chemotherapy consisted of leucovorin on day 1, followed by the continuous infusion of 5-FU on days 1 and 2, and oxaliplatin on day 3. In the second and subsequent cycles of chemotherapy, oxaliplatin was administered simultaneously with leucovorin on day 1. 18F-FLT PET scans were obtained 3 times during the first cycle of chemotherapy: before chemotherapy, 24 h after infusion of 5-FU (day 2), and 48 h after completion of chemotherapy (day 5). The maximum standardized uptake value (SUVMAX) of 18F-FLT was measured. Treatment responses were assessed by CT after 3 cycles of FOLFOX. Results: Eighteen patients were included in the study. The response rate after 3 cycles of FOLFOX was 27.8% (5/18). The SUVMAX was increased in responders (P = 0.043) and nonresponders (P < 0.001) on day 2 and was decreased, compared with baseline values, on day 5 in responders only (P = 0.043). Receiver-operating-characteristic curve analysis indicated that the use of a threshold of an SUVMAX increase on day 2 of ≤45.8% resulted in a sensitivity of 100%, specificity of 69.2%, and relative risk of 2.250 (P = 0.029) for the diagnosis of responders. Use of a threshold of an SUVMAX decrease on day 5 of ≥10.6% resulted in a sensitivity of 100%, specificity of 76.9%, and relative risk of 2.667 (P = 0.007). Patients with low 18F-FLT flare tended to have longer survivals than patients with high flare (2-y overall survival rate, 77.8% vs. 44.4%; P = 0.051). Conclusion: The 18F-FLT flare observed during 5-FU infusion was associated with poor treatment response in patients with mCRC. The degree of 18F-FLT flare might be used to predict the outcome of patients who receive infusional 5-FU–based chemotherapy.

The role of radiofrequency ablation for treatment of metachronous isolated hepatic metastasis from colorectal cancer.

AbstractWe investigated recurrence pattern and oncologic outcomes after treatment of metachronous isolated liver metastases from colorectal cancer according to treatment modality.We retrospectively analyzed 123 patients treated with hepatic resection and 82 patients treated with radiofrequency ablation (RFA) for metachronous isolated hepatic metastasis from colorectal cancer (HMCRC). We compared clinicopathological data, recurrence pattern, and recurrence-free survival (RFS) rates after the treatment of hepatic metastasis between patients treated with RFA and resection.The patients in the 2 groups were similar in gender, location of primary tumor, disease-free interval to hepatic metastasis, pathologic stage of primary tumor, and number of hepatic metastasis. The age was older in RFA group but it was not statistically different. The mean diameter of the largest hepatic mass was greater in the resection group than in the RFA group (3.1 vs 1.9 cm, P < 0.001). Chemotherapy after the treatment of hepatic metastasis was more commonly given in hepatic resection group (76.4% vs 62.2%, P = 0.04). Recurrence after the treatment of hepatic metastasis was not significantly different between the 2 groups (54.5% vs 65.9% in the resection and RFA groups). However, intrahepatic recurrence without extra-hepatic metastases was more common in the RFA group than in the resection group (47.5% vs 12.1%, P < 0.001). The RFS rate after the treatment of hepatic metastasis was significantly higher in resection group (48.6% vs 33.7%, P = 0.015). The size and number of hepatic metastasis, primary tumor stage, disease-free interval to hepatic metastasis, and the modality of treatment (RFA vs resection) for hepatic metastasis were confirmed as associated factors with re-recurrence after the treatment of hepatic metastasis. Among patients with solitary hepatic metastases of ⩽3 cm, marginal recurrence was higher in the RFA group (3% vs 17.2%) and re-RFA was performed to achieve comparable recurrence rate (3% vs 5.2%, P = 0.662), the RFS rate was not different between the resection and RFA group (52.4% vs 53.4%, P = 0.491).Surgical resection for HMCRC showed higher RFS. However, the RFS rate in patients with a solitary hepatic metastasis of ⩽3 cm was similar between the resection and RFA groups.

Non-L-cell immunophenotype and large tumor size in rectal neuroendocrine tumors are associated with aggressive clinical behavior and worse prognosis.

According to the 2010 World Health Organization classification, all gastrointestinal neuroendocrine tumors (NETs) are classified as malignant except for L-cell-type (glucagon-like peptide [GLP] and peptide YY [PYY]-producing) NETs. However, L-cell immunophenotype in rectal NETs has not been widely studied previously. Immunohistochemical labeling of L-cell markers with GLP1 and PYY was performed in 208 surgically or endoscopically resected rectal NET cases with tissue microarrays and was compared with clinicopathologic features and patient survival. Rectal NETs with non-L-cell immunophenotype and large tumor size (>1 cm) were associated with increased tumor grading, advanced T category, lymphovascular and perineural invasions, and lymph node and distant metastases (P<0.001, each). Rectal NET patients with non-L-cell phenotype and measuring >1 cm had significantly worse survival outcome than other groups by univariate (P<0.001) and multivariate (P<0.001) analyses. In summary, non-L-cell immunophenotype and large tumor size are associated with increased tumor grading and staging, concurrently indicating that they are independently poor prognostic indicators in rectal NET patients. Therefore, combining L-cell phenotype and tumor size can demonstrate the clinical behavior of rectal NETs more precisely than use of L-cell immunophenotype alone.

Comparison of abdominal and perineal procedures for complete rectal prolapse: an analysis of 104 patients

Purpose Selecting the best surgical approach for treating complete rectal prolapse involves comparing the operative and functional outcomes of the procedures. The aims of this study were to evaluate and compare the operative and functional outcomes of abdominal and perineal surgical procedures for patients with complete rectal prolapse. Methods A retrospective study of patients with complete rectal prolapse who had operations at a tertiary referral hospital and a university hospital between March 1990 and May 2011 was conducted. Patients were classified according to the type of operation: abdominal procedure (AP) (n = 64) or perineal procedure (PP) (n = 40). The operative outcomes and functional results were assessed. Results The AP group had the younger and more men than the PP group. The AP group had longer operation times than the PP group (165 minutes vs. 70 minutes; P = 0.001) and longer hospital stays (10 days vs. 7 days; P = 0.001), but a lower overall recurrence rate (6.3% vs. 15.0%; P = 0.14). The overall rate of the major complication was similar in the both groups (10.9% vs. 6.8%; P = 0.47). The patients in the AP group complained more frequently of constipation than of incontinence, conversely, in the PP group of incontinence than of constipation. Conclusion The two approaches for treating complete rectal prolapse did not differ with regard to postoperative morbidity, but the overall recurrence tended to occur frequently among patients in the PP group. Functional results after each surgical approach need to be considered for the selection of procedure.

Impression of prognosis regarding pathologic stage after preoperative chemoradiotherapy in rectal cancer

AIM To ascertain pathologic stage as a prognostic indicator for rectal cancer patients receiving preoperative chemoradiotherapy (PCRT). METHODS Patients with mid- and low rectal carcinoma (magnetic resonance imaging - based clinical stage II or III) between 2000 and 2009 and treated with curative radical resection were identified. Patients were divided into two groups: PCRT and No-PCRT. Recurrence-free survival (RFS) was examined according to pathologic stage and addition of adjuvant treatment. RESULTS Overall, 894 patients were identified. Of these, 500 patients received PCRT. Adjuvant chemotherapy was delivered to 81.5% of the No-PCRT and 94.8% of the PCRT patients. Adjuvant radiotherapy was given to 29.4% of the patients in the No PCRT group. The 5-year RFS for the No-PCRT group was 92.6% for Stage I, 83.3% for Stage II, and 72.9% for Stage III. The 5-year RFS for the PCRT group was 95.2% for yp Stage 0, 91.7% for yp Stage I, 73.9% for yp Stage II, and 50.7% for yp Stage III. CONCLUSION Pathologic stage can predict prognosis in PCRT patients. 5-year RFS is significantly lower among PCRT patients than No-PCRT patients in pathologic stage II and III. These results should be taken into account when considering adjuvant treatment for patients treated with PCRT.

Assessment by Using a Water-Soluble Contrast Enema Study of Radiologic Leakage in Lower Rectal Cancer Patients With Sphincter-Saving Surgery

Purpose This study evaluated the efficacy of a water-soluble contrast enema (WCE) in predicting anastomotic healing after a low anterior resection (LAR). Methods Between January 2000 and March 2012, 682 consecutive patients underwent a LAR or an ultra-low anterior resection (uLAR) and were followed up for leakage. Clinical leakage was established by using physical and laboratory findings. Radiologic leakage was identified by using retrograde WCE imaging. Abnormal radiologic features on WCE were categorized into four types based on morphology: namely, dendritic, horny, saccular, and serpentine. Results Of the 126 patients who received a concurrent diverting stoma, only two (1.6%) suffered clinical leakage due to pelvic abscess. However, 37 patients (6.7%) in the other group suffered clinical leakage following fecal diversion (P = 0.027). Among the 163 patients who received a fecal diversion, 20 showed radiologic leakage on the first WCE (eight with and 12 without a concurrent diversion); 16 had abnormal features continuously until the final WCE while four patients healed spontaneously. Eleven of the 16 patients (69%), by their surgeons decision, underwent a stoma restoration based on clinical findings (2/3 dendritic, 3/4 horny, 5/7 saccular, 1/2 serpentine). After stoma reversal, only 2 of the 11 (19%) complained of complications related to the rectal anastomosis. Conclusion WCE is helpful for detecting radiologic leakage before stoma restoration, especially in patients suffering clinical leakage after an uLAR. However, surgeons appear to opt for stoma restoration despite the persistent existence of radiologic leakage in cases with particular features on the WCE.

Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer

Colorectal cancer (CRC) with microsatellite instability (MSI) is characterized by frequent poor differentiation or mucinous histology. The purpose of this study was to evaluate the association of MSI with clinicopathological features and the oncological outcome in patients with a mucinous component.

Association of immunologic markers from complete blood counts with the response to preoperative chemoradiotherapy and prognosis in locally advanced rectal cancer

We investigated retrospectively whether immunologic markers from a complete blood count (CBC) are associated with the responsiveness to preoperative chemoradiotherapy (PCRT) and oncologic outcomes in 984 patients with locally advanced rectal cancer (LARC) who also underwent radical surgery from 2005 to 2013. CBC parameters including the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) were recorded. Pathologic responses to PCRT were evaluated in the resected specimens using the tumor regression grade system. The cut-off values of the immunologic markers were calculated to analyze their association with recurrence-free survival (RFS). One hundred ninety-five patients achieved total regression of their primary tumor. By receiver operating characteristic analysis, NLR, PLR, and LMR could not distinguish total regression from residual disease after PCRT. The NLR, LMR and PLR cut-off values were 1.7, 6.8 and 92.88, respectively. By univariate analysis, low NLR (≤1.7), high LMR (>6.8) and high PLR (>92.88) were indicators of a favorable RFS outcome. By multivariate analysis, high PLR was associated with an improved RFS (HR, 0.649; 95% CI, 0.473-0.89; P=0.007). High NLR (>1.7) was an independent negative prognostic factor for RFS in stage II (HR, 1.868; 95% CI, 1.08-3.109; P=0.025) and high PLR was a positive prognostic factor in stage III (HR, 0.675; 95% CI, 0.421-0.957; P=0.03). Immunologic markers derived from CBCs are independently associated with the RFS outcome in LARC patients treated with PCRT followed by radical resection. However, these markers are not predictive of total primary tumor regression after PCRT.We investigated retrospectively whether immunologic markers from a complete blood count (CBC) are associated with the responsiveness to preoperative chemoradiotherapy (PCRT) and oncologic outcomes in 984 patients with locally advanced rectal cancer (LARC) who also underwent radical surgery from 2005 to 2013. CBC parameters including the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) were recorded. Pathologic responses to PCRT were evaluated in the resected specimens using the tumor regression grade system. The cut-off values of the immunologic markers were calculated to analyze their association with recurrence-free survival (RFS). One hundred ninety-five patients achieved total regression of their primary tumor. By receiver operating characteristic analysis, NLR, PLR, and LMR could not distinguish total regression from residual disease after PCRT. The NLR, LMR and PLR cut-off values were 1.7, 6.8 and 92.88, respectively. By univariate analysis, low NLR (≤1.7), high LMR (>6.8) and high PLR (>92.88) were indicators of a favorable RFS outcome. By multivariate analysis, high PLR was associated with an improved RFS (HR, 0.649; 95% CI, 0.473-0.89; P=0.007). High NLR (>1.7) was an independent negative prognostic factor for RFS in stage II (HR, 1.868; 95% CI, 1.08-3.109; P=0.025) and high PLR was a positive prognostic factor in stage III (HR, 0.675; 95% CI, 0.421-0.957; P=0.03). Immunologic markers derived from CBCs are independently associated with the RFS outcome in LARC patients treated with PCRT followed by radical resection. However, these markers are not predictive of total primary tumor regression after PCRT.