An evidence-based medicine approach to the laparoscopic treatment of colorectal cancer.

During the 1990s, laparoscopic resection was established as a treatment for gastrointestinal malignant tumors.　A number of randomized controlled trials comparing laparoscopic-assisted colorectal surgery with conventional open colorectal surgery for colon cancer have been conducted.　These trials have shown short-term benefits, and the vast majority demonstrated no significant difference in long-term outcomes.　Laparoscopic-assisted colorectal surgery is widely performed for the treatment of colon cancer, whereas laparoscopic-assisted colorectal surgery for rectal cancer is less commonly performed.　In recent years, there have been an increasing number of reports of laparoscopic-assisted colorectal surgery for rectal cancer, where improving short-term outcomes was shown, but no definitive effect on long-term survival has been shown to date.　Randomized controlled trials focusing on long-term survival are currently ongoing.

The Clinical Effects of Dai-kenchu-to on Postoperative Intestinal Movement and Inflammatory Reaction in Colorectal Surgery.

BACKGROUND/AIMS: We analyzed the effects of the Kampo medicine "Dai-kenchu-to" (DKT) on clinical aspects in colorectal surgery. METHODOLOGY: Total 122 patients who underwent colorectal cancer surgery were divided into a DKT group (n = 53) and a non-DKT group (n = 69). The differences of postoperative course and anti-inflammatory responses between those two groups were analyzed. RESULTS: The 53 out of 59 patients could completely take DKT. In the postoperative course, significant difference was observed in the first flatus day. In the anti-inflammatory effects, differences were observed in the heart rate (HR) of the 3rd POD. In the change between 1st POD and 3rd POD, HR in the DKT group was well controlled compared to the non-DKT group. In the patients who had over 37.5°C of body temperature in 1st POD (n = 53), inflammatory response of the DKT group was reduced compared to the non-DKT group. CONCLUSIONS: The DKT might have the favorable influences on postoperative bowel movement and systemic inflammatory reaction, and induce the better postoperative course.

Practical use of capecitabine plus oxaliplatin (CAPEOX) with bevacizumab for patients with metastatic colorectal cancer that cannot expect conversion therapy.

BACKGROUND/AIMS: The cytotoxic regimens and bevacizumab (Bev) or anti-EGFR antibody are used for metastatic colorectal cancer (mCRC) that can expect conversion therapy. In this paper, we would present our practical data including the response, survival and toxicity of the capecitabine plus oxaliplatin (CAPEOX) with Bev for mCRC that cannot expect conversion therapy. METHODOLOGY: Nineteen patients with mCRC who were treated with CAPEOX with Bev were enrolled. All the patients had the disseminated hepatic, lung, peritoneal metastases or distant lymph node metastasis assessed as no possibility of R0 resection. RESULTS: The median age was 66 (45-85) years old. Target lesion was liver and lung in 9 patients, peritoneum in 5 patients and distant lymph node in 3 patients. CAPEOX with Bev therapy was administered for a median of 8.0 cycles (range, 4-21 cycles). In the 16 evaluable cases, there were no patient with complete response (CR), 9 patients with partial response (PR), 6 with stable disease (SD), and 1 with progressive disease. The objective response rate (CR plus PR) was 56.3%, and disease control rate (CR, PR plus SD) was 93.8%. The median TTP was 9.3 months and the median OS was 21.1 months. No patients treated with surgery even though the good responses were obtained. No severe hematologic adverse toxicities were observed except only one case with grade 3 platelet decrease. Nonhematologic grade 3 events were observed totally 8 patients including 3 for peripheral neuropathy, 2 for bilirubin, and 1 for nausea/vomiting, amylase and stomatitis. CONCLUSIONS: We obtained the quite good results of CAPEOX plus Bev as the first-line treatment practically. This regimen might be useful for mCRC that cannot expect conversion therapy.

Clinicopathological differences between proximal and distal pT3 colon cancer and the clinical significance of the depth of cancer invasion beyond the muscularis propria.

BACKGROUND/AIMS: To investigate differences in clinicopathological features between proximal and distal pT3 colon cancers and to determine whether the depth of the cancer invasion beyond the muscularis propria (DBM) serves as an objective indicator of the depth of tumor invasion in proximal colon cancer and in distal colon cancer. METHODOLOGY: A total of 207 patients who underwent surgery for proximal and distal pT3 colon cancer between 1996 and 2001 were included in the analysis. RESULTS: No differences were noted between proximal and distal cancers in lymph node metastasis, distant metastasis, lymphatic/venous invasion, histological type and curability of surgical resection, although proximal cancer patients were significantly older. High-grade malignancy appeared to be more commonly noted in the proximal colon cancer cases but there was no significant difference in prognosis between proximal and distal cancer patients. CONCLUSIONS: Regarding the correlation between DBM and prognosis, there was a significant decrease in the 5-year survival rate in patients with proximal lesions of DBM 3000µm or more, and patients with distal lesions of DBM 5000µm or more. DBM is thus an objective indicator of depth of tumor invasion for both proximal and distal lesions, a prognostic factor and a guide to determining whether postoperative adjuvant chemotherapy is indicated for pT3 colon cancer cases.

[Two cases of colorectal cancer patients with poor performance status who had unresectable liver metastasis effectively treated by cetuximab].

We reported two cases of colorectal cancer patients with EGFR-positive unresectable synchronous liver metastasis effectively treated by cetuximab after the progression of the prior chemotherapy. Case 1: A 49-year-old female with unresectable synchronous liver metastasis from colon cancer received cetuximab monotherapy as fifth-line therapy. Then, abdominal CT showed shrinkage of the liver metastasis (PR) and the performance status was improved from 3 to 0 as upper abdominal pain reduced. Case 2: A 67-year-old female with unresectable liver metastasis from colon cancer received cetuximab with CPT-11 combined therapy as fourth-line therapy. After that, liver metastasis also decreased (PR), and upper abdominal pain and PS were improved from 2 to 0. These two cases of KRAS status on cancer tissue also showed wild-type, and in these cases cetuximab proved effective.

[Our experience of the treatment with cetuximab for unresectable advanced colorectal cancer].

We report here the experience of the treatment with cetuximab in our department. Thirteen patients were treated with cetuximab. Median age was 65-year-old including 8 males and 5 females. Six cases were treated with single administration, and seven were with CPT-11. Median number of treatment was 13 times. In evaluable 9 cases, partial response (PR) was obtained in 3 cases and stable disease (SD) and progressive disease (PD) were in 2 and 4 cases, so that the response rate and disease control rate were 33% and 56%, respectively. Median survival after initiation of cetuximab was 219 days. Skin toxicity was observed in 91% including only one case with grade 3. We think that it is important to control skin toxicity for a continuation of cetuximab.

[A case of multiple lung and liver metastases from colon cancer treated with clinical benefit by hepatic arterial infusion chemotherapy plus cetuximab mono-therapy after standard chemotherapy failure].

We report a case of multiple lung and liver metastases from colon cancer treated with clinical benefit by hepatic arterial infusion chemotherapy plus cetuximab mono-therapy after a standard chemotherapy was failed. A 61-year-old female who had sigmoid colon cancer with unresectable multiple lung and liver metastases underwent sigmoidectomy. Bevacizumab plus mFOLFOX6 was performed as first-line therapy. Partial response was obtained temporarily. After the first-line therapy failed, bevacizumab plus FOLFIRI as second-line, and cetuximab plus CPT-11 as third-line therapy were performed. Since these regimens did not work, her performance status got worse by cholangitis due to progressive liver metastases and anemia. Hepatic arterial infusion chemotherapy for liver metastases and cetuximab for lung metastases as fourth therapy were chosen because we thought her liver metastases should be critical for the maintenance of her QOL and diagnosis. After that, serum CEA was reduced from 14,715 to 6,940 ng/mL during the 3 month period. And her performance status got better as cholongitis and anemia were improved. Additionally, lung metastases were controlled by cetuximab.

[A case of successful treatment with OK-432 administration into lymphatic cyst formed after resection of rectal cancer].

We herein report a case of successful treatment with OK-432 administration into lymphatic cyst formed after resection of rectal cancer. A 61-year-old male patient underwent a very low anterior resection with D3 lymphadenectomy for locally advanced rectal cancer. Four months after the surgery, he arrived at our department with lower abdominal fullness. He was diagnosed as having bilateral intra-pelvic abscess by CT scan, and underwent a tube-drainage. After drainage, abscess lesions were shrunk, but a serous discharge remained. Because we diagnosed lymphatic cysts caused by the delayed lymphatic discharge after lymphadenectomy, an administration of OK-432 into cysts was performed. After administration, the discharge was decreased, and then fistula was closed.

[A prediction of prognosis by A-L score in patients with stage IV colorectal cancer].

We analyzed the relationship between A-L score classified by serum albumin level and lymphocytes/white blood cells ratio and clinicopathological features in patients with Stage IV colorectal cancer. Seventy-nine patients were classified by the A-L score. In lower-scored cases, the populations of elderly patients, patients with emergency operation and patients with poorer PS were increased. Additionally, the 2-year survival rate was decreased as low as A-L score. In the multivariate analysis, the A-L score was independent prognostic factor in Stage IV colorectal cancer.

[Phase I study of combination therapy with peptide vaccine and anti-cancer drug for colorectal cancer].

Phase I study of combination therapy with peptide vaccine and anti-cancer drug for colorectal cancer has been performed in our hospital. The purpose of this study was to evaluate the safety and immune response of different dose of RNF43-721 emulsified with Montanide ISA 51 in combination with S-1/CPT-11 chemotherapy. The study design was a dose escalation of peptide (0.5, 1.0, 3.0 mg) with three patients' cohort. Nine patients were enrolled. All patients were treated with peptide subcutaneously every week and two courses with S-1/CPT-11 chemotherapy. Vaccinations were well tolerated without any major adverse events. Immunological reactions are not analyzed yet. We herein report a case who has been evaluated to be long SD with this intervention for para-aortic LN metastasis from sigmoid colon cancer.

[A phase I study of combination-therapy with gemcitabine and epitope peptides derived from human vascular endothelial growth factor receptor for unresectable or recurrent pancreas cancer].

We are performing a phase I clinical trial of combination-therapy with gemcitabine and epitope peptide derived from human vascular endothelial growth factor receptor (VEGFR) for advanced pancreas cancer. The aim of this study was to evaluate the safety, immunological response and tumor response. Six patients have been enrolled at present. During the clinical course, no major adverse events were observed. Additionally, two out of 6 cases showed a minor shrinkage of the tumor. Immunological response has not been analyzed yet. These results indicated that a combination-therapy with gemcitabine and epitope peptides derived from VEGFR could be tolerable.

[A clinical experience in treatment with bevacizumab for unresectable colorectal cancer].

Bevacizumab, a humanized monoclonal antibody to VEGF for advanced recurrent colorectal cancer, has been known for complications of gastrointestinal perforation, hemorrhage, thromboembolism and proteinuria, as adverse effects. These findings must be taken care as well as adverse drug reactions (ADR) caused by combination chemotherapy. We here in present a clinical experience in treatment with bevacizumab for unresectable colorectal cancer. Six patients treated with bevacizumab for over two courses until April 2008 were analyzed for this study. PR was obtained in one case with mFOLFOX6. Even though, grade 3 neutropenia was observed in only one case with FOLFIRI, the other cases had grade 2 or less in ADR. In addition, there were no any specific ADRs related with bevacizumab, so we concluded that combination chemotherapy for advanced recurrent colorectal cancer with bevacizumab was well-tolerated.

The depth of tumor invasion beyond the outer border of the muscularis propria as a prognostic factor for T3 rectal/rectosigmoid cancer.

UNLABELLED: The distance of tumor invasion beyond the outer border of the muscularis propria (DBM) was measured whether it would be useful as a prognostic factor of the locally advanced rectal and rectosigmoid cancer was analyzed. PATIENTS AND METHODS: One hundred patients with rectal and rectosigmoid cancer invaded beyond muscularis propria who underwent surgery between 1996 and 2000 were included in this study. Patients who died due to other disease were excluded. Univariate and multivariate analyses of the risk factors including DBM for disease-free and cancer-related survival after surgery were performed. RESULTS: The median DBM was 4,000 microm and patients were thus classified into 2 groups by DBM (<4,000 microm and > or =4,000 microm). In univariate analysis, patients with a DBM of > or =4000 microm had a significantly poorer prognosis both for cancer-related survival (CRS) (p=0.004) and disease-free survival (DFS) (p=0.0025). Within many prognostic factors, lymphatic invasion (p=0.025), venous invasion (p=0.0402) and pattern of tumor infiltration (p=0.043) significantly correlated with DBM. In multivariate analysis with other factors including histology (p=0.0403), node status (p=0.0003), lymphatic invasion (p=0.0004), venous invasion (p<0.0001), tumor budding (p=0.0343) and pattern of tumor infiltration (p=0.0160), DBM was selected as the most significant prognostic factor for both CRS (hazard ratio (HR): 2.1682, 95% confidence interval (CI): 1.3606-3.8097, p=0.0019) and DFS (HR: 2.0654, 95% CI: 1.2696-3.8257, p=0.0075). CONCLUSION: Since DBM was the most significant prognostic factor, it could be used to categorize T-factor in clinical staging of advanced rectal and rectosigmoid cancer.

Changes of immunological parameters reflect quality of life-related toxicity during chemotherapy in patients with advanced colorectal cancer.

UNLABELLED: Anticancer drugs may frequently induce host immunosuppression and symptomatic toxicities. Once symptomatic toxicity occurs, the patient's quality-of-life (QOL) is reduced. Since little is known of the relationship between host immunity and the toxicity of chemotherapy, the host immunity before and after chemotherapy was compared to assess whether it is related to symptomatic toxicity during chemotherapy. PATIENTS AND METHODS: Fourteen patients with colorectal cancer underwent leucovorin /5-fluorouracil (LV/5-FU) treatment, or S-1/irinotecan (CPT-11). Host immunity (cytokine production of peripheral blood mononuclear cell (PBMC), serum soluble interleukin-2 receptor (sIL-2R) levels and phenotypic analyses of PBMC were measured before and after the first chemotherapy. RESULTS: An increase of sIL-2R, CD4+CD25+ T-cells and the CD4/8 ratio in patients with symptomatic adverse reactions were found. These changes in the first chemotherapy were significantly different (p = 0.0211, p = 0.0087, p = 0.0234). CONCLUSION: The current study indicated that there are some parameters correlated with toxicity during chemotherapy which effect QOL. In such patients, negative influences on host immunity, such as an increase of sIL-2R and regulatory T-cells, and a decrease of cytotoxic T-cells could occur.

Successful treatment with S-1 plus CPT-11 for lymph node metastasis from colon cancer: report of a case.

S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo), based on the biochemical modulation of 5-fluorouracil (5-FU). S-1 plus irinotecan (CPT-11) for advanced colorectal cancer as expected showed equally good results as these with CPT-11 plus infusional 5-FU/LV (FOLFIRI regimen). A case of unresectable lymph node metastasis from colon cancer successfully treated with S-1 plus CPT-11 is reported here. A 65-year-old man had metastasis to the lymph nodes in the left supra clavicular region and the superior mesenteric artery. S-1 plus CPT-11 was chosen for the treatment. After 2 courses, since grade 2 toxicity for dysgeusia was observed, S-1 administration was shortened. After 3 courses of the revised regimen, the enlarged lymph nodes disappeared on conventional CT and fluorine-18 fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT) and the case was assessed as a complete response (CR). Because CR was continued by an additional four courses of treatment, the regimen was changed to a single administration of S-1. Although eighteen months have passed since the induction of CR by S-1 plus CPT-11 therapy, no symptoms or findings of relapse have been observed.

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer.

Elevated levels of procarcinogenic prostaglandins (PG) are found in a variety of human malignancies including non-small cell lung cancer (NSCLC). Overexpression of cyclooxygenase-2 and microsomal prostaglandin synthase 1 occurs in tumors and contributes to increased PG synthesis. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for metabolic inactivation of PGs, is down-regulated in various malignancies. The main objective of this study was to elucidate the effect of loss of 15-PGDH on levels of bioactive lipids in NSCLC. We found that levels of cyclooxygenase-2 and microsomal prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reduced expression of 15-PGDH occurred in tumor cells and was paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE1, PGE2, and PGF(2alpha), known substrates of 15-PGDH, were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2, a catabolic product of PGE2, were markedly reduced in NSCLC compared with normal lung. Complementary in vitro and in vivo experiments were done to determine whether these changes in PG levels were a consequence of down-regulation of 15-PGDH in NSCLC. Similar to NSCLC, amounts of PGE1, PGE2, and PGF(2alpha) were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2 were decreased in the lungs of 15-PGDH knockout mice compared with wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly down-regulated in NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.

Low-dose chemotherapy is practically useful for the patients with intrapelvic recurrence of rectal cancer.

UNLABELLED: The aim was to assess the practical efficacy of low-dose chemotherapy in patients with intrapelvic recurrence of rectal cancer without radiotherapy. PATIENTS AND METHODS: The records of 13 patients treated with low-dose chemotherapy for intrapelvic recurrence of rectal cancer between 1996 and 2003 were retrospectively reviewed. The patients had received low-dose leucovorin and 5-fluorouracil (LV/5-FU) as first-line and low-dose irinotecan and cisplatin regimen (CPT-11/CDDP) as second-line therapy without radiotherapy. RESULTS: With the LV/5-FU treatment, no patients showed a complete response (CR), two patients showed a partial response (PR), three patients had stable disease (SD), and eight patients experienced progressive disease (PD), giving a response rate (RR) of 15.4% and a disease control rate (DCR) of 38.5%. With the CPT-1/CDDP treatment, no patients showed CR or PR, three patients had SD, and ten patients had PD, which results in a DCR of 23.1%. The progression-free survival (PFS) of LV/5-FU and CPT-11/CDDP were 4.7 months and 4.7 months respectively. The median survival time (MST) of all the patients was 17.3 months. There were no patients who experienced grade 3 or 4 of any adverse reaction during the course of these regimens. CONCLUSION: The results suggest that low-dose chemotherapy for intrapelvic recurrence of rectal cancer without radiotherapy could be acceptable. For patients who refused radiotherapy in order to avoid adverse effects, these low-dose low toxicity chemotherapy regimens might be recommended.

First-line chemotherapy with low-dose leucovorin plus 5-fluorouracil (LV/5-FU) for elderly patients with metastatic colorectal cancer.

AIM: To assess the practical efficacy of low-dose leucovorin plus 5-fluorouracil (LV/5-FU) in elderly patients with metastatic colorectal cancer. PATIENTS AND METHODS: The records of 20 patients treated with LV/5-FU for unresectable metastatic disease from colorectal cancer from 1999 to 2004 were retrospectively reviewed. The patients received LV/5-FU as first-line, and low-dose CPT-11 and CDDP regimen (CPT-11/CDDP) as second-line therapy. RESULTS: In the treatment of LV/5-FU, no patients had CR, 3 patients had PR, 4 patients had SD and 13 patients had PD, which results in a response rate (RR) of 15% and in a disease control rate (DCR) of 35%. MST of all patients was 18.4 months. There was one patient who experienced grade 3 or 4 adverse reactions during the course of these regimens. CONCLUSION: Low-dose LV/5-FU chemotherapy in elderly patients with metastatic colorectal cancer could be acceptable in order to avoid adverse effects and to obtain quite a favorable survival time.

Pilot study of simplified low-dose S-1 plus CPT-11 as first-line chemotherapy for patients with advanced colorectal cancer.

BACKGROUND: S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1. S-1 plus irinotecan (CPT-11) administered for advanced colorectal cancer could be expected to show as equally good results as the infusional 5-fluorouracil/leucovorin (5-FU/LV) with CPT-11 (FOLFIRI) regimen. When toxicity is too severe preventing patients from receiving an intensive chemotherapeutic regimen, survival benefit might be forfeited. A pilot study of low-dose S-1 plus CPT-11 therapy with constant doses without consideration of body surface area (BSA) was therefore performed. PATIENTS AND METHODS: Twenty-two patients were enrolled in this study. S-1 was given orally at 40 mg b.i.d. for 21 consecutive days followed by a 14-day rest period. CPT-11 was administered as a 90-minute intravenous infusion at a dose of 80 mg on days 1 and 15. Courses of treatment were repeated every 35 days. RESULTS: The median age was 62.5 years (26-74). The median cycles were 8.5 (3-20). The overall response rate was 45.5% (complete response (CR), 1; partial response (PR), 9). Median progression-free survival (PFS) and median overall survival time (MST) were 9.0 and 20.2 months respectively. No grade 3 or 4 toxicities were observed. Eight patients (36.4%) did not have any sign or symptom of toxicity throughout all the treatment courses. The response, survival and toxicity were not significantly different according to BSA. CONCLUSION: These results suggest that simplified low-dose S-1 plus CPT-11 treatment might be of considerable advantage as first-line chemotherapy for patients with advanced colorectal cancer who would like to avoid toxicity.

Overexpression of human X-box binding protein 1 (XBP-1) in colorectal adenomas and adenocarcinomas.

BACKGROUND: Human X-box binding protein 1 (XBP-1) is a transcription factor essential for hepatocyte growth, as well as for plasma cell differentiation. Recently, overexpression of XBP-1 has been reported in breast cancer including non-invasive carcinomas, and was suggested to play an important role in breast carcinogenesis. To investigate the involvement of XBP-1 in colorectal tumorigenecity, the expression of XBP-1 was examined in four colon cancer cell lines, six colorectal polyps and five colorectal carcinomas. MATERIALS AND METHODS: The study population consisted of eleven patients who had undergone resection for colorectal cancer or adenoma from 2000 to 2002. Four colon cancer cell lines, DLD1, SW480, HCT15 and WiDr, were also analyzed for expression of XBP-1. Reverse transcription-polymerase chain reaction was performed using eleven primary colon tumors. XBP-1 expression was then investigated using an immunohistochemical method for archived paraffin-embedded sections. RESULTS: The XBP-1 gene was overexpressed in four cases out of five primary colorectal carcinomas and in four cases out of six colorectal adenomas. Also all four cancer cell lines expressed XBP-1 mRNA. Immunohistochemical staining demonstrated that XBP-1 protein was strongly stained in the cytoplasms of cancer cells, whereas it was unreactive in the normal colon epithelial cells and stromal cells. CONCLUSION: These data indicate that increased expression of XBP-1 gene may play some role in human colon carcinogenesis through impairment of cell differentiation regulation.