Tumour characteristics, treatment patterns and survival of patients aged 80 years or older with colorectal cancer.

AIM: This study aimed to clarify tumour characteristics and treatment patterns for patients with colorectal cancer aged 80 years or older and the impact of age on survival using a large-scale cancer registry database. METHOD: The database was used to identify 40 851 colorectal cancer patients who underwent surgery between 1995 and 2004. Patients were stratified into four age groups (< 50, 50-64, 65-79, ≥ 80 years). Demographics, tumour characteristics, treatment pattern and survival were compared between age groups. Additionally, the impact of lymph node dissection and adjuvant chemotherapy on survival was studied using the propensity score-matching method. RESULTS: In the over 80 age group, patients were more commonly female, with right colon cancer, multiple primary cancers, history of colorectal cancer, high serum carcinoembryonic antigen values, large tumour, undifferentiated histology, and more frequent pT3/pT4 tumours. In contrast, metastatic disease, central lymph node dissection and adjuvant chemotherapy were less frequent. Overall survival and cancer-specific survival decreased with increasing age for any stage. Multivariate analysis showed age to be an independent predictor of overall survival (hazard ratio 1.45, 95% CI 1.34-1.58, P < 0.001). In the propensity score-matched cohort, overall survival of the patients with central node dissection and having adjuvant chemotherapy was significantly better than for those without. This difference was not statistically significant in patients aged 80 and above. CONCLUSION: This study showed a significant difference in tumour characteristics and treatment patterns in patients aged 80 and above. Even after adjustment for clinicopathological factors, the difference in survival persisted and age was considered a robust prognostic factor.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Incorporation of apical lymph node status into the seventh edition of the TNM classification improves prediction of prognosis in stage III colonic cancer.

BACKGROUND: The node classification outlined in the seventh edition of the TNM classification is based solely on the number of metastasized lymph nodes. This study examined the prognostic value of apical lymph node (ALN) metastasis and the additional value of incorporating ALN status into a risk model based on the seventh edition. METHODS: This was a cohort study of patients with stage III colonic cancer who underwent tumour resection with dissection of regional (including apical) lymph nodes at 71 hospitals across Japan between 2000 and 2002. The main exposure was pathologically confirmed ALN metastasis, and the primary endpoint was cancer-specific death. RESULTS: ALN metastasis was present in 113 (8·3 per cent) of 1355 patients. During 5356 patient-years of follow-up (median 5·0 years), 221 instances (16·3 per cent) of cancer-specific death were observed. After adjustment for tumour and node classification (as described in the seventh edition of the TNM classification) and other prognostic factors, ALN metastasis was found to be independently associated with cancer-specific death (hazard ratio 2·29, 95 per cent confidence interval (c.i.) 1·49 to 3·52). Incorporation of ALN metastasis into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for cancer-specific death (difference in concordance index 0·0146, 95 per cent c.i. 0·0030 to 0·0262) and risk reclassification for cancer-specific death at 5 years (category-free net reclassification improvement 19·4 (95 per cent c.i. 5·0 to 33·4) per cent). CONCLUSION: Assessment of ALN metastasis provided independent prognostic information beyond that achievable with the seventh edition of the TNM classification in patients with stage III colonic cancer.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Evaluation of the seventh edition of the tumour, node, metastasis (TNM) classification for colon cancer in two nationwide registries of the United States and Japan.

AIM: The new TNM classification is currently being implemented. We evaluated the TNM-7 staging system based on the two nationwide colon cancer registries in the United States and Japan to clarify whether this system better stratifies patients' prognoses than the TNM-6 did and to determine whether stratification can be effectively simplified. METHODS: The Surveillance, Epidemiology, and End Results population-based data from 1988 to 2001 for 50139 colon cancer patients and the multi-institutional registry data from the Japanese Society for Cancer of the Colon and Rectum from 1984 to 1994 for 10754 patients were analysed. We devised a modified version of the TNM-7 staging system to allow simpler classification of the TN categories and compared the TNM-6, TNM-7, modified TNM-7, and the Dukes staging system based on survival curves and objective statistical tests such as likelihood ratio χ(2) tests, Akaike's information criterion, and Harrell's c-index. RESULTS: The TNM-7 was superior to the TNM-6 in all objective statistical tests in the United States (c-index; 0.700 vs 0.696, P<0.001) as well as in the Japan data sets (0.732 vs 0.729, P=0.035). The modified TNM-7 is much simpler, but it nevertheless showed similar values to those of the original TNM-7 (c-index; the United States 0.702, Japan 0.733). CONCLUSIONS: The new TNM-7 is complicated but better at stratifying patients than the TNM-6 in the United States and Japan, and could be effectively simplified.

S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Colorectal cancer in Japan.

There is the increase in colorectal cancer incidence in Japan. The increase in the rate of colon cancer compared with rectal cancer was noticed. The proximal migration of the tumor site from the left colon to right colon is shown in the study. The evident shift toward earlier stage was clearly revealed. According to the extended lymph node resection, the improvement of overall 5-year survival rate from 55% to 69% is important trend.

Possible involvement of protein kinase C in proliferation and differentiation of osteoblast-like cells.

In cloned osteoblast-like cells, MC3T3-E1, 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C activating phorbol ester, and 1-oleoyl-2-acetylglycerol (OAG), a specific activator for protein kinase C, stimulated DNA synthesis in a dose-dependent manner. Both TPA and OAG acted synergistically with insulin-like growth factor I to stimulate DNA synthesis. TPA as well as OAG suppressed the increase in alkaline phosphatase activity of MC3T3-E1 cells induced by parathyroid hormone. These results suggest that protein kinase C is involved in the process which directs osteoblast-like cells toward proliferation.

An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures.

In vitro chemosensitivity testing using a collagen gel droplet embedded culture drug sensitivity test (CD-DST), was conducted with several types of solid cancer. The overall evaluable rate was 80% (443/554), including 76% for lung (n=243), 78% for breast (n=110), 87% for gastric (n=62), 83% for colorectal (n=107) cancers and 88% for 32 metastatic brain tumors. The in vitro sensitivity of breast, gastric and colorectal cancers to mitomycin C (MMC), cisplatin (CDDP), 5-fluorouracil (5-FU) and doxorubicin (DXR) was similar to the efficacy rates reported for each drug. This was also observed with lung cancer, the sensitivity of which to MMC, CDDP, vindesine (VDS) and etoposide (VP-16) was similar to the clinical efficacy. The clinical response to chemotherapy was compared with the results of in vitro chemosensitivity testing in Il patients: the clinical correlation was 91%, with a 80% true positive and 100% true negative rate. These results suggest that the CD-DST may be clinically useful by allowing the prediction of clinical response in various solid cancers.

Effects of chronic liver diseases on mitochondrial DNA transcription and replication in human liver.

To evaluate the effects of chronic liver diseases on mitochondrial DNA (mtDNA) transcription and replication, nuclear respiratory factor-1 (NRF-1) mRNA, mitochondrial transcription factor A (mtTFA) mRNA, a RNA component of ribonuclease (RNase) for mitochondrial RNA processing (MRP), mitochondrial cytochrome b mRNA, and mtDNA were measured in normal, chronically viral-hepatitic and cirrhotic human livers. The mRNA levels of the regulatory factors for mitochondrial gene (NRF-1 and mtTFA) and cytochrome b were significantly increased by chronic hepatitis (160, 280, and 175%, respectively) compared with those in normal livers, but were not different between cirrhotic and normal livers. On the other hand, concentrations of mtDNA and RNA component of RNase MRP were not different among normal, chronically hepatitic, and cirrhotic livers. These results suggest that either persistent hepatitis viral infection or repeated cell necrosis and regeneration in chronically hepatitic liver may be associated with increase in mtDNA transcription.

Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial DNA deletion than normal human livers.

We measured the populations of mutated mitochondrial DNAs with the 7,436 bp or the 4,977 bp deletion from apparently normal human liver and human livers with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The amount of the mutated mitochondrial DNA was at the same level between normal and chronically hepatitic livers but was significantly lower in human livers with cirrhosis and hepatocellular carcinoma, especially the latter, suggesting that the mutated mitochondrial DNAs may be decreased with the progress of liver disease from chronic hepatitis to cirrhosis and hepatocellular carcinoma. This phenomenon is opposite to that occuring in the ageing process.

Significance of para-aortic lymph node dissection in patients with advanced and recurrent gastric cancer.

Among 243 patients who underwent radical gastrectomy for advanced gastric cancer, 19 patients underwent radical gastrectomy with extended lymphadenectomy including cancer-positive para-aortic lymph nodes. Their prognosis was unexpectedly good, with a mean postoperative survival time of 24.1 months and a 2-year-survival rate of 42.4 percent. Another 4 patients developed para-aortic lymph node recurrence detected by computed tomographic scan during a follow-up examination. These 4 patients were treated with macroscopic curative dissection of the para-aortic lymph nodes. Although 2 of the 4 patients died within 6 months after re-operation, the prognosis of the other two patients was rather good when treated with active combination chemotherapy consisting of 5-fluorouracil, adriamycin and cisplatin. Dissection of para-aortic lymph nodes is considered of valuable in the treatment of advanced gastric cancer, and dissection of the para-aortic lymph node recurrence may also be valid when combined with potent chemotherapy.

5-fluorouracil sensitivity and dihydropyrimidine dehydrogenase activity in advanced gastric cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. Several studies have demonstrated the clinical importance of DPD in cancer patients, suggesting that the efficacy of 5-FU may be related to DPD activity in tumor tissue. In the present study, DPD activity and chemosensitivity to 5-FU were evaluated in advanced gastric cancer. MATERIALS AND METHODS: Thirty-four gastric cancers from 32 patients were studied and chemosensitivity to 5-FU was evaluated by histoculture drug response assay. RESULTS AND CONCLUSION: DPD activity and tumor inhibition of 5-FU among all cases showed no significant correlation, but among 14 histologically differentiated cases significant correlation was observed. DPD activity may be useful in determining the 5-FU sensitivity of differentiated gastric cancer.

A case of solitary metastatic pancreatic cancer from rectal carcinoma: a case report.

A 79 year-old male who had undergone resection of the rectum for rectal cancer was shown to have metastasis to the pancreas 11 years after surgery. The metastatic lesion was located at the tail and body of the pancreas, and was resected with distal pancreatectomy. The same patient also had metastasis to the lung 8 years after initial rectal surgery. Therefore, the course of metastasis to the pancreas was suggested to be from the metastatic lung tumor to the pancreas by hematogenous spread. The patient was considered disease-free 8 months after the pancreatectomy. Recent advances in the technology of diagnostic imaging have facilitated the selection of surgical therapy for metastasis to the pancreas in rectal cancer patients after follow-up by imaging diagnosis.

Endoscopic polypectomy of the large bowel: management of cancer-bearing polyps.

From January 1974 to May 1979, among 2,338 endoscopic examinations of the large bowel, 184 polypectomies were performed. Forty-two cases of familial polyposis coli were excluded from this study. Of the remaining 142 cases, 21 had cancer foci: fourteen were mucosally confined carcinomas, and seven submucosally invading carcinomas. Endoscopic polypectomy was considered a radical treatment for the former and not satisfactory for the latter. Therefore macroscopic type of polyp, location of carcinoma in the polyp, and lymphatic and venous permeation were the main criteria evaluated for the strategy of treatment in cases of submucosally invading carcinoma-bearing polyps. Radical resections are necessary in cases of semipedunculated polyp with carcinoma located near the base, and in cases of pedunculated polyps with carcinoma extending to the stalk. However, as general criteria for the management of submucosally invading carcinoma-bearing polyps have not yet been established, radical resections are indicated in cases which do not fit the generally accepted criteria, in order to attempt a curative treatment. Endoscopic polypectomy therefore seems to be of great value in the early detection of colorectal cancers and their treatment.

[Neoadjuvant therapy for colorectal cancer].

To assess the role of neoadjuvant therapy in the treatment of colorectal cancer, we reviewed the literature investigating the effects of chemotherapy and/or radiotherapy given prior to surgery. Rationales for enteral administration of fluoropyrimidines preoperatively, in terms of pharmacokinetic and antitumor effects, have been demonstrated in clinical studies. For instance, the concentration of 5-FU in cancer tissue was shown to be significantly higher than in normal tissue, and a dose-response relationship between the cumulative doses of the agent and the histological antitumor effect was observed. Among several comparative studies, there were reports suggesting the efficacy of preoperative chemotherapy. The treatment group had a slight, but insignificant, improvement in disease-free interval or long-term survival. On the other hand, some randomized trials for rectal cancer demonstrated that preoperative radiotherapy could decrease local failure, and that patients who underwent curative surgery appeared to have an improved 5-year survival compared to the controls, although overall survival was not improved. Recent reports on combined modality treatment with chemotherapy and radiotherapy clearly showed a downstaging effect on the primary tumor and the decreased prevalence of regional involved lymph node. Further developments through rationally designed study are necessary to ascertain the efficacy of neoadjuvant therapy for colorectal cancer.

[Treatment of advanced colorectal cancer with long-term continuous infusion of 5-fluorouracil].

The purpose of the study was to evaluate the efficacy of long-term continuous administration of 5-fluorouracil (5-FU) in ambulatory patients with colorectal cancer. Nineteen patients with advanced colorectal cancer were treated with continuous intravenous infusion of 5-FU (500 mg/day). The minimum duration of therapy was projected to be four weeks. In some patients 4 weeks interval therapy was selected and in other patients the duration of therapy was open-ended. A portable pump was used to deliver 5-FU continuously into the venous system at home. The pump had a subcutaneously placed port connected to a central venous catheter. In 19 patients, the duration of 5-FU infusion was 56 to 427 days (median: 139 days), and cumulative doses of 5-FU ranged from 28 to 173.5 g (median 69.5 g). Five patients achieved partial response (response rate: 26.3%), and the response lasted 80 to 339 days (median: 204 days). The fifty-percent survival time was 17 months. In 16 patients whose serum CEA level was elevated, there was a decrease to less than 50% among 11 patients (69%). Dose limiting toxicity was stomatitis in 4 patients and hand-foot syndrome in one, but they recovered after interruption of the infusion. Hematological toxicity was generally mild. No infusion-system related complication was encountered. Patients were able to be discharged and live at home during 82% of their survival period, while receiving this therapy. We concluded that this treatment is effective with tolerable toxicity and can be conducted at home.

[Neoadjuvant chemotherapy with tegafur suppository for rectal cancer--effects of tegafur on nuclear DNA content of cancer cells--Tochigi Colorectal Cancer Study Group].

To assess the significance of neoadjuvant chemotherapy for large bowel cancer, we investigated an effect of tegafur on cancer cell kinetics by DNA content flow cytometric analysis. The pathologic specimens analyzed in this study were obtained from 28 patients with rectal cancer who had received tegafur suppositories prior to surgery. Mean cumulative doses administered were 13.4 g, and mean duration was 12.7 days. In 24 of the 28 specimens, the DNA ploidy and DNA index of the cancer cells were essentially unchanged after the chemotherapy, and DNA aneuploidy was present in 67%. The proportion of cells in S-phase in DNA aneuploid tumors was significantly higher than in DNA diploid tumors. The proportion of cells in G0G1-phase was inversely correlated to that in S-phase. After the chemotherapy, the proportions of cells in S-phase increased both in DNA diploid and aneuploid tumors, although a significantly higher mean value was found only for the latter (p < 0.05). In the DNA aneuploid tumors, there was a higher frequency of responders confirmed by histological evaluation (44%) as compared to the DNA diploid tumors (25%), and a tendency for increases in S-phase fraction of the responders to be greater than in non-responders. These results suggest that DNA flow cytometry-derived parameters may conceivably be useful in predicting the antitumor effect of 5-FU and its derivatives against large bowel cancer.

[Clinical evaluation and problem of intra-arterial infusion chemotherapy of liver metastasis from digestive organ cancer].

Intra-arterial infusion chemotherapy using an implantable reservoir was used for 22 patients with liver metastasis from September 1986 to March 1990. The material consisted of 8 subjects with gastric cancer and 14 with colorectal cancer. One had metastasis in one lobe (H1), 10 had a few scattered metastases in both lobes (H2) and 11 had numerous metastases in both lobes (H3). In 5 cases, a reservoir was implanted to prevent the recurrence after hepatectomy. Infusion catheter was placed in the proper hepatic artery in 5 cases via the gastroduodenal artery at laparotomy and it was carried out subcutaneously via the femoral artery in 17 cases. In all cases intra-arterial infusion of 5-FU was continuously administered followed by intermittent one shot injection of ADM. The clinical effectiveness of the therapy was well evaluated. One-year cumulative survival rate of all cases by Kaplan-Meier method was 55% and that of H2 cases was 78%. No recurrence was noted in post hepatectomy cases. Eight cases (36.3%) showed remarkable complications, which made it impossible to continue intra-arterial infusion chemotherapy: hepatic artery occlusion (3 cases), infection (2 cases), abdominal pain (1 case), hematoma in the implanted site (1 case) and dislocation of the infusion catheter (1 case). From the present study, it is considered that intra-arterial infusion chemotherapy is a useful procedure for the control of liver metastasis. Regimens for improved chemotherapy and the maintenance of more useful and safer catheters should therefore be investigated for further development of the therapeutical estimation.

[Neo-adjuvant chemotherapy with tegafur suppository for rectal cancer--evaluation of the antitumor effects, tissue levels of 5-FU and inhibition of thymidylate synthase. Tochigi Colorectal Cancer Study Group].

We evaluated antitumor effect histologically and assayed the tissue levels of 5-fluorouracil (5-FU) and thymidylate synthase (TS) activity using surgical specimens obtained from the patients with rectal cancer, who were given tegafur suppositories prior to surgery. The antitumor effect was evaluated histologically according to classification of the general rules for the gastric cancer study (Japanese Research Society for Gastric Cancer). In 39 patients, 16 tumor specimens revealed no effect (grade-0), 22 tumors grade-1 effect, and one was not evaluable because of the severe inflammatory changes. In 23 of these patients, resected specimens were available for the assay. 5-FU levels in cancer tissues were significantly higher than those in normal tissues, and TS inhibition rates (TSIR) were almost identical, averaging around 20%, in both cancer and normal tissues. Comparing the 5-FU levels and TS activity according to the histological effects (i.e.: 'grade-0' vs 'grade-1'), the 5-FU levels in the tumors achieved grade-1 were significantly higher than in the tumors showed 'grade 0' (p less than 0.01), and TSIR in the former were relatively greater than in the latter (p = 0.053). It is suggested that both tissue levels of 5-FU and TSIR may be useful parameters to predict the anti-tumor effect against rectal cancer after administration of 5-FU and its derivatives.