A prospective, single-arm, multicenter trial of neoadjuvant chemotherapy with mFOLFOX6 plus panitumumab without radiotherapy for locally advanced rectal cancer.

PURPOSE: The present study evaluated the safety and efficacy of neoadjuvant chemotherapy with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab in clinical stage III rectal cancer with KRAS wild-type. METHODS: We conducted a prospective multicenter phase II trial. KRAS wild-type clinical stage III rectal cancer patients were enrolled. Patients received 6 cycles of mFOLFOX6 with 6 mg/kg panitumumab as neoadjuvant chemotherapy. The primary outcome was the response rate (RR) defined by RECIST. Lateral lymph node dissection (LLDN) was performed when patients had a locally advanced tumor < 9 cm from the anal margin. RESULTS: A total of 50 patients were enrolled. Twelve (24.0%) experienced grade 3-4 adverse events during neoadjuvant chemotherapy. The RR was 88.0% (complete response 2.0%, partial response 86.0%), which met the primary outcome. All patients underwent laparoscopic surgery and achieved R0 resection. Seven patients underwent resection of other adjacent organs, and 43 underwent LLND. Twelve patients (24.0%) experienced grade 3-4 postoperative complications, and 4 (8.0%) had pathological complete response (pCR). Thirteen patients (26.0%) had lymph node metastasis. Forty-five patients (90.0%) received postoperative adjuvant chemotherapy. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 79.0% and 93.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy of mFOLFOX6 plus panitumumab without radiotherapy resulted in a low pCR rate but a high PR rate, low local recurrence rate, and good long-term outcome, suggesting that this treatment strategy may be a viable option for patients unable or unwilling to receive radiotherapy. The trial was registered with the UMIN Clinical Trials Registry, number 000006039.

[Effectiveness of L-Carnitine in the Treatment of Fatigue Associated with Chemotherapy in Patients with Gastric Cancer].

AIM: Low serum carnitine levels have been reported in patients with cancer receiving chemotherapy and are considered one of the factors causing fatigue associated with chemotherapy. We evaluated the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with gastric cancer(GC). MATERIALS AND METHODS: We performed a randomized controlled trial between December 2013 and December 2018. Untreated patients with advanced GC were included in the study; 1 patient developed an allergy after receiving the first chemotherapy and was excluded from the study. The primary endpoint was brief fatigue inventory(BFI). Patients were categorized into 2 groups: those who received L-carnitine oral supplements(group C)and those who did not receive L-carnitine oral supplements(group N). RESULTS: The serum carnitine levels were improved significantly in group C compared with group N. BFIwas more aggravated in group N than group C; however, the difference was not significant. CONCLUSION: We could not demonstrate the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with GC.

The Effect of Pyridoxine for Prevention of Hand-Foot Syndrome in Colorectal Cancer Patients with Adjuvant Chemotherapy Using Capecitabine: A Randomized Study.

UNLABELLED: BACKGROUND/Aims: To determine the effect of the pyridoxine for prevention of hand-foot syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine. METHODOLOGY: Colorectal cancer patients scheduled for capecitabine chemotherapy as adjuvant setting were randomly assigned to with or without concurrent oral pyridoxine (60 mg/d) groups. Patients were monitored whether being a development of National Cancer Institute Common Toxicity Criteria grade 2 or worse HFS until chemotherapy ended. RESULTS: Sixty patients were enrolled in this study. Relative dose intensity was 89.5% in total. The median number of chemotherapy cycles to grade 2 or worse HFS was four in both groups. Grade 2 or worse HES developed in 18 (60.0%) of 30 control patients and in 18 (60.0%) of 30 pyridoxine patients. The cumulative dose of capecitabine to grade 2 or worse HFS was not different between the two groups. CONCLUSIONS: Pyridoxine is not effective in prevention of capecitabine-associated HFS.

The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease.

BACKGROUND: The guidelines established by the National Comprehensive Cancer Network do not describe mucinous histology as a clinical factor that should influence the therapeutic algorithm. However, previous studies show conflicting results regarding the prognosis of colorectal mucinous adenocarcinoma. In this study, we described the clinicopathological features of mucinous adenocarcinoma in Japan, to identify optimal therapeutic strategies. METHODS: 144 patients with mucinous and 2673 with non-mucinous adenocarcinomas who underwent primary resection in two major centers in Yokohama, Japan were retrospectively evaluated for clinicopathological features and treatment factors. A multivariate analysis for overall survival followed by the comparison of overall survival using Cox proportional hazard model were performed. RESULTS: Patients with mucinous adenocarcinoma had larger primary lesions, higher preoperative CEA levels, a deeper depth of invasion, higher rates of nodal and distant metastasis, and more metastatic sites. A multivariate analysis for overall survival revealed a mucinous histology to be an independent prognostic factor. In the subgroup analysis stratified by stage, Patients diagnosed as stageIII and IV disease had a worse survival in mucinous adenocarcinoma than non-mucinous, while survival did not differ significantly in patients diagnosed as Stage0-II disease. In stageIII, local recurrence in rectal cases and peritoneal dissemination were more frequently observed in patients with a mucinous histology. CONCLUSIONS: Our study indentified that mucinous adenocarcinoma was associated with a worse survival compared with non-mucinous in patients with stageIII and IV disease. In rectal StageIII disease with mucinous histology, additional therapy to control local recurrence followed by surgical resection may be a strategical alternative. Further molecular investigations considering genetic features of mucinous histology will lead to drug development and better management of peritoneal metastasis.

Usefulness of multidisciplinary therapy combining neoadjuvant chemotherapy with S-1 plus cisplatin and postoperative sequential chemotherapy in patients with scirrhous gastric cancer.

BACKGROUND/AIMS: The outcomes of patients with scirrhous gastric cancer (SGC) remain poor. We retrospectively compared outcomes according to historically different treatments for SGC and studied the therapeutic usefulness of NAC with S-1 plus cisplatin followed by postoperative sequential chemotherapy. METHODOLOGY: We studied 93 patients with SGC. Between 1995 and 2000, 29 patients did not receive NAC and were instead given conventional anti-cancer drugs. Between 2000 and 2003, 20 patients received 4 weeks of NAC with low-dose cisplatin plus 5-fluorouracil (5-FU) followed by postoperative sequential treatment with new anticancer agents (neoadjuvant low-dose FP group). Between 2003 and 2006, 44 patients received 2 courses of NAC with S-1+cisplatin followed by postoperative sequential administration of new anticancer agents (neoadjuvant S-1+cisplatin group). Response rates and overall survival were compared among the treatment groups. RESULTS: The rates of response to NAC were 15% in the neoadjuvant low-dose FP group and 36% in the neoadjuvant S-1+cisplatin group. Overall survival was significantly longer in the neoadjuvant S-1+cisplatin group than the other groups. CONCLUSIONS: Our results suggest that multidisciplinary therapy combining NAC with S-1+cisplatin and postoperative sequential administration of new anticancer drugs is therapeutically useful in patients with SGC.

[A resected case of huge advanced hepatocellular carcinoma(BCC)treated with intra-arterial infusion chemotherapy combined with interferon-alpha].

A58-year-old man with upper abdominal pain had a duodenal perforation and a huge hepatocellular carcinoma (BCC). Atumor embolism in the main portal vein was also seen. Extended right lobectomy against a huge tumor in right lobe and ethanol injection to a tumor in the lateral segment were performed. In addition, fluorouracil arterial infusion and interferon therapy(FAIT)were carried out. He has been for 4 years and 6 months without recurrence. Although prognosis of patients with a huge BCC is miserable even if curative hepatic resection is performed, it may be possible for adjuvant FAIT to suppress the recurrence after hepatic resection for huge BCC.

Therapeutic outcomes of continuous hyperthermic peritoneal perfusion against advanced gastric cancer with peritoneal carcinomatosis.

BACKGROUND/AIMS: To clarify the efficacy of therapeutic continuous hyperthermic peritoneal perfusion in peritoneal carcinomatosis of gastric cancer. METHODOLOGY: The subjects of this study were 73 advanced gastric cancer patients who underwent palliative surgery between 1992 and 1999. Therapeutic continuous hyperthermic peritoneal perfusion (T-CHPP) was performed in 21 patients, who had macroscopic peritoneal carcinomatosis or positive lavage cytology, were under 65 years old, had no concomitant disease, and gave informed consent. Fifty-two patients who did not meet the inclusion criteria formed the control group. After reconstruction of the alimentary tract, T-CHPP was carried out for 40 min with 300 mg of Cisplatin, 30 mg of mitomycin C, and 300 mg of etoposide in 5-6 L of physiological saline maintained at 42 degrees C to 43 degrees C. RESULTS: The survival of patients who had CY1, P1, P2, P3 was not affected by T-CHPP. Univariate analysis revealed that the degree of peritoneal carcinomatosis and adjuvant chemotherapy were prognostic factors. Furthermore, ill-defined macroscopic appearance and P3 independently affected prognosis, according to multivariate analysis. Patients treated by T-CHPP had higher incidences of respiratory failure (76.2% vs. 17.3%; p < 0.0001) and renal failure (14.3% vs. 0%; p < 0.0054) than those undergoing T-CHPP. CONCLUSIONS: As T-CHPP had no efficacy, a new therapeutic strategy such as chemosensitivity assessment or a well-structured randomized controlled trial is necessary to obtain good therapeutic results with T-CHPP.

Predicting 5-fluorouracil chemosensitivity of liver metastases from colorectal cancer using primary tumor specimens: three-gene expression model predicts clinical response.

We identified genes related to 5-fluorouracil (5-FU) sensitivity in colorectal cancer and utilized these genes for predicting the 5-FU sensitivity of liver metastases. Eighty-one candidate genes involved in 5-FU resistance in gastric and colon cancer cell lines were previously identified using a cDNA microarray. In this study, the mRNA expression levels of these 81 selected genes and the genes of 5-FU-related enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT), were measured using real-time quantitative RT-PCR assays of surgically resected materials from primary colorectal tumors in 22 patients. Clinical responses were estimated by evaluating the effects of 5-FU-based hepatic artery injection (HAI) chemotherapy for synchronous liver metastases. Four genes (TNFRSF1B, SLC35F5, NAG-1 and OPRT) had significantly different expression profiles in 5-FU-nonresponding and responding tumors (p < 0.05). A "Response Index" system using three genes (TNFRSF1B, SLC35F5 and OPRT) was then developed using a discriminate analysis; the results were well correlated with the individual chemosensitivities. Among the 11 cases with positive scores in our response index, 9 achieved a reduction in their liver metastases after 5-FU-based chemotherapy, whereas only 1 of the 11 cases with negative scores responded well to chemotherapy. Our "Response Index" system, consisting of TNFRSF1B, SLC35F5 and OPRT, has great potential for predicting the efficacy of 5-FU-based chemotherapy against liver metastases from colorectal cancer.

Therapeutic strategy for scirrhous type gastric cancer.

BACKGROUND/AIMS: As no appropriate therapeutic strategy has yet been established in scirrhous type gastric cancer, we retrospectively analyzed the therapeutic outcomes in patients with this type of cancer. METHODOLOGY: A total of 183 patients with scirrhous type gastric cancer were enrolled in the study. 127 of them underwent resection; 61 potentially curative gastrectomy; 66 palliative resection; and 56 had no surgery. RESULTS: Univariate analysis revealed that the number of metastatic lymph nodes and the depth of invasion influenced prognosis in curatively resected cases, whereas no factor did so after palliative resection. Multivariate analysis showed that prognosis was affected independently by peritoneal metastasis and non-regional lymph node metastasis in all resected cases, but by the number of metastatic lymph nodes in curatively resected cases. There was no significant difference in survival between patients undergoing and those not undergoing palliative gastrectomy. Prophylactic (6) and therapeutic CHPP (12) had no efficacy on peritoneal metastasis. Furthermore, left upper abdominal evisceration (LUAE) (9) did not improve long-term results in curatively resected cases. CONCLUSIONS: In scirrhous type gastric cancer, gastrectomy including extended lymph node dissection is justified only in patients with limited lymph node metastasis, and palliative gastrectomy should be not performed because it has no efficacy on survival.

[Effectiveness of continuous hyperthermic peritoneal perfusion for the peritoneal dissemination of gastric cancer].

We investigated the effectiveness of continuous hyperthermic peritoneal perfusion (CHPP) for the peritoneal dissemination of gastric cancer. A total 124 patients with advanced gastric cancer were enrolled in this study. Prophylactic CHPP (P-CHPP) was performed in 45 patients who had macroscopic serosal invasion without peritoneal dissemination, and 79 patients without CHPP were a control group. Therapeutic CHPP (T-CHPP) was performed in 21 patients with peritoneal dissemination, and 52 patients without CHPP were a control group. There was no significant difference in 5 year survival between patients treated and not treated with P-CHPP. Univariate analysis showed that location of tumor, tumor diameter, and lymph node metastasis influenced prognosis, but there was no prognostic factor in the Cox proportional regression hazard model. There was no significant difference in 5-year survival between patients treated and not treated with T-CHPP. Univariate analysis showed that degree of peritoneal dissemination and adjuvant chemotherapy influenced prognosis, and the Cox proportional regression hazard model showed that the macroscopic types and degree of peritoneal dissemination affected prognosis. In the patients with CHPP, the incidences of respiratory failure and renal failure were each statistically greater than in the patients undergoing CHPP.

Lack of efficacy of prophylactic continuous hyperthermic peritoneal perfusion on subsequent peritoneal recurrence and survival in patients with advanced gastric cancer.

BACKGROUND: Peritoneal recurrence is a major cause of death in advanced gastric cancer. Although many kinds of chemotherapy intended to prevent peritoneal recurrence of gastric cancer have been evaluated, few have been successful. Few studies have assessed the clinical significance of continuous hyperthermic peritoneal perfusion in peritoneal recurrence. METHODS: From 1992 to 1999, a total of 124 patients with advanced gastric cancer with tumors invading deeper than the serosa but with no peritoneal metastasis underwent potentially curative gastrectomy and were enrolled in this study. Prophylactic continuous hyperthermic peritoneal perfusion (P-CHPP) was performed in 45 patients younger than 65 years old and without comorbidity who gave informed consent. Seventy-nine patients who did not meet the inclusion criteria represented the control group. After reconstruction of the alimentary tract, P-CHPP was carried out for 40 minutes with 150 mg cisplatin, 15 mg mitomycin C, and 150 mg etoposide in 5 to 6 L physiologic saline maintained at 42 degrees C to 43 degrees C. The surgical results, recurrent pattern, and postoperative morbidity were assessed by univariate and multivariate analysis. RESULTS: When compared with patients not undergoing P-CHPP, patients treated by P-CHPP had higher incidences of respiratory failure (73% vs 19%; P <.0001) and renal failure (7% vs 0%; P <.03). Neither 5-year survival (49% vs 56%) nor the patterns of recurrence (peritoneal, hematogenous, and lymphatic) were affected by P-CHPP. CONCLUSIONS: P-CHPP by our methods had no efficacy as prophylactic treatment for peritoneal recurrence induced by gastric cancer. New therapeutic strategies, such as chemosensitivity assessment, are necessary to obtain good therapeutic results with CHPP.