Perioperative Nutritional Support With Beta-hydroxy-beta-methylbutyrate, Arginine, and Glutamine in Surgery for Abdominal Malignancies.

Although beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) may contribute to wound healing, no prospective studies have investigated the efficacy of a compound consisting of HMB, Arg, and Gln (HMB/Arg/Gln) for reducing wound complications following open abdominal surgery. OBJECTIVE: This study evaluates the usefulness of perioperative nutrition using HMB/Arg/Gln in patients who were scheduled to undergo open surgery for abdominal malignancies in a randomized controlled trial. MATERIALS AND METHODS: Patients scheduled for open surgery for abdominal malignancies were randomized to receive HMB/Arg/Gln (1.2 g HMB, 7 g L-Arg, and 7 g L-Gln) or placebo (isocaloric juice). The supplements were provided once daily for 3 days preoperatively and once daily for 7 days postoperatively. The primary endpoint was the incidence of wound complications. Secondary endpoints included the incidence of other complications, postoperative duration of hospital stay, total-body skeletal muscle mass, handgrip strength, and skin water content. RESULTS: Sixty-one patients were randomly assigned to either the HMB/Arg/Gln (n = 31) or the placebo (n = 30) group. One patient in the HMB/Arg/Gln group was ineligible because laparoscopic surgery was performed; thus, 60 patients were analyzed. The incidence of wound complications (20%) was the same in both groups (P = 1.000). There were no significant differences in the incidence of other complications, body composition, handgrip strength, or skin water content between the 2 groups. Serum growth hormone (GH) levels were significantly higher for patients whose total intake was > 80% of planned volume in the HMB/Arg/Gln group. CONCLUSIONS: The incidence of wound complications would not be reduced by perioperative HMB/Arg/Gln administration in patients who underwent open surgery. The efficacy of HMB/Arg/Gln for increasing serum GH levels needs to be validated in another large-scale randomized controlled trial.

Randomized study of the clinical effects of ω-3 fatty acid-containing enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer.

OBJECTIVES: Omega-3 (ω-3) fatty acids have potential positive effects during chemotherapy, such as body weight maintenance and muscle mass preservation. However, little is known about the effect this supplement might have on reducing chemotherapy-induced toxicities. The aim of this study was to determine the usefulness of ω-3 fatty acid supplementation in the reduction of chemotherapy-related toxicities. METHODS: Sixty-one patients undergoing neoadjuvant chemotherapy for esophageal cancer randomly received ω-3-rich enteral nutrition (EN; n = 31) or ω-3-poor EN support (n = 30) for 15 d during chemotherapy. The daily dosage of ω-3 fatty acids was 900 mg in the ω-3-rich group and 250 mg in the ω-3-poor group. The primary endpoint was the frequency of grade 3/4 neutropenia, and secondary endpoints included other chemotherapy-related adverse events, body weight, and inflammatory markers. RESULTS: The total and dietary intake calories during chemotherapy were equal in both groups. There was no significant difference in the body weight change after chemotherapy between the two groups. There was no significant difference in the incidence of grade 3/4 leukopenia and neutropenia (P > 0.05). However, stomatitis was significantly less frequent in the ω-3-rich group, than in the ω-3-poor group (P = 0.018). Grade 3/4 diarrhea occurred relatively less frequently in the ω-3-rich group than in the ω-3-poor group; however, this difference was not significant (16.1% versus 36.7%, respectively, P = 0.068). Increases in the aspartate aminotransferase and alanine aminotransferase levels were seen significantly less frequently in the ω-3-rich group than in the ω-3-poor group (P = 0.012 and P = 0.015, respectively). CONCLUSIONS: ω-3-rich EN support decreased the frequency of chemotherapy-induced mucosal toxicities, such as stomatitis and diarrhea, and exhibited a hepatoprotective effect during chemotherapy, compared with the ω-3-poor EN support.

ω-3 Fatty Acids Reduce Chemotherapy-Induced Hematological Toxicity by Bone Marrow Stimulation in Mice.

BACKGROUND: ω-3 Fatty acids exert several benefits during chemotherapy, such as preventing intestinal mucosal damage and improving response to chemotherapy. However, little is known about the effect of ω-3 fatty acids on chemotherapy-induced hematological toxicities. METHODS: Mice that had consumed either an ω-3-rich or an ω-3-poor diet for 2 weeks were intraperitoneally administered cisplatin. The resultant changes in blood cell count, bone marrow cell count, and cytokine levels in bone marrow supernatant were analyzed. The effect of ω-3 fatty acids on human peripheral blood mononuclear cells (PBMCs) exposed to cisplatin was also examined. RESULTS: Although peripheral blood cell counts decreased after cisplatin treatment in both groups of mice, the decrease in white blood cell count was significantly lower in mice that consumed the ω-3-rich diet. The decrease in bone marrow cells after cisplatin treatment was also reduced in mice that consumed the ω-3-rich diet. Levels of stem cell factor (SCF) and fibroblast growth factor 1 (FGF-1) were significantly higher in bone marrow supernatants from mice that consumed the ω-3-rich diet. The rate of apoptosis in PBMCs (after exposure to cisplatin) cultured in medium containing ω-3 fatty acids was significantly lower than in PBMCs cultured in control medium. CONCLUSION: ω-3-Rich diets reduced chemotherapy-induced leukopenia in mice. This may be the result of increased numbers of bone marrow cells due to higher levels of SCF and FGF-1 in the bone marrow.

[Adjuvant treatment for esophagogastric junction cancer].

Conducting clinical trials to establish evidence of the benefits of adjuvant treatment for resectable esophagogastric junction (EGJ) cancer is difficult because it is a very rare disease compared with gastric or esophageal cancer. In the West, where esophageal cancer occurs more frequently than gastric cancer, a phase III trial (the CROSS trial) demonstrated the efficacy of preoperative chemoradiotherapy using carboplatin plus paclitaxel for patients with esophageal or EGJ cancer. Thus, this preoperative regimen is considered to be the standard adjuvant treatment for resectable EGJ cancer in the West. On the other hand, the Western evidence is not widely accepted in Asia because there are many differences in surgical techniques, particularly in the field of lymph node dissection, between the West and Asia. The standard adjuvant treatment for resectable EGJ cancer in Asia is postoperative chemotherapy using S-1 alone or capecitabine plus oxaliplatin based on the results of two large-scale phase III trials in gastric cancer conducted in East Asia. The incidence of EGJ cancer has recently increased in Japan, and nationwide studies to develop more effective adjuvant treatment for resectable EGJ cancer should be conducted in the near future.

Prognostic Significance of (18)F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET)-Positive Lymph Nodes Following Neoadjuvant Chemotherapy and Surgery for Resectable Thoracic Esophageal Squamous Cell Carcinoma.

PURPOSE: Patients with resectable thoracic esophageal squamous cell cancer (TESCC) and positron emission tomography (PET)-positive lymph nodes (PET-N positive) are likely to have ≥3 pathological lymph node metastases (pLNMs) and show a higher rate of postoperative recurrence despite curative resection than PET-N-negative TESCC patients. We examined the prognostic significance of (18)F-fluorodeoxyglucose uptake into lymph node metastases after neoadjuvant chemotherapy (NAC) for PET-N positive TESCC and aimed to propose the optimal NAC response criteria for these patients. METHODS: Fifty-one patients with PET-N positive TESCC underwent two courses of NAC followed by surgery. Metabolic responses of primary tumors and LNs were prospectively evaluated and associations with clinicopathological data and patient survival assessed by univariate and multivariate analyses. RESULTS: After NAC, 21 patients were post-treatment (post-) PET-N positive and 30 post-PET-N negative. A significantly (p < 0.001) high proportion of the post-PET-N-negative group had ≤2 pLNMs than the post-PET-N positive group (86.7 vs. 28.6 %). The PET-N negative group also had a significantly lower distant metastasis rate (23.3 vs. 75.0 %) and higher 5-year relapse-free survival (RFS) rate (69.0 vs. 20.0 %). Univariate and multivariate Cox's proportional hazard regression analyses identified post-PET-N negative status as the only significant favorable predictive factor for low postoperative recurrence (p = 0.015) independent of the primary tumor response. CONCLUSIONS: PET-N negative status predicts ≤2 pLNMs and longer RFS in resectable TESCC patients even after NAC. Therefore, post-PET-N status, not the effects on the primary tumor, is a critical NAC treatment response criterion for evaluating prognosis and guiding subsequent treatment.

Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy.

BACKGROUND: Gastric cancer patients who undergo gastrectomy suffer from a post-gastrectomy syndrome that includes weight loss, dumping syndrome, reflux esophagitis, alkaline gastritis, and finally malnutrition. It is important to ameliorate the post-gastrectomy symptoms to restore postoperative quality of life (QoL). The aim of this study was to investigate the effect of rikkunshito, a Japanese herbal medicine, on postoperative symptoms and ghrelin levels in gastric cancer patients after gastrectomy. METHODS: Twenty-five patients who had undergone gastrectomy received 2.5 g of rikkunshito before every meal for 4 weeks, and a drug withdrawal period was established for the next 4 weeks. Changes in gastrointestinal hormones, including ghrelin, and appetite visual analog scale scores were measured, and QoL was estimated by using the European Organization for Research and Treatment of Cancer core questionnaire QLQ-C30. The Dysfunction After Upper Gastrointestinal Surgery for Cancer (DAUGS) scoring system was used to evaluate gastrointestinal symptoms after gastrectomy. RESULTS: Sixteen men and nine women (mean age 61.9 years) were enrolled in the study. All patients had either stage I (n = 24) or II (n = 1) disease and had undergone either distal gastrectomy (n = 17) or total gastrectomy (n = 8) by a laparoscopy-assisted approach. The mean ratio of the acyl-/total ghrelin concentration increased significantly after rikkunshito administration (Pre: 7.8 ± 2.1, 4 weeks: 10.5 ± 1.7 %, p = 0.0026). The total DAUGS score, as well as the scores reflecting limited activity due to decreased food consumption, reflux symptoms, dumping symptoms, and nausea and vomiting significantly improved after rikkunshito administration. CONCLUSIONS: The present study demonstrated a significant attenuation of gastrointestinal symptoms after gastrectomy by treatment with rikkunshito. Rikkunshito is potentially useful to minimize gastrointestinal symptoms after gastrectomy.

Randomized study of clinical effect of enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer.

BACKGROUND & AIMS: Enteral nutrition (EN) is provided for patients with cancer. However, Little is known about the clinical efficacy of EN support during chemotherapy in patients with cancer. METHODS: Ninety-one patients who received neoadjuvant chemotherapy (5-fluorouracil, cisplatin and adriamycin) for esophageal cancer were enrolled to receive either EN (n = 47) or PN (n = 44) at random. The primary endpoint was the incidence of chemotherapy-related toxicities during chemotherapy. RESULTS: Total and dietary intake calories during chemotherapy were equal in the two groups. There were no significant differences in serum albumin level and body weight change after chemotherapy between the two groups. There was no significant difference in tumor response to chemotherapy between the two groups (EN: 51%, PN: 55%, p = 0.886). Leukopenia and neutropenia of grade 3 or 4, defined according to the Common Toxicities Criteria of the National Cancer Institute, were significantly less frequent in the EN group than PN group (leukopenia: 17% vs 41%, p = 0.011, neutropenia: 36% vs 66%, p = 0.005). Lymphopenia and thrombocytopenia tended to be less frequent in the EN group, albeit insignificantly. CONCLUSIONS: Compared with PN support, EN support during neoadjuvant chemotherapy reduced the incidence of chemotherapy-related hematological toxicities in patients with esophageal cancers.

[Peritoneal lavage cytology under local anesthesia for detection of peritoneal recurrence after surgery].

Gastric cancer with positive peritoneal lavage cytology shows a very poor prognosis due to frequent peritoneal recurrence after surgery. Therefore, we have introduced neoadjuvant intra-peritoneal and systemic chemotherapy( NIPS) for gastric cancer with peritoneal microscopic and/or microscopic dissemination before surgery. In patients subjected to the strategy, we have experienced two cases of advanced gastric cancer with CY1, which had been treated with NIPS and curative surgery, had been performed with second peritoneal lavage cytology two years after surgery. In those two cases, S-1 was discontinued due to the negative results of peritoneal lavage cytology. We will present the cases.

Multimodal treatment for resectable esophageal cancer.

Surgical resection has been traditionally the mainstay of treatment for localized esophageal cancers. However, survival after surgery alone for advanced esophageal cancer is not satisfactory. In Japan, the development of multimodal therapy for esophageal cancers has centered mainly on systemic chemotherapy plus surgery to control distant metastasis. Based on the results of the recent Japan Clinical Oncology Group (JCOG) 9907 study, preoperative chemotherapy (consisting of 5-FU and cisplatin) followed by surgery has emerged as the standard treatment. In Western countries, where chemoradiotherapy followed by surgery has been mainly explored for patients with resectable esophageal cancers, two large controlled trials that evaluated the effectiveness of preoperative chemotherapy reported conflicting results. However, a recent meta-analysis reported significant survival benefits for preoperative chemotherapy in patients with adenocarcinoma of the esophagus. We need to find new effective preoperative chemotherapeutic regimens, including molecular target agents, with response rates higher than that of the conventional chemotherapy of 5-FU and cisplatin. However, we also must compare the survival benefits of preoperative chemotherapy with preoperative chemoradiotherapy.

Neoadjuvant intraperitoneal and systemic chemotherapy for gastric cancer patients with peritoneal dissemination.

BACKGROUND: The present study was designed to assess the feasibility and efficiency of intraperitoneal and intravenous neoadjuvant chemotherapy in gastric cancer patients with peritoneal dissemination. METHODS: The study subjects were 25 treatment-naïve patients with gastric cancer. Patients with positive cytology or with peritoneal carcinomatosis received neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), comprising intraperitoneal (i.p.) mitomycin C (MMC) and cisplatin (CDDP), followed by two cycles of intravenous triplet chemotherapy of docetaxel, 5-fluorouracil (5-FU), and CDDP. Gastrectomy with lymph node dissection was performed after NIPS in patients free of peritoneal deposits, confirmed by staging laparoscopy. RESULTS: Seventeen patients had measurable lymph node metastases by the RECIST criteria. CT examination showed response to the treatment in ten (59%, 0 complete response, 10 partial response). Of the 25 patients, 14 (56%) showed negative results on peritoneal cytology with no macroscopic peritoneal metastasis, whereas the remaining 11 were cancer cell-positive on peritoneal cytology or macroscopic peritoneal metastasis even after NIPS. The median survival time for all 25 patients was 16.7 months. Prognosis was better in patients who showed negative cytology and disappearance of peritoneal cancer metastases after NIPS than in those with positive cytology or existing peritoneal deposits (P < 0.0001). The predominant toxicity was myelosuppression and grade 3-4 leukopenia and neutropenia occurred in 20 (80%) patients, which were manageable. No treatment-related mortality was observed during and after NIPS and surgery. CONCLUSIONS: The results of this prospective phase II study indicated that the newly designed NIPS was highly effective and well tolerated in patients with advanced gastric cancer and peritoneal dissemination.

Parthenolide, an NF-κB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer.

AIM: This study evaluated the sesquiterpene lactone parthenolide, an inhibitor of transcription factor nuclear factor-kappaB (NF-κB), in the treatment of gastric cancer in vitro and in vivo. MATERIALS AND METHODS: In vitro, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to evaluate the effect of parthenolide on growth inhibition and chemosensitization to antitumor drugs of three gastric cancer cell lines (MKN-28, MKN-45 and MKN-74). Microarray analysis was performed to identify genes which were up- or down-regulated on the treatment of parthenolide. The isobologram analysis was introduced to evaluate the synergic effect of parthenolide on antitumor drugs. In vivo, the effect of parthenolide was investigated in a mouse peritoneal dissemination model with and without chemotherapy. RESULTS: Parthenolide significantly inhibited cell growth in three gastric cancer cell lines. The phosphorylation of NF-κB was down-regulated by the treatment of parthenolide. The synergic effect of parthenolide was confirmed in combination with paclitaxel and cisplatin. In the peritoneal dissemination model, parthenolide significantly suppressed the disseminated nodules as a single agent and also enhanced chemosensitivity to paclitaxel. Furthermore, the combined therapy of parthenolide and paclitaxel significantly contributed to prolonging the survival duration. CONCLUSION: The NF-κB inhibitor, parthenolide, may enhance chemosensitivity to paclitaxel in the treatment of patients with gastric cancer.

Pre- and post-therapy nodal status equally affects survival of patients with oesophageal squamous cell carcinoma receiving preoperative chemoradiation.

Patients with deeply invading (T3-T4) oesophageal cancers usually receive chemoradiotherapy with or without surgery. However, the prognostic significance of pre-therapy and post-therapy lymph node (LN) status remains unclear. We studied 195 patients who received chemoradiotherapy for deeply invading oesophageal cancers (T3-4, N0-1, M0). Of these, 105 patients underwent surgery while 90 were treated by chemoradiotherapy alone. Of the 105 surgically treated patients, overall survival was significantly better in cN0 patients than in cN1 (3-year survival rate, 65.3 vs. 25.8%, P=0.0014). This difference was similarly observed in 90 patients who received chemoradiotherapy alone. Patient survival differed significantly among patients with no positive LN, 1 positive LN and 2-4 positive LN (3-year survival rate, 57.1 vs. 40.5 vs. 17.6%, P<0.0001). However, there was no significant difference in survival between patients with 2-4 positive LN and > or =5 positive LN. Multivariate analysis identified pre-therapy LN status and the number of involved LNs as the most important independent prognostic factors prior to histopathological tumour regression. In conclusion, pre-therapy LN status and the number of post-therapy involved LNs equally affect survival of patients who receive neo-adjuvant chemoradiotherapy. Control of systemic metastasis is required, based on pre- and post-therapy LN status.

Salvage esophagectomy after definitive chemoradiotherapy for thoracic esophageal cancer.

BACKGROUND AND OBJECTIVES: Although locoregional failure frequently occurs after definitive chemoradiotherapy (CRT), the role of salvage esophagectomy has not been fully evaluated. The aim of this study was to compare the outcome of salvage esophagectomy after high-dose definitive CRT with neoadjuvant CRT. METHODS: From 1994 to 2007, 33 patients with thoracic esophageal cancer underwent salvage esophagectomy after definitive CRT, and 115 patients underwent neoadjuvant CRT followed by surgery. RESULTS: The postoperative mortality rate in the salvage group (12%) was higher than in the neoadjuvant group (3.6%, P = 0.059). The rates of postoperative complications were significantly higher in the salvage group than in neoadjuvant group: Anastomotic leakage (39% vs. 22%, respectively, P = 0.049), bleeding (15% vs. 1.7%, respectively, P = 0.002), cardiovascular complications (24% vs. 5.4%, respectively, P = 0.001). Univariate analysis showed that pretherapy T stage, pretherapy lymph node status, pathological T stage, and operative curability were significant prognostic factors affecting survival of patients who underwent salvage esophagectomy. In particular, patients with cT3-T4 tumors or cN1 tumors before definitive CRT showed worse prognosis after salvage esophagectomy. CONCLUSIONS: Salvage esophagectomy after high-dose definitive CRT was associated with higher postoperative mortality and morbidity rates compared with neoadjuvant CRT. Only selected patients can be rescued by salvage esophagectomy.

Tumor budding in tumor invasive front predicts prognosis and survival of patients with esophageal squamous cell carcinomas receiving neoadjuvant chemotherapy.

BACKGROUND: In neoadjuvant chemotherapy for advanced esophageal cancers, complete tumor regression has been difficult to achieve, and tumor often remained after chemotherapy. However, the best method for evaluating the response to chemotherapy based on histopathologic examination of residual tumors has not been established. METHODS: Studied were 74 patients who received neoadjuvant chemotherapy (5-fluorouracil, cisplatin, and doxorubicin), followed by surgery for advanced esophageal squamous cell carcinoma. The correlation between various histopathologic factors and clinical response with survival was examined, including the importance of tumor budding in the invasive front of tumors on clinical response and survival. RESULTS: Among 74 patients, 3 achieved a pathologic complete response, and 29 (41%) of 71 residual tumors demonstrated high-grade budding in the invasive front. The 5-year survival rate of patients with low-grade budding tumors was 49%, compared with 17% for those with high-grade budding (P < .001). Budding correlated inversely with good response, which was observed in 44 (60%) of 74 patients. Univariate analysis showed that pathologic tumor depth, number of lymph node metastases, pathologic stage, lymphatic invasion, budding and clinical response were significant prognostic factors. Multivariate analysis identified budding as the most important prognostic factor followed by number of lymph node metastases. CONCLUSIONS: The results of the current study indicated that tumor budding in the invasive front of tumors correlated significantly with clinical response and prognosis of patients with esophageal squamous cell carcinomas who received neoadjuvant chemotherapy. However, the mechanism of tumor budding in the invasion front of esophageal squamous cell carcinomas treated with chemotherapy was not clarified.

[omega-3 Fatty acid-containing diet (Racol) reduces toxicity of chemoradiation therapy for patients with esophageal cancer].

Recently, it is reported that a omega-3 fatty acid-containing diet (Racol) enhances innate immunity and reduces mucosal damage in the small intestine during chemotherapy. The aim of this study is to examine the effects of a omega-3 fatty acid-containing diet (Racol) on the toxicity of chemoradiation therapy (CRT) for patients with esophageal cancers. Toxicity of CRT was evaluated in 10 patients who took Rakol at a maximum dose of 600 mL/day during CRT, compared with 10 patients who did not take Rakol. Regarding blood toxicity, the decrease of platelets did not differ between the former and the latter. However, the incidence of grade 2~4 neutropenia was lower in the former than in the latter (p=0.0043). With regard to gastrointestinal toxicity, the incidence of grade 2~4 diarrhea was also lower in the former than in the latter (p=0.0118). Moreover, the incidence of grade 2~4 stomatitis/pharyngitis tended to decrease in patients who took Rakol compared with those who did not (p=0.0812). The current results indicated that a omega-3 fatty acid-containing diet (Racol) may be beneficial to patients with esophageal cancers who receive CRT by reducing CRT toxicity.

The effect of neoadjuvant chemotherapy on lymph node micrometastases in squamous cell carcinomas of the thoracic esophagus.

BACKGROUND: Neoadjuvant chemotherapy (NACT) has been postulated but not yet proven to eradicate micrometastases and improve the prognosis of patients with advanced esophageal squamous cell carcinomas (ESCC). Cytokeratin immunohistochemistry of the lymph nodes of ESCC revealed immunohistochemical micrometastases (IHM) and cytokeratin deposits (CD), which are hyalinized denucleated particles considered to be cadavers of carcinoma cells. Successful chemotherapy should convert cancer cells from IHM to CD and improve the status of ESCC patients from systemic disease to regional disease. METHODS: Cytokeratin immunostaining of surgically removed lymph nodes was performed for 107 patients with node-positive ESCC, including 32 patients without preoperative treatment (Surgery group) and 75 patients undergoing NACT using CDDP, doxorubicin hydrochroride, and 5-fluorouracil (NACT group). Cytokeratin-positive staining was done for serial hematoxylin-eosin-stained sections and classified as pathologic metastasis, IHM, or CD. RESULTS: CD was observed less frequently in the Surgery group than in the NACT group (6% vs 43%, P < .0001), whereas IHM was more frequent in the former (47% vs 24%, P = .019). IHM was a poor prognostic factor in both groups, whereas CD was a favorable one in the NACT group. The effect of chemotherapy on IHM was classified as eradicated, IHM(-)/CD(+); persistent, IHM(+)/CD(+); no effect, IHM(+)/CD(-); or not informative, IHM(-)/CD(-). This classification correlated well with the clinical response of the primary neoplasm, number of pathologic metastases, and postoperative survival (3-year survival rates: 78%, 18%, 0%, and 38%). IHM/CD was found to be an independent prognostic factor together with the number of pathologic metastases in the multivariate analysis. CONCLUSIONS: Disappearance of IHM and the emergence of CD suggest the eradication of micrometastases by NACT. The clinical benefit of NACT was apparent for IHM(-)/CD(+) patients with node-positive ESCC.