Prevention and management of diarrhea associated with naldemedine among patients receiving opioids: a retrospective cohort study.

BACKGROUND: Naldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied. METHODS: We conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group. RESULTS: Among 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p < 0.001), but remained stable after early naldemedine administration (median 1.00 to 1.00, p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives. CONCLUSIONS: The early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

Skeletal muscle loss and prognosis of breast cancer patients.

PURPOSE: The aim of this study was to clarify the changes in the cross-sectional area of skeletal muscle and muscle attenuation (MA) during 12-month period before death in breast cancer patients. METHODS: Breast cancer patients who received treatment between September 2002 and July 2014 at Shizuoka Cancer Center or between December 2005 and July 2014 at Teikyo University Hospital were identified. Computed tomography (CT) scans during the 12-month period before death of consecutive female patients who died of breast cancer were reviewed. Skeletal muscle quantity and quality were evaluated by a cross-sectional area of skeletal muscle and MA, respectively, on CT scans taken 10-12 months (T1), 7-9 months (T2), 4-6 months (T3), and within 3 months (T4) prior to death. Wilcoxon signed rank test was used to compare the differences between the two-time points with Bonferroni correction (p = 0.0083). RESULTS: The medical records of 99 patients (median age at death, 57 years; range, 40-83 years) were retrospectively analyzed. Both the cross-sectional area and MA continued to decrease during 12-month period before death. Statistically significant differences were observed in the cross-sectional areas between T1 and T4 (p = 0.0011), T2 and T4 (p = 0.0019), and T3 and T4 (p = 0.0026), as well as in MA between T2 and T4 (p = 0.0012) and T3 and T4 (p = 0.0061). CONCLUSIONS: These results suggest that both quantity and quality of the skeletal muscle continued to decrease during 12-month period before death in breast cancer patients.

[Assessment and Strategy for Nociceptive Pain in Cancer].

Pain is classified as either nociceptive pain, which results from a nociceptor stimulation, or neuropathic pain, which results from a lesion of the neural pathway. Clinically, in many cases, pain consists of a single origin but multiple origins are also possible. In this paper, we outline an assessment and strategy for nociceptive pain in cancer. The onset time, location, feature, strength, and etiology were included as categories for the assessment of pain. Furthermore, we added a psychosocial assessment to the physical assessment, which ensured comprehensive pain evaluation. We performed the investigation according to the WHO method for cancer pain relief. According to the effects and adverse effects, we chose a non-opioid analgesic and an opioid analgesic as medications. However, nonpharmacological therapy, such as radiotherapy and nerve block, is not a concern with the WHO analgesic ladder. It is important that a multi-disciplinary team, which includes physicians, nurses, physiotherapists, and pharmacists, support the patients to manage their pain by themselves through the knowledge of the factors affecting their pain and the medication methods for easing it when it gets worse. Although we cannot ease pain completely, it is important to define the goal of treatment with patients and to examine the strategy for maximum pain relief.

[A Case of Early Anal Canal Cancer with Pagetoid Spread with Different Antitumor Effects of Chemotherapy on Different Metastatic Sites].

A 78-year-old man visited our hospital with a prolapsed hemorrhoid. He was referred to the dermatology unit due to the thickness and redness of the perianal skin. He was diagnosed as having extra mammary Paget's disease by skin biopsy. After a biopsy of the anal polyp was performed to investigate the primary site, he was diagnosed with early anal canal cancer with Pagetoid spread and underwent a radical operation. Abdominoperineal resection with skin(D2 prx D3 lymphadenectomy) was performed with perineal reconstruction using a gracilis muscle graft. Postoperative surveillance without adjuvant therapy was performed because the pathological stage was stage I. Two years and 2 months after surgery, multiple liver metastases were found, and the patient was diagnosed with multiple liver, bone, and lymph node metastases(K-ras and UGT1A1 wild type)on PET. XELOX plus bevacizumab was used as first-line treatment and the liver metastases showed remarkable shrinkage; however, disease progression occurred in the bone. IRIS plus bevacizumab was started as second-line therapy but grade 3 hematotoxicity was observed during the first course. After 4 courses, it was difficult to maintain the therapy due to toxicity and cancer-related pain. The liver metastases had almost disappeared but the patient died 11 months after the initiation of chemotherapy.

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.

Hepatic Arterial Infusion Chemotherapy for Life Threatening Patients due to Liver Metastases from Colorectal Cancer with Cetuximab.

BACKGROUND/AIMS: This retrospective report evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) for life threatening patients with unresectable hepatic metastases. METHODOLOGY: Seven life threatening patients with hepatic metastases who were treated with HAIC up to September 2011 were retrospectively analyzed. As HAIC regimen, 5-FU (1000mg/m2) was administered weekly via continuous 5-hour infusion using a continuous-infusion device. After improvement of liver dysfunction, cetuximab was administered simultaneously by the same dose of single administration. Treatment was repeated weekly until progression of hepatic lesion or discontinuity by unacceptable toxicity or patients' proposal. RESULTS: In 5 patients with hepatic metastasis related complaints, 3 patients improved after the initiation of HAIC. Three out of 4 patients with PS 2 or 3 were improved by the initiation of HAIC. The median OS was 9.5 months. No severe adverse toxicities and no treatment death related to HAIC were observed. The most severe non-hematologic adverse events were ALP in 3 patients, transaminase and bilirubin in 1 patient with grade 3. CONCLUSION: HAIC may be considered to perform when the hepatic metastases progress as life threatening status even though those are refractory to standard systemic chemotherapy.

Usefulness of the Palliative Prognostic Index in Predicting Prognosis when Considering the Transition from Hospital to Home Care in Patients with Terminal Stage Cancer.

BACKGROUND: No accurate prognostic tool is available for patients with cancer who spend their final days at home. In this study, we examined whether performance status (PS) and the palliative prognostic index (PPI), a well-known prognostic tool in palliative care units, could be used to predict prognosis in the home care setting at the time of intervention by home physicians. SUBJECTS AND METHODS: Using medical records, we conducted a retrospective analysis of 132 patients who were referred to the Home Clinic Naginoki for home care for terminal stages of carcinoma in situ. Based on the status at the time of the first visit, the PPI-Low group was defined as those scoring six or below and the PPI-High group as those scoring greater than six. RESULTS: The PPI-high group had a significantly poorer prognosis within 21 days than the PPI-low group (21-day-OS; Low 71.4% vs. High 13.2%; p<0.001). The Eastern Cooperative Oncology Group (ECOG) PS alone predicted better prognosis in the group with PS of one or two (21-day survival 90.1%), and the PPI score further significantly stratified the prognosis for patients with PS three or four, with a trend toward poor prognosis (p ≤ 0.005). CONCLUSION: ECOG PS 1 or 2 has a favorable prognosis and that using PPI in ECOG PS 3 or 4 leads to a more accurate prognosis prediction. PPI evaluated during the hospital-based treatment of patients with terminal cancer can also be used to predict prognosis if the patient is transitioned to a home care environment.

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.

[Assessment of host status in patients treated with mFOLFOX6 adjuvant chemotherapy after colorectal cancer surgery].

BACKGROUND: We examined the association of the physical, nutritional, and immune status with adverse events in patients treated with mFOLFOX6 adjuvant chemotherapy after colorectal cancer surgery. METHOD: This study included 17 patients, 7 male and 10 female. The median age was 62( range, 32-75) years. The median number of treatment cycles was 12 (range, 4-12). Age, performance status( PS), body mass index( BMI),serum albumin level( Alb),Onodera's prognostic nutritional index( PNI), controlling nutritional status( CONUT),Glasgow prognostic score( GPS),the granulocyte/lymphocyte ratio( G/L),neutrophil count, and the total lymphocyte count( TLC) were evaluated with regard to the nutrition and immunity status of the host before chemotherapy. The incidents of toxicity of greater than Grade 2 severity, excluding gastrointestinal events or gastrointestinal toxicities, were analyzed to determine the correlation with host status. RESULT: Any toxicities and toxicities without digestive symptoms were observed in 11 patients( 64.7%),and the number of incidents was significantly increased in patients with a PNI of <45. Gastrointestinal toxicities were observed in 4 patients (23.5%), but there were no significant correlations with any of the factors investigated. CONCLUSION: Toxicities are observed to a greater extent in patients with a PNI of <45 during adjuvant chemotherapy. These findings suggest that nutritional support may be required to safely administer mFOLFOX6 adjuvant chemotherapy.

[Two cases of locally advanced colorectal cancer curatively resected after neoadjuvant chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin plus panitumumab].

Case1: A 63-year-old woman with diarrhea and hematochezia was diagnosed as having rectal cancer invading the pelvis. Six courses of the 5-fluorouracil, leucovorin, and oxaliplatin( mFOLFOX6) plus panitumumab regimen were administered after sigmoid colostomy, following which low anterior resection was performed. Since the 6 courses of mFOLFOX6 were administered postoperatively, no evidence of recurrence has been observed for 18 months. Case2: A 52-year-old man with high fever and abdominal pain was diagnosed as having rectal cancer invading the bladder with a vesicorectal fistula. After transverse colostomy and 6 courses of mFOLFOX6 plus panitumumab, high anterior resection with partial cystectomy was performed. Since the 8 courses of capecitabine plus oxaliplatin (XELOX) were administered postoperatively, no evidence of recurrence has been observed for 12 months. Although no consensus has been reached pertaining to the use of neoadjuvant chemotherapy for the treatment of colorectal cancer, we could, in this study, demonstrate the efficacy of neoadjuvant chemotherapy with panitumumab for the treatment of locally advanced colorectal cancer.

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.

[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.

[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.

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.

[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 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.

[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.