Survival impact of occult liver metastasis and peritoneal dissemination compared with radiologically defined distant organ metastasis in pancreatic ductal adenocarcinoma.

BACKGROUND: Characteristics and prognoses of patients with occult metastases (OM) of pancreatic ductal adenocarcinoma (PDAC) compared with radiologically defined metastases (RM) have been rarely reported. OBJECTIVE: We aimed to clarify the prognosis of OM compared with RM and to establish a treatment strategy for PDAC patients with OM. METHODS: This single-institution, retrospective study evaluated patients with unresectable PDAC between 2008 and 2018. OM was defined as abdominal metastasis that was detected by staging laparoscopy or open laparotomy but not in the initial assessment of radiological images. RESULTS: OM and RM were identified in 135 and 112 patients, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS), neutrophil to lymphocyte ratio (NLR), tumor diameter, and rate of local unresectability were significantly lower in the OM group. Median overall survival (OS) of OM was significantly better than that of RM (13.0 vs 8.9 months, p < 0.001). In multivariate analysis of OS, ECOG PS ≥ 1 (HR 1.64, p = 0.009), NLR ≥5 (HR 1.97, p = 0.004), carbohydrate antigen (CA) 19-9 ≥1000 (HR 1.68, p = 0.001), tumor diameter ≥40 mm (HR 1.40, p = 0.027), conversion surgery (HR 0.12, p < 0.001), and multiple lines of chemotherapy (HR 0.38, p < 0.001) were independent predictors. However, type of metastasis (OM vs RM) not an independent predictor (HR 1.10, p = 0.590). CONCLUSION: The prognosis of PDAC with OM was relatively better than that with RM, but general and nutritional statuses, primary tumor size and CA19-9, conversion surgery and multiple lines of chemotherapy were independent predictors but not tumor burden.

High tumor budding predicts a poor prognosis in resected duodenal adenocarcinoma.

PURPOSE: Tumor budding is a histological characteristic defined as the presence of small clusters of cancer cells at the invasion front. Its significance in duodenal adenocarcinoma (DA) has not been fully described. METHODS: A single-center, retrospective study was conducted. Patients who underwent curative surgery for histologically diagnosed DA from January 2006 to December 2018 at Kansai Medical University Hospital were included. Tumor budding was counted per 0.785 mm2 and classified as low (0-4 buds), intermediate (5-9 buds), or high (≥ 10 buds). RESULTS: In total, 47 patients were included. The 5-year overall survival and relapse-free survival rates were 77% and 72%, respectively. High tumor budding was seen in 15 patients (32%). Excluding patients with superficial type (pT1) DA (n = 22), high tumor budding [hazard ratio (HR) 13.4, p = 0.028], regional lymph node metastasis (HR 19.9, p = 0.039), and adjuvant chemotherapy (HR 0.056, p = 0.036) were independent factors related to the overall survival in multivariate analyses. Distant metastases occurred significantly more often in patients who had high tumor budding than in others (p = 0.039). CONCLUSION: The data suggest that high tumor budding is a predictor of a poor prognosis in resected DA.

Does direct invasion of peripancreatic lymph nodes impact survival in patients with pancreatic ductal adenocarcinoma? A retrospective dual-center study.

BACKGROUND: Pancreatic ductal adenocarcinoma can directly invade the peripancreatic lymph nodes; however, the significance of direct lymph node invasion is controversial, and it is currently classified as lymph node metastasis. This study aimed to identify the impact of direct invasion of peripancreatic lymph nodes on survival in patients with pancreatic ductal adenocarcinoma. METHODS: A total of 411 patients with resectable/borderline resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection at two high-volume centers from 2006 to 2016 were evaluated retrospectively. RESULTS: Sixty (14.6%) patients had direct invasion of the peripancreatic lymph nodes without isolated lymph node metastasis (N-direct group), 189 (46.0%) had isolated lymph node metastasis (N-met group), and 162 (39.4%) had neither direct invasion nor isolated metastasis (N0 group). There was no significant difference in median overall survival between the N-direct group (35.0 months) and the N0 group (45.6 month) (p = 0.409), but survival was significantly longer in the N-direct compared with the N-met group (25.0 months) (p = 0.003). Similarly, median disease-free survival was similar in the N-direct (21.0 months) and N0 groups (22.7 months) (p = 0.151), but was significantly longer in the N-direct compared with the N-met group (14.0 months) (p < 0.001). Multivariate analysis identified resectability, adjuvant chemotherapy, and isolated lymph node metastasis as independent predictors of overall survival. However, direct lymph node invasion was not a predictor of survival. CONCLUSION: Direct invasion of the peripancreatic lymph nodes had no effect on survival in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma, and should therefore not be classified as lymph node metastasis.

Para-sacral approach followed by laparoscopic low anterior resection of a gastrointestinal stromal tumour at the anterior wall of the lower rectum.

AIM: We present a para-sacral approach followed by a laparoscopic low anterior resection of gastrointestinal stromal tumours located between the urethra and the low rectum. METHOD: Case 1 is a 56-year-old male patient whose tumour (37 × 28 mm) was located 3.0 cm above the anal verge between the anterior wall of the rectum and the urethra; he underwent surgery after 14 months' administration of imatinib mesylate (400 mg/day). Case 2 is a 68-year-old male patient who presented with dysuria; a tumour (89 × 84 mm) was detected between the urethra and the anterior wall of the low rectum by MRI. He underwent surgery after 5 months' administration of imatinib mesylate (400 mg/day). In order to perform sphincter-preserving surgery and avoid injury not only to the tumour capsule but also to the urethra, a para-sacral approach followed by laparoscopic low anterior resection was adopted in these patients. Restoration of bowel continuity was done by coloanal anastomosis in case 1 and the double stapling technique in case 2. The postoperative course of the patients was uneventful. In case 2, tumour dissection from the urethra caused injury to the posterior wall of the urethra, which could be repaired easily under direct vision. The urethral catheter was removed after 117 postoperative days, and the diverting stoma was closed after 143 postoperative days. CONCLUSION: The para-sacral approach followed by a laparoscopic low anterior resection of an extraluminal gastrointestinal stromal tumour located between the urethra and anterior wall of the low rectum enables R0 resection of the tumour and an appropriate reconstruction of the rectum.

Nutritional impact of active hexose-correlated compound for patients with resectable or borderline-resectable pancreatic cancer treated with neoadjuvant therapy.

Active hexose-correlated compound (AHCC) is a standardized extract from cultured Lentinula edodes mycelia, used as a potent biological response modifier in cancer treatment. We evaluated the nutritional effect of AHCC, given during neoadjuvant therapy, to patients with pancreatic ductal adenocarcinoma (PDAC). Thirty patients with resectable or borderline-resectable PDAC received neoadjuvant therapy with gemcitabine plus S-1. We compared, retrospectively, the outcomes of 15 patients who received AHCC combined with neoadjuvant therapy with those of 15 patients who did not receive AHCC combined with neoadjuvant therapy. The median changes of the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) were significantly better in the AHCC group. The relative dose intensity of neoadjuvant therapy was also significantly higher in the AHCC group. Thus, AHCC may improve the nutritional status during neoadjuvant therapy of patients with pancreatic ductal adenocarcinoma. To validate these results and examine the long-term impact of AHCC, a prospective phase II study for PDAC is ongoing.

[A Case of Recurrent Gastric Cancer with Durable Complete Response after Short-Term Nivolumab Therapy].

We report the case of a patient with recurrent gastric cancer that showed a complete response(CR)after short-term nivolumab administration. A 76-year-old woman was diagnosed with unresectable advanced gastric cancer(T4b, N+, M0, cStage ⅣA). The patient was administered 7 courses of SOX. Since the primary lesion was reduced significantly after the chemotherapy, radical gastrectomy was performed. Although postoperative adjuvant chemotherapy with weekly nab-PTX was performed, cancer recurrence occurred in the abdominal cavity, and another surgery was performed. However, complete resection was difficult to achieve. Postoperatively, chemotherapy was continued; however, CEA levels increased, and thus RAM+PTX was administered as second-line treatment. Stable disease was maintained for a while; however, disease progression occurred eventually. Thus, RAM+PTX was discontinued after 8 courses, and nivolumab was administered as the third-line treatment. However, due to the rapid deterioration of renal function, nivolumab could not be continued after 3 courses. After nivolumab discontinuation, CEA levels normalized and the image showed CR. Approximately 1.5 years have passed since then, with no report of recurrence without any treatment. Although nivolumab has been shown to be useful as a third-line treatment for unresectable advanced/recurrent gastric cancer, there are few reports demonstrating CR and none showing maintenance of CR after short-term nivolumab administration. Moreover, the rationale of continuing nivolumab is unclear once clinical CR is achieved. Our experience shows the feasibility of discontinuation of short-term nivolumab if CR is achieved.

Bile Duct Stones Predict a Requirement for Cholecystectomy in Older Patients.

BACKGROUND: The requirement for elective cholecystectomy in older patients is unclear. To determine predictors for requiring elective cholecystectomy in older patients, a prospective cohort study was performed. METHODS: All patients with gallstone disease who presented to our department from 2006 to 2018 were included if they met the following criteria: (1) age 75 years or older, (2) presentation for elective cholecystectomy, and (3) preoperative diagnosis of cholecystolithiasis. Two therapeutic options, elective surgery and a wait-and-see approach, were offered at their initial visit. Enrolled patients were assigned to one arm of the study according to their choice of the therapeutic options. The primary endpoint was the incidence of gallstone-related complications. The endpoint was compared between patients who underwent cholecystectomy (CH group) and those who chose a wait-and-see approach (No-CH group). RESULTS: During the study period, there were 344 patients in the CH group and 161 in the No-CH group. Among patients with a history of bile duct stones, the incidence of gallstone-related complications in the No-CH group was significantly higher (45% within 3 years, including two gallstone-related deaths) than that in the CH group (RR 2.66, 95% confidence interval 1.50-4.77, p = 0.0009). Among patients with no history of bile duct stones, the incidence of gallstone-related complications in the No-CH group reached only 10% over the 12 years. CONCLUSION: Cholecystectomy is recommended for older patients with both histories of cholecystolithiasis and bile duct stones, whereas a wait-and-see approach is preferable for patients with no bile duct stone history. A history of bile duct stones is a good predictor for cholecystectomy in older patients.

The past, present, and future status of multimodality treatment for resectable/borderline resectable pancreatic ductal adenocarcinoma.

A multimodal approach to treating pancreatic ductal adenocarcinoma (PDAC) is now widely accepted. Improvements in radiological assessment have enabled us to define resectability in detail. Multimodality treatment is essential for patients, especially for those with PDAC in the borderline resectable (BR) stage. Even for disease in a resectable (R) stage, adjuvant and neoadjuvant therapies have demonstrated beneficial outcomes in several trials and analyses. Thus, there is growing interest in optimization of the perioperative therapeutic strategy. We discuss the transition of resectability criteria and the global standard of adjuvant and neoadjuvant treatments for patients with R/BR-PDAC.

Surgical treatment of metastatic pancreatic ductal adenocarcinoma: A review of current literature.

BACKGROUND: There is no international consensus concerning the role of surgical treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC), but favorable prognoses can be expected for highly selected patients. METHODS: A comprehensive literature search of the PubMed and Cochrane databases was conducted using combinations of keywords to 4 July 2018. Eligible studies were those reporting on patients with histologically confirmed mPDAC undergoing surgery with curative intent. We excluded case reports with fewer than five patients, insufficient descriptions of survival data, and palliative or cytoreductive surgery as well as studies that assessed para-aortic lymph node metastasis or peritoneal washing cytology. RESULTS: Thirteen studies were deemed eligible, and six studies were identified from their references. The studies involved 428 patients who underwent surgical resection for liver metastases (n = 343), lung metastases (n = 57), and peritoneal dissemination (n = 28). Median overall survival (OS) in patients with synchronous liver metastases who underwent conversion surgery following favorable response to initial chemotherapy was 27 or 34 months, and peritoneum metastases was 28 months. Median OS after the initial treatment was varied from 51 to 121 months in metachronous lung metastasis and from 24 to 40 months in metachronous liver metastasis, respectively. CONCLUSION: Encouraging OS was indicated in patients with synchronous mPDAC of liver and peritoneum who underwent conversion surgery. Metastasectomy for metachronous lung and liver oligometastases could be considered a practical treatment option.

Active Hexose Correlated Compound Has Protective Effects in Ischemia-Reperfusion Injury of the Rat Small Intestine.

BACKGROUND: Ischemia-reperfusion (IR) injury of the small intestine is a serious problem in abdominal aortic aneurysm surgery or small intestine transplantation. Active hexose correlated compound (AHCC) is a popular anti-inflammatory drug in complementary and alternative medicine. The aim of this study was to examine whether pretreatment with AHCC reduces intestinal IR injury. METHODS: Rats were given a normal diet (IR group) or normal diet supplemented with 2% AHCC (IR + AHCC group) ad libitum for 10 d. After 1 d of fasting, the superior mesenteric artery was occluded by clipping for 45 min. Intestinal and blood samples were collected for 1-6 h after reperfusion. The messenger RNA (mRNA) and protein levels of inflammatory factors were analyzed. RESULTS: The IR + AHCC group had reduced mucosal abrasion and significantly increased mucosal thickness of the intestinal tissues 6 h after reperfusion, compared with the IR group. AHCC decreased mRNA expression of inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant 1 and interleukin 6 in the mucosa of the small intestine. AHCC also decreased expression of iNOS protein. Serum levels of cytokine-induced neutrophil chemoattractant 1 and tumor necrosis factor α were decreased in the IR + AHCC group compared with the IR group. Electrophoretic mobility shift assay of mucosal nuclear extracts revealed that AHCC inhibited the activation of nuclear factor kappa B. AHCC also inhibited the expression of iNOS antisense transcript, which stabilizes iNOS mRNA. CONCLUSIONS: Our findings suggest that AHCC reduces expression of inflammatory mediators, in part, by inhibiting nuclear factor kappa B activation. AHCC may have anti-inflammatory effect in patients with intestinal IR injury.

Loss of skeletal muscle mass in patients with chronic liver disease is related to decrease in bone mineral density and exercise tolerance.

AIM: This study aimed to identify the relationship between loss of skeletal muscle mass and clinical factors such as osteoporosis in patients with chronic liver disease. METHODS: The subjects were 112 patients (85 men and 27 women) with hepatocellular carcinoma who were scheduled to undergo hepatectomy. Skeletal muscle reduction was diagnosed according to the cut-off level of the skeletal mass index (SMI) for Asians (men <7.0 kg/m2 , women <5.4 kg/m2 ). Osteoporosis was diagnosed according to T-score ≤-2.5 standard deviation. The SMI and T-score were assessed using the results of dual-energy X-ray absorption. Peak oxygen consumption (PeakVO2 ), an index of exercise tolerance, was evaluated using the cardiopulmonary exercise test. The characteristics of patients with low SMI (low SMI group) were compared with those of patients whose SMI was not low (control group). Outcomes are presented as median (interquartile range). RESULTS: The T-score was significantly lower in the low SMI group (control vs. low SMI -1.1 [1.8] vs. -1.6 [1.9], P = 0.049). T-score positively correlated with SMI (r = 0.409, P < 0.0001). PeakVO2 was significantly decreased in the low SMI group (17.7 [6.3] vs. 14.4 [4.5], P = 0.006). In multivariate logistic regression analysis, T-score (odds ratio [OR], 3.508; 95% confidence interval [CI], 1.074-11.456; P = 0.038) and PeakVO2 (OR, 3.512; 95% CI, 1.114-11.066; P = 0.032) were significantly related to SMI, independent of age and sex. CONCLUSIONS: Skeletal muscle reduction in chronic liver disease is closely related to exercise tolerance and osteoporosis, and these factors are believed to be associated with physical inactivity in daily life.

Phase I Study of Sorafenib in Combination with Intermittent Hepatic Arterial Infusion Chemotherapy for Unresectable Hepatocellular Carcinoma.

OBJECTIVES: We conducted a phase I study of sorafenib and intermittent hepatic arterial infusion chemotherapy using cisplatin for unresectable hepatocellular carcinoma. METHODS: Sorafenib was administered continuously, whereas cisplatin was administered once every 3 weeks. We estimated the safety and efficacy. RESULTS: Fifteen patients were enrolled into this study. The dose-limiting toxicities occurred at sorafenib 800 mg and cisplatin 20 mg/m2. The recommended dose was at sorafenib 400 mg and cisplatin 30 mg/m2. The disease control rate was 73.3%. CONCLUSIONS: This treatment is feasible for unresectable hepatocellular carcinoma. Further evaluation of the regimen in a randomized controlled trial is warranted.

Influence of Rictor and Raptor Expression of mTOR Signaling on Long-Term Outcomes of Patients with Hepatocellular Carcinoma.

BACKGROUND: Aberrant signaling mediated by the mammalian target of rapamycin (mTOR) occurs at high frequency in hepatocellular carcinoma (HCC), indicating that mTOR is a candidate for targeted therapy. mTOR forms two complexes called mTORC1 (mTOR complexed with raptor) and mTORC2 (mTOR complexed with rictor). There are minor studies of the expression kinetics of mTORC1 and mTORC2 in HCC. METHODS: We studied 62 patients with HCC who underwent curative resection. We used univariate and multivariate analyses to identify factors that potentially influence disease and overall survival after hepatectomy. The mRNA and protein levels of mTOR, rictor and raptor in cancer and non-cancer tissues were analyzed using quantitative RT-PCR, immunohistochemistry and Western blotting. RESULTS/CONCLUSION: High ratio of the levels of rictor and raptor mRNAs in tumors was identified as independent prognostic indicators for disease-free survival. Low and high levels of preoperative serum albumin and mTOR mRNA in the tumor, respectively, were identified as independent indicators of overall survival. HCC is likely to recur early after hepatic resection in patients with high levels of mTOR and rictor mRNAs and high rictor/raptor ratios in cancer tissues. We conclude that analysis of mTOR expression in cancer tissues represents an essential strategy to predict HCC recurrence after curative treatment.

Segmental dilatation of the intestine: results of a nationwide survey in Japan.

PURPOSE: To clarify the status of segmental dilatation of the intestine (SD) using a nationwide retrospective cohort survey. METHODS: Supported by the Ministry of Health, Labour and Welfare in Japan, preliminary questionnaires requesting the numbers of SD cases from 2000 to 2009 were sent to 161 Japanese major institutes of pediatric surgery and gastroenterology. We present the results of our analysis of the data from secondary questionnaires. RESULTS: Twenty-eight cases of SD were reported, including 19 males and 9 females. The average gestational age was 30.2 weeks and the average birth weight was 2.319 g. The period of onset was neonatal in 18 cases and infancy in 6 cases, including 7 cases diagnosed prenatally. The dilated segment was ileum in 14 cases and colon in 10 cases, and symptoms included abdominal distention, vomiting, and chronic constipation. Concurrent intestinal malformation such as malrotation, intestinal atresia, and anal atresia were present in 4 cases and 27 of 28 cases were successfully treated by surgical resection. Histologically, abnormal muscle layers were found in three cases and ectopic tissue in two cases. CONCLUSION: We determined the clinical features of SD based on data from 28 cases occurring over 10 years.

[A Case of Local Recurrence of Bile Duct Cancer Completely Responding to Chemoradiotherapy with S-1].

An 80-year-old man with common bile duct cancer was treated by pancreaticoduodenectomy with D2 lymph node dissection in October 2005. The patient presented with frequent episodes of bloody-mucous rectal discharge in July 2009. An abdominal CT demonstrated local recurrence at the hepatoduodenal ligament. We treated him with concurrent chemoradiotherapy (CRT) with single-dose S-1 chemotherapy. After 6 months, we diagnosed a complete response (CR) by follow-up CT. The patient was treated with S-1 for 3 years after the diagnosis of a CR. He is alive without disease 6 years after the diagnosis of the recurrence. Concurrent CRT with S-1 chemotherapy may be the therapy of choice for recurrence of bile duct cancer.

[OBJECTIVE ASSESSMENT OF POSTOPERATIVE PAIN AFTER DIGESTIVE TRACT SURGERY].

Pain is a sensation associated with subjective factors, making it difficult to measure and assess. Currently, there is no widely accepted method of objectively assessing pain, and therefore subjective assessments such as the Visual Analogue Scale (VAS) are generally used. The PainVision system has been developed for the quantitative analysis of pain and comparison of postoperative pain intensity. In this study, we investigated whether postoperative pain could be objectively assessed using this system in digestive tract surgery patients. Pain scores were measured with the VAS, the PainVision system, and the short-form McGill Pain Questionnaire in patients undergoing open or laparoscopic hepatectomy, open or laparoscopic gastrectomy, and laparoscopic cholecystectomy. As measured using the PainVision system, postoperative pain intensity was lower in patients who underwent laparoscopic surgery compared with open hepatectomy. In open hepatectomy patients, pain intensity measured by the PainVision system was significantly lower on postoperative days (POD) 7 and 10 than on POD 1. Preemptive use of nonsteroidal antiinflammatory drugs significantly reduced postoperative pain in open hepatectomy patients. The results showed that PainVision effectively quantifies pain intensity after digestive tract surgery. Objective assessment of postoperative pain may lead to earlier mobility and improved quality of life.

High survival in patients operated for small isolated liver metastases from gastric cancer: a multi-institutional study.

BACKGROUND: Although several studies have reported the outcomes of surgery for the treatment of liver metastases of gastric cancer (GLM), indications for liver resection for gastric metastases remain controversial. This study was designed to identify prognostic determinants that identify operable hepatic metastases from gastric cancer and to evaluate the actual targets of surgical therapy. METHODS: Retrospective analysis was performed on outcomes for 24 consecutive patients at five institutions who underwent gastrectomy for gastric cancer followed by curative hepatectomy for GLM between 2000 and June 2012. RESULTS: Overall 5-year survival and median survival were 40.1 % and 22.3 months, respectively. Uni- and multivariate analyses showed that liver metastatic tumour size less than 5 cm was the most important predictor of overall survival (OS, p = 0.03). Four patients survived >5 years. Repeat hepatectomy was performed in three patients. Two of these patients have remained disease-free since the repeat hepatectomy. CONCLUSIONS: GLM patients with metastatic tumour diameter less than 5 cm maximum are the best candidates for hepatectomy. Hepatic resection should be considered as an option for gastric cancer patients with liver metastases.

[A novel technique of laparoscopic hepatectomy].

We report a novel technique of laparoscopic hepatectomy (lap-HT) performed at our hospital and the outcomes.Lap -HT was performed in 90 cases at our hospital, including 38 cases of anatomical resection of the liver.After mobilization of the right lobe with the patient in the half-lateral position, we resected the liver tissue using cavitron ultrasonic surgical aspirator (CUSA) and AquamantysTM Bipolar®.This surgical instrument is useful for laparoscopic anatomical resection of the liver because it is based on vessel sealing technology.In the 90 cases in which lap-HT was performed, the mean duration of surgery and mean blood loss were 332.9 minutes and 381 mL, respectively. The mean duration of hospitalization after surgery was 12.1 days, and postoperative complications were noted in 5 cases(5.6%). Comparison of the clinical factors and short-term performance of the surgery between liver cirrhosis patients who underwent open hepatectomy and lap-HT revealed that blood loss was significantly lower and the hospital stay duration was significantly shorter in patients who underwent lap-HT. Our findings suggest that laparoscopic anatomical resection of the liver can be safely performed using this novel technique and surgical instrument.

Cancer-related breathlessness: opioids other than morphine - comprehensive literature review.

INTRODUCTION: Although there is low-quality evidence, there has been an increase in publications on the experience of evaluating and managing cancer-related breathlessness using opioids other than morphine. METHODS: The author conducted a non-systematic literature review in the PubMed/Medline and Embase until 4 October 2022. Eligible studies have evaluated the efficacy of opioids other than morphine for cancer-related breathlessness. Studies focused on sedation, anaesthesia, paediatric patients, opioid toxicity or basic research were excluded. Reviews/meta-analyses and non-English language publications were also excluded. RESULTS: A total of 1556 records were identified, of which 23 studies including 469 patients who were treated with fentanyl (n=223), oxycodone (n=171) and hydromorphone (n=75) were considered eligible. Six phase II randomised clinical trials (RCTs), four observational studies and four case reports of fentanyl were found. For breathlessness on exertion, fentanyl yielded promising results, but no RCT showed significant superiority of fentanyl to placebo or morphine. For terminal breathlessness, three RCTs, five non-randomised or observational studies and one case report on oxycodone or hydromorphone were found. Although the results of the observational studies suggested that oxycodone and hydromorphone might be effective alternatives to morphine, the superiority over placebo or non-inferiority to morphine had not been demonstrated in the RCTs. CONCLUSION: As an alternative to morphine, the author recommends fentanyl for breathless crisis or breathlessness on exertion, and oxycodone or hydromorphone for terminal breathlessness in advanced cancer. Larger and well-designed studies based on firm research policies are needed to confirm this current knowledge.