Clinical Guidelines for Management of Gastrointestinal Symptoms in Cancer Patients: The Japanese Society of Palliative Medicine Recommendations

Abstract

Background:

Gastrointestinal symptoms, including nausea, vomiting, bowel obstruction, ascites, constipation, and anorexia, are common and often refractory in advanced cancer patients. The palliation of gastrointestinal symptoms is important in improving the quality of life of cancer patients, as well as that of their families and caregivers. Currently published clinical guidelines for the management of gastrointestinal symptoms in cancer patients do not comprehensively cover the topics or are not based on a formal process for the development of clinical guidelines.

Methods:

The Japanese Society for Palliative Medicine (JSPM) developed comprehensive clinical guidelines for the management of gastrointestinal symptoms in cancer patients after a formal guideline development process.

Results:

This article summarizes the recommendations along with their rationale and a short summary of the development process of the JSPM gastrointestinal symptom management guidelines. We established 31 recommendations, all of which are based on the best available evidence and agreement of expert taskforce members.

Discussion:

Future clinical studies and continuous guideline updates are required to improve gastrointestinal symptom management in cancer patients.

Introduction

Gastrointestinal symptoms, including nausea, vomiting, bowel obstruction, ascites, constipation, and anorexia, are common and often refractory in patients with advanced cancer. An estimated 20–70% of patients with advanced cancer have nausea and vomiting,^1,2 10–50% have bowel obstruction,^3,4 15–50% have ascites,^5,6 40–90% have constipation,^7,8 and 6–74% have anorexia.^9,10 These symptoms distress patients and decrease their quality of life (QOL).

Several clinical guidelines for gastrointestinal symptom management in cancer patients have been published worldwide in an effort to improve symptom control.^{1,3,4,9,11–16} The Japanese Society for Palliative Medicine (JSPM) first published its Clinical Guidelines for Digestive Symptoms in Cancer Patients in 2011.¹⁷ However, the first JSPM guidelines focused only on the management of nausea, vomiting, and bowel obstruction, while the guidelines from other authorities did not cover the topics comprehensively or were not developed based on a formal scientific process. Thus, the JSPM decided to comprehensively revise the clinical guidelines for managing gastrointestinal symptoms in cancer patients using a validated methodology.

In this study, we present a short summary of the JSPM recommendations for the management of gastrointestinal symptoms in cancer patients with the rationale underlying the recommendations and their development process.

Development process

The objective of developing these clinical guidelines was to establish standard palliative interventions for gastrointestinal symptoms in cancer patients. The target patients of these guidelines are all cancer patients with gastrointestinal symptoms (nausea, vomiting, bowel obstruction, ascites, constipation, and anorexia), excluding those with symptoms induced by chemotherapy or radiotherapy, while the primary users are all health care providers who care for cancer patients, including palliative care physicians, primary care physicians, oncologists, nurses, and pharmacists. The interventions included in our recommendations are those which are available and commonly used in Japan.

Systematic literature search

First, 31 clinical questions (CQs) were developed based on the previous JSPM guidelines and a consensus meeting of taskforce members (11 palliative care physicians, 3 palliative care nurses, 2 pharmacists, and 1 epidemiologist for external evaluation). Thereafter, we performed a systematic literature search for each CQ in PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL), with searches limited to articles written in English or Japanese and published before February 2016. We searched for Japanese articles not included in PubMed or CENTRAL in the Ichushi Web of the Japan Medical Abstracts Society. The policy used to identify relevant articles based on study design was as follows: first, we selected randomized controlled trials (RCTs). If none or only one such article was identified, we extended the search to observational studies. If no relevant articles were identified, we extended the search to RCTs in noncancer patients, since it is known that high-quality research in the area of gastrointestinal symptom management in cancer patients is poor.

The primary screening process included reviewing the titles and abstracts of all articles identified from the databases to select articles potentially relevant to each CQ. All potentially relevant articles underwent a secondary screening process in which the full texts were reviewed. After the secondary screening process, we selected relevant articles to provide evidence for each CQ. Additional articles were identified from the reference lists of selected articles and major palliative care textbooks by manual searches.¹⁸ The literature search for each CQ was performed independently by two taskforce members.

Drafting recommendations and Delphi method

First, draft recommendation statements for each CQ with rationales were written by two-member taskforce teams. We did not consider the specific administration (dose, route, frequency, and time to onset) of each treatment. We used a modified Delphi method to examine the validity of each draft recommendation statement.¹⁹ In brief, the Delphi method is a structured communication technique based on bringing together a group of experts who answer questions in two or more rounds, facilitating the formation of a consensus and recommendations. Delphi rounds were conducted by 11 palliative care physicians; 1 epidemiologist for external evaluation; 4 representatives from other specialties, including an oncologist (Japanese Society of Clinical Oncology), primary care physician (Japan Primary Care Association), nurse (Japanese Society of Cancer Nursing), and pharmacist (Japanese Society for Pharmaceutical Palliative Care and Sciences); and 1 representative of a cancer patient group. The scores for validity of each question were rated on a 9-point scale by each Delphi member. If the median was 8 or more and the difference between the minimum and the maximum was 5 or less, consensus was confirmed. After Delphi rounds and an external review by five external reviewers (three palliative care specialists [JSPM physician, nurse, and pharmacist] and two oncologists [Japanese Society of Medical Oncology and Japanese Society of Gastroenterology]), the final version of the recommendation statements was approved.

Evidence and recommendation levels

We used the grading system developed by the Medical Information Network Distribution Service (Minds) to articulate the level of evidence and the strength of the recommendations following the concepts of The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system²⁰ (Table 1).

Table 1.

Recommendation Table

Strength of recommendation	Comments
1 (strong)	The benefit of the recommended treatment certainly overweighs the harm or burden. In the guideline, statements are described as “recommend.”
Strong recommendation to do (or not to do).
2 (weak)	The benefit of the recommended treatment may be closely balanced with the harm or burden. In the guideline, statements are described as “suggest.”
Weak recommendation to do (or not to do).
Level of evidence
A (high)	The evidence is established on the basis of the results of studies. Further research is very unlikely to change our confidence in the estimate of effect. For example, high-quality randomized controlled trials with concordant results or a meta-analysis of randomized controlled trials.
B (moderate)	Although some moderate-/high-quality studies support the result, evidence is not sufficient. Further research is likely to significantly impact our confidence in the estimate of effect and may change the estimate. For example, randomized controlled trials with inconsistent results, low-quality controlled trials, or high-quality observational trials with consistent results.
C (low)	Although some low-quality studies support the result, evidence is insufficient. Further research is very likely to significantly impact our confidence in the estimate of effect and is likely to change the estimate. For example, low-quality observational trials with consistent results.
D (very low)	There is insufficient or no scientific evidence for the result. Any estimate of effect is very uncertain. For example, observational trials with inconsistent results, case reports, or expert opinions

Recommendations

Management of nausea and vomiting not induced by chemotherapy or radiotherapy

Selection of antiemetic drugs

Etiology-based antiemetic management

Etiology-based antiemetic management is suggested (2D): If the nausea and vomiting are not caused by chemotherapy or radiotherapy in a cancer patient, treat the etiology and use the appropriate antiemetic drug according to etiology (Fig. 1). If the first-line drug is ineffective or the symptom is refractory to treatment, another antiemetic drug in combination or a second-line antiemetic drug is suggested (2D).

FIG. 1.

Overview of recommendations for the management of nausea/vomiting.

For this CQ, there were four observational studies but no RCTs.^2,21–23 One RCT was published after the publication of this guideline and is not reflected in the result.²⁴

Four observational studies classified disease etiology into central nervous system stimuli, motion and positional sickness, drugs and biochemical disorders, visceral stimuli, gastric stasis, and others. Depending on etiology, cyclizine, hyoscine, haloperidol, domperidone, metoclopramide, or levomepromazine was used, with an efficacy rate of 70–100%. In all studies in which the first-line drugs were ineffective, another class of antiemetic drug was used in combination with it or a second-line drug of another class was used.

There is insufficient evidence that etiology-based antiemetic management relieves nausea and vomiting in cancer patients. However, based on these observational studies, the etiology-based antiemetic approach has the potential benefit of relieving nausea and vomiting in this population. In contrast, all studies included a single arm and simultaneous treatment according to etiology; therefore, the treatment effect of an antiemetic drug alone cannot be judged. Thus, we suggest that the etiology-based antiemetic approach be used in cancer patients with nausea and vomiting.

Antiemetic drugs

Prokinetics: metoclopramide

The use of metoclopramide is suggested (2C). We found two RCTs that compared the efficacy of metoclopramide with placebo or other drugs. In 1 double-blind RCT of 26 patients with cancer-related dyspepsia that compared the efficacy of metoclopramide and placebo, metoclopramide significantly improved nausea on day 4.²⁵ In another RCT of metoclopramide, ondansetron, and placebo, no significant intergroup difference was observed in 92 cancer patients with opioid-induced nausea and vomiting.²⁶ Due to the risk of tardive dyskinesia, the U.S. Food and Drug Administration and the European Medicines Agency advise against its long-term use.

The results of these two RCTs were different, and the evidence is insufficient. In addition, extrapyramidal symptoms were caused by long-term administration. However, it was widely used in the clinical setting, and there were no severe adverse events in these trials. The taskforce members agree that metoclopramide is suggested to be used, but limited to four weeks if possible.

Prokinetics: domperidone

The usefulness of domperidone is inconclusive since we found no study regarding its effects in cancer patients with nausea and vomiting. By contrast, epidemiologic studies that did not include cancer patients showed that a domperidone dose >30 mg/day, elderly people (>60 years old), serious liver disorders or heart disease, and the concomitant drug that causes QT prolongation or CYP3A4 inhibitory action increased the risk of severe ventricular arrhythmias and sudden cardiac death.^27–29 For this reason, individual countries have different restrictions and monitoring protocols; however, in Japan, there are few restrictions, and domperidone is widely used.

Due to the lack of evidence and adverse events not being evaluated in cancer patients, no recommendation about the use of domperidone can be made.

Haloperidol

The use of haloperidol is suggested (2C). We found one observational study that evaluated the effects of haloperidol in 42 cancer patients with nausea and vomiting. Regarding the primary end point, complete response was noted in 8 patients, while a partial response was noted in 12.³⁰ Another systematic review concluded that incomplete evidence is available from published research.³¹

The evidence from previous studies is insufficient, and it is possible that adverse events were not sufficiently verified. However, it has been widely used in the clinical setting and was judged by taskforce members to have an assumed benefit that exceeds its harm. Therefore, we suggest the use of haloperidol for nausea and vomiting in cancer patients. However, since adverse events have not been sufficiently verified, the dosage and administration period should be minimized.

Anticholinergics

The use of anticholinergics (scopolamine hydrobromide) is suggested (2D). We found two observational studies that evaluated the effects of anticholinergics. Scopolamine was administered sublingually to 26 cancer patients with nausea, and the nausea score decreased significantly after 15 minutes.³² In another study, transdermal scopolamine was administered to 13 cancer patients, 11 of whom reported significant improvement.³³ Evidence is insufficient from previous studies, but based on agreement among the taskforce members, the use of scopolamine hydrobromide is suggested in cancer patients with nausea and vomiting.

Histamine H1 receptor antagonist

The use of histamine H1 receptor antagonists is suggested (2D). We found one observational study that evaluated the effects of the histamine H1 receptor antagonist promethazine in 98 cancer patients with nausea and vomiting; the mean score improved significantly.³⁴ Evidence from previous research is insufficient, but based on agreement among the taskforce members, histamine H1 receptor antagonist use is suggested for cancer patients with nausea and vomiting.

Phenothiazine antipsychotics (chlorpromazine, levomepromazine, and prochlorperazine)

The use of phenothiazine antipsychotics is suggested (2D). We found two RCTs on chlorpromazine, two observational studies on levomepromazine, and one observational study on prochlorperazine.

One RCT compared the effects of tropisetron and chlorpromazine in 160 end-stage cancer patients with nausea and vomiting. No significant intergroup difference was observed on the third day.³⁵ Similarly, no significant difference was observed in another RCT of 280 patients.³⁶ In these two trials, patients treated with chlorpromazine reported significantly improved nausea and vomiting compared to before and after administration.

In an observational study in which levomepromazine was administered to 70 cancer patients with refractory nausea and vomiting, the nausea intensity decreased significantly.³⁷ As an adverse event, 6 patients had numeric rating scale scores ≥7 for drowsiness. Similarly, another observational study on levomepromazine reported improvement in 62% of patients.³⁸

One observational study that evaluated the effects of prochlorperazine in 359 cancer patients with nausea and vomiting reported significantly improved nausea and vomiting scores.³⁴

The evidence from previous studies is insufficient, but based on agreement among the taskforce members, the use of phenothiazine antipsychotics is suggested for cancer patients with nausea and vomiting. However, attention should be paid to adverse events, including drowsiness, circulation inhibition, and extrapyramidal symptoms.

Atypical antipsychotics (perospirone, risperidone, and olanzapine)

The use of atypical antipsychotics is suggested (2D). We found three observational studies that evaluated the effects of atypical antipsychotics, showing 64–100% improvement with perospirone, risperidone, and olanzapine administered to 5–20 patients with nausea and vomiting that were refractory to first-line antiemetic drug treatment.^39–41 Although the evidence from previous studies is insufficient, based on agreement among the taskforce members, the use of atypical antipsychotics is suggested for cancer patients with nausea and vomiting that is refractory to first-line antiemetic drug treatment.

Serotonin 5HT3 receptor antagonist

The use of serotonin 5HT3 receptor antagonists is suggested for patients in whom the nausea and vomiting are refractory to first-line antiemetic drug treatment (2D). We found three RCTs that compared serotonin 5HT3 receptor antagonists with placebo or other drugs. One double-blind RCT of 92 cancer patients compared the efficacies of ondansetron, metoclopramide, and placebo for relieving nausea and vomiting. No significant intergroup differences were noted.²⁶ Two other unblinded RCTs of 160 and 280 cancer patients compared the efficacies of tropisetron and other drugs. In the two trials, patients receiving tropisetron reported significantly improved nausea and vomiting compared to controls.^35,36 In a previous study, the results were inconsistent and the evidence was insufficient, but based on agreement among taskforce members, serotonin 5HT3 receptor antagonist use is suggested for cancer patients with nausea and vomiting that is refractory to the initial treatment.

Corticosteroids

Corticosteroid use is suggested when a cancer patient's nausea and vomiting are caused by tumor-induced inflammation or cerebral edema (2C). One double-blind RCT of 84 cancer patients compared the efficacies of dexamethasone and placebo for cancer-related fatigue. The secondary endpoint of nausea improved after dexamethasone administration, but the intergroup difference was nonsignificant.⁴² Another double-blind RCT of 51 cancer patients whose symptoms were refractory to metoclopramide compared the efficacy of dexamethasone and placebo.⁴³ Although patients reported symptom improvement after dexamethasone administration, the intergroup difference was nonsignificant.

In previous studies, the therapeutic effect of corticosteroids did not differ from that of a placebo, and evidence of their efficacy was insufficient. However, since corticosteroids are considered to be effective in tumor-induced inflammation and cerebral edema by the taskforce members, the use of corticosteroids is suggested when a cancer patient's symptoms are caused by tumor-induced inflammation or cerebral edema.

Mirtazapine

The usefulness of mirtazapine is inconclusive. We found one observational study that evaluated the effects of mirtazapine. Of the 42 cancer patients diagnosed with depression with nausea or insomnia, 28 reported improvement in their nausea.⁴⁴ However, it is possible that the depression simply improved with mirtazapine, and since high-quality research is lacking, we cannot determine whether mirtazapine use should be recommended.

Management of nausea and vomiting in malignant bowel obstruction

Nasogastric tube

The use of a nasogastric tube is suggested, but limited to short periods (2D). We found no studies regarding the effects of a nasogastric tube on malignant bowel obstruction (MBO). However, it is frequently used in clinical practice, and its treatment effect has been established. In addition, its effect can be quickly and easily evaluated. In contrast, patient preference and adverse events (esophageal erosion, sore throat, sinusitis, and aspiration pneumonitis) require attention.⁴ There is insufficient evidence of whether nasogastric tube use relieves nausea and vomiting in patients with MBO. Nonetheless, based on taskforce member agreement, nasogastric tube use is suggested.

Percutaneous endoscopic gastrostomy/percutaneous transesophageal gastro-tubing

The use of percutaneous endoscopic gastrostomy (PEG) and percutaneous transesophageal gastro-tubing (PTEG) is suggested when patients have a prognosis that exceeds two months (2C). We found four observational studies of PEG and one observational study of PTEG for relieving nausea and vomiting caused by MBO. In these observational studies, the effective rate for nausea/vomiting in cases wherein the procedure could be performed was 77–97%, the incidence of infections was 8–14%, and the rate of serious complication such as death was 0.2%.^45–49 The evidence from previous studies is insufficient; however, based on agreement among the taskforce members, PEG/PTEG is suggested for nausea and vomiting due to MBO.

Corticosteroids

Corticosteroids are suggested to be used (2C). We found two RCTs that compared the efficacy of corticosteroids and placebo. One double-blind RCT of 39 cancer patients compared the efficacy of dexamethasone and placebo in MBO. However, the study was terminated because of slow accrual; moreover, comparison between the groups was not performed.⁵⁰ Another double-blind RCT of 58 MBO patients compared the efficacy of methylprednisolone and placebo. There was no significant difference between the two groups with regard to the primary end point, but corticosteroid use showed a significant improvement in patients without a nasogastric tube.⁵¹ The previous studies were small-scale RCTs, and the superiority to placebo was not clearly evident; however, based on agreement among the taskforce members, corticosteroids are suggested to be used.

Octreotide

Octreotide is suggested to be used (2C). We found six RCTs that compared the efficacy of octreotide and placebo or butylscopolamine. One double-blind RCT of 87 MBO patients compared the efficacy of octreotide and placebo. There was no significant difference in the number of days free of vomiting between groups and total number of people free of vomiting for 3 days.⁵² Another double-blind RCT of 64 MBO patients compared the efficacy of long-acting release octreotide and placebo. There were no significant intergroup differences because of insufficient recruitment and premature discontinuation.⁵³ Another double-blind RCT of 97 patients with MBO due to ovarian cancer compared the efficacies of octreotide and butylscopolamine for nausea. Octreotide showed significant improvement compared to butylscopolamine on days 2 and 3.⁵⁴ In three other small RCTs, compared to butylscopolamine, octreotide significantly reduced the number of vomiting episodes, degree of nausea, and drainage from the stomach.^55–57 The evidence from previous studies is insufficient and the evaluation methods differed among studies, but based on taskforce member agreement, the use of octreotide is suggested.

Butylscopolamine

The use of butylscopolamine is suggested (2C). We found four RCTs that compared the efficacy of butylscopolamine and octreotide. All studies were designed as control groups of octreotide and showed significant inferiority of butylscopolamine to octreotide. However, the degree of nausea and number of vomiting episodes were significantly improved.^54–57 The evidence was insufficient, but based on taskforce member agreement, the use of butylscopolamine is suggested.

Histamine H2 receptor antagonist or proton pump inhibitor

The use of a histamine H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) is suggested (2D). We found no studies regarding the effects of H2RA or PPI on nausea and vomiting in MBO patients. Using a review of seven studies of patients in the perioperative period as a reference, we found that both PPI and H2RA reduced gastric secretions and that the most superior agent is ranitidine.⁵⁸ Although only indirect evidence is currently available, the drugs are safe and widely used as a cotreatment for MBO; thus, the use of H2RA or PPI is suggested.

Antiemetic drugs

The use of antiemetic drugs is suggested (2D). We found five observational studies that evaluated the effects of antiemetic drugs against nausea and vomiting in MBO patients. Haloperidol, phenothiazine antipsychotics, olanzapine, metoclopramide, and granisetron were administered. The effective rate was 75–100%, and some agents caused drowsiness as a side effect.^59–63 Most of the previous studies could not exclude the effects of corticosteroids as cotreatment, and the evidence was insufficient. However, based on taskforce member agreement, the use of antiemetic drugs is suggested.

Management of malignant ascites

Diuretics

The use of diuretics (spironolactone and furosemide) is suggested (2D). We found three observational studies that evaluated the effects of diuretics for abdominal distension of malignant ascites. In the three trials of spironolactone, spironolactone and/or furosemide, and tolvaptan, the drugs were administered to 15, 16, and 10 patients, respectively, and their abdominal distension improved significantly. Adverse events included renal dysfunction and electrolyte abnormalities.^64–66 Previous studies were small in size and observational by design with insufficient evidence, but based on taskforce member agreement, the use of spironolactone and furosemide is suggested. Tolvaptan use requires caution because of the risk of electrolyte abnormalities and renal failure; thus, it is not recommended.

Abdominal paracentesis

The use of abdominal paracentesis is suggested. If puncture occurs frequently, the use of an indwelling peritoneal catheter should be considered (2D). We found seven observational studies that used peritoneal catheters for continuous drainage^67–73 and one on simple paracentesis using needles⁷⁴ and evaluated the effects of abdominal paracentesis for abdominal distension induced by malignant ascites. In these studies, the devices and outcome assessment methods were different, and the improvement rate of abdominal distension was 37.5–100%, which is a large difference. Evidence is insufficient despite its established effectiveness; however, based on taskforce member agreement, the use of abdominal paracentesis is suggested.

Cell-free and concentrated ascites reinfusion therapy

The usefulness of cell-free and concentrated ascites reinfusion therapy (CART) cannot be concluded. We found one observational study that evaluated the effect of CART. Although abdominal symptoms improved in this study, symptom improvement cannot be determined to be a benefit of CART treatment alone because reinfusion is performed after peritoneal puncture drainage.⁷⁵ No previous studies are of high quality, the evidence is insufficient, and practicing medical institutions are limited in Japan; thus, a recommendation of its use cannot be made.

Denver peritoneovenous shunts

The usefulness of Denver peritoneovenous shunts cannot be concluded. We found four observational studies that evaluated the effects of Denver shunts. In these studies, in 87 MBO patients, the abdominal symptom improvement rates were 67–100%. However, serious adverse events such as heart failure, pulmonary edema, and disseminated intravascular coagulation syndrome were observed in 20% of the patients.^76–79 It is possible that abdominal paracentesis is unnecessary in patients using peritoneovenous shunts, but the safety evidence is inadequate; thus, its use cannot be recommended.

Management of constipation

Osmotic laxative and stimulant laxative

The use of osmotic laxatives is recommended (1C). The use of a stimulant laxative is recommended (1C). We found one RCT and one non-RCT that compared the efficacy of osmotic, stimulant, and other laxatives.

One RCT of 75 cancer patients using opioids compared the efficacy of lactulose and senna for constipation. In the 7-day study period, the number of defecations over 72 hours was 0.9 in the lactulose group and 0.9 in the senna group, a nonsignificant intergroup difference.⁸⁰ Another non-RCT of 348 cancer patients compared the efficacies of lactulose, sodium picosulfate, and polyethylene glycol for constipation. There was a nonsignificant intergroup difference in the incidence of constipation.⁸¹ There were no significant differences in adverse events and tolerability in these two trials. Thus, the superiority and inferiority of each laxative in previous studies are unclear,⁸² but their clinical efficacies have been established and they have been widely used. Osmotic and stimulant laxatives are recommended to be used.

Lubiprostone

The use of lubiprostone is suggested (2C). We found no RCTs regarding the effects of lubiprostone for constipation in cancer patients. However, we found four RCTs that compared the efficacy of lubiprostone and placebo or senna in noncancer patients with opioid-induced constipation. Three trials compared lubiprostone to placebo in 413, 431, and 124 constipation patients, respectively, and a significantly increased spontaneous bowel movement trend was observed compared to placebo.^83–85 In one trial that compared lubiprostone with Senna use in 56 patients, a nonsignificant intergroup difference in constipation symptoms and QOL was reported.⁸⁶ Therefore, there is no research on cancer patients and only indirect evidence is available. However, similar improvement of constipation is expected in cancer patients. In contrast, considering the high cost, and taskforce member agreement, lubiprostone use is suggested only when necessary.

Peripherally acting μ-opioid receptor antagonists

Peripherally acting μ-opioid receptor antagonists were excluded because they were not available in Japan at the time of the systematic literature search.

Management of anorexia not induced by chemotherapy or radiotherapy

Corticosteroids

The use of corticosteroids is recommended (1B). We found six RCTs that compared the efficacy of corticosteroids and placebo for cancer-related anorexia. One double-blind RCT of 50 cancer patients compared the efficacy of methylprednisolone and placebo and demonstrated that the anorexia on day 7 improved significantly compared with placebo.⁸⁷ Although evaluation methods and periods differed, four of the other five studies also showed significant improvement,^88–91 and there was no significant difference in only one trial.⁴³

The available evidence is almost consistent and shows a significant improvement in anorexia in cancer patients with corticosteroid use compared to placebo. Corticosteroid use is recommended. However, careful attention is necessary because efficacy and safety in patients with long-term administration or poor general condition have not been sufficiently evaluated.

Metoclopramide

The use of metoclopramide is suggested (2D). We found one RCT that compared the efficacy of metoclopramide and placebo and two observational studies. One double-blind RCT of 26 cancer patients with cancer-related dyspepsia compared the efficacy of metoclopramide and placebo. The nausea on day 4 improved significantly compared with the effect of placebo, but there was no difference in anorexia.²⁵ In one observational study, although nausea improved, there was no improvement in anorexia.⁹² In another observational study, appetite improved in 65% of patients after usage.⁹³ Thus, the evidence is insufficient, but based on agreement among the taskforce members, metoclopramide is suggested to be used.

Rikkunshito, a Japanese herbal medicine

The usefulness of rikkunshito is inconclusive. We found no studies regarding the effects of rikkunshito for anorexia in cancer patients. One observational study evaluated rikkunshito in gastric cancer patients after gastrectomy. Although this study showed an improvement in appetite, the pathophysiology differs from that of cancer-bearing patients with anorexia.⁹⁴ Thus, the evidence is insufficient to make a recommendation.

Eicosapentaenoic acid

Eicosapentaenoic acid (EPA) is suggested not to be used (2B). We found one RCT that compared the efficacy of EPA and placebo. In a study comparing the effects of EPA and placebo on anorexia in 518 cancer patients with weight loss, no significant differences were observed.⁹⁵ In a review that included patients currently receiving chemotherapy, no significant differences from placebo were noted in terms of anorexia.⁹⁶ Therefore, EPA has not been shown to improve anorexia compared to placebo, and with concordance between the results of multiple high-quality studies, EPA is not suggested for use.

Progestogen

The use of progestogen is suggested (2B). We found five RCTs that excluded patients currently receiving chemotherapy, one RCT, one systematic review that included patients receiving chemotherapy on the effect of megestrol (MA; not available in Japan), and four RCTs, including chemotherapy, regarding the effect of medroxyprogesterone acetate.

In the five studies of MA, 240–480 mg significantly improved anorexia compared to placebo, and all the studies provided consistent results. Serious adverse events did not differ between groups.^97–101 In a study comparing MA, dexamethasone, and fluoxymesterone, MA and dexamethasone improved appetite more significantly than fluoxymesterone.¹⁰² In a systematic review, including patients currently receiving chemotherapy, the relative ratio of efficacy compared to placebo was 2.57 (95% confidence interval 1.48–4.49); the risk of pulmonary embolism has been shown to increase in the case of higher doses (800 mg).¹⁰³ Three of the four trials on medroxyprogesterone acetate showed significant improvement in anorexia.^104–107

Available evidence indicates significant improvement of anorexia in cancer patients by progestogen, but in Japan, it has been approved only for breast cancer and endometrial cancer, and its use for other cancers is lacking.

Discussion

To the best of our knowledge, this is the first set of published clinical guidelines for the management of gastrointestinal symptoms in cancer patients that has been established following a formal guideline development process (Table 2). The recommendations of the JSPM gastrointestinal symptom guidelines presented in this study are based on the combination of the best available evidence and expert consensus. It is difficult to conduct high-quality clinical research of symptom control in advanced cancer patients because of the vulnerability of patients, as well as ethical conflicts. In fact, the evidence levels for most of our recommendations were low. Because of the lack of rigorous evidence, recommendation statements based on expert consensus and the best available evidence, such as ours, play an important role in guiding health care providers to the optimal clinical decisions. Despite our best efforts, we could not find sufficient data regarding the effect of treatment on QOL and pharmacoeconomic outcomes. Thus, we discourage the use of individual recommendations in isolation without the consideration of patient preference and the pharmacoeconomic aspect of treatment.

Table 2.

Summary of Recommendations

Treatments	Evidence and recommendation levels	Conditions for adaptation/major findings
Management of nausea and vomiting
Etiology-based antiemetic management	2D	There is no evidence superior to an empirical approach.
Metoclopramide	2C	Limited to four weeks if possible, because of extrapyramidal symptoms.
Domperidone	Inconclusive	There may be a risk of severe ventricular arrhythmias and sudden cardiac death.
Haloperidol	2D	The dosage and administration period should be minimized.
Anticholinergics (scopolamine hydrobromide)	2D	There is only evidence of sublingual and transdermal administration.
Histamine H1 receptor antagonist (promethazine)	2D	Adverse events were not evaluated in the eligible study.
Phenothiazine antipsychotics (chlorpromazine, levomepromazine, and prochlorperazine)	2D	Attention should be paid to adverse events, including drowsiness, circulation inhibition, and extrapyramidal symptoms.
Atypical antipsychotics (perospirone, risperidone, and olanzapine)	2D	Consider use in cases refractory to first-line antiemetic drug treatment.
Serotonin 5HT3 receptor antagonist	2C	Consider use in cases refractory to first-line antiemetic drug treatment.
Corticosteroids	2C	Consider use if symptoms are caused by tumor-induced inflammation or cerebral edema.
Mirtazapine	Inconclusive	There is only one observational study for depression with nausea or insomnia.
Management of nausea and vomiting in MBO
Nasogastric tube	2D	Limited to short periods, because of patient preference and adverse events.
PEG/PTEG	2C	Consider use if patients have a prognosis that exceeds two months.
Corticosteroids	2C	The superiority to a placebo was not clearly evident.
Octreotide	2C	The previous studies were inconsistent results, and the evaluation methods differed among studies.
Butylscopolamine	2C	Consider use in case of colic pain or as an alternative to octreotide.
H2RA/PPI	2D	There is only one review of gastric secretion reduction of patients in the perioperative period.
Antiemetic drugs	2D	There is no evidence to indicate which antiemetics are effective.
Management of malignant ascites
Diuretics (spironolactone and furosemide)	2D	Attention should be paid to adverse events, including renal dysfunction and electrolyte abnormalities.
Abdominal paracentesis	2D	If puncture occurs frequently, the use of an indwelling peritoneal catheter should be considered.
CART	Inconclusive	Symptom improvement could not be determined to be a benefit of CART treatment alone in the eligible study.
Denver peritoneovenous shunts	Inconclusive	Serious adverse events such as heart failure, pulmonary edema, and disseminated intravascular coagulation syndrome were observed.
Management of constipation
Osmotic laxative	1C	The superiority of osmotic laxative to other laxatives in eligible studies is unclear.
Stimulant laxative	1C	The superiority of stimulant laxative to other laxatives in eligible studies is unclear.
Lubiprostone	2C	There is no research in cancer patients, only in noncancer patients.
Management of anorexia
Corticosteroids	1B	Attention should be paid to long-term use or in patients with poor general condition.
Metoclopramide	2D	Consider use in case of anorexia with cancer-related dyspepsia.
Rikkunshito	Inconclusive	There is no research on cancer patients.
EPA	2B (not to be used)	EPA has not been shown to improve anorexia compared to placebo.
Progestogen (megestrol and medroxyprogesterone acetate)	2B	The risk of pulmonary embolism has been shown to increase in the case of higher doses.

CART, concentrated ascites reinfusion therapy; EPA, eicosapentaenoic acid; H2RA, H2 receptor antagonist; MBO, malignant bowel obstruction; PEG, percutaneous endoscopic gastrostomy; PPI, proton pump inhibitor; PTEG, percutaneous transesophageal gastro-tubing.

Finally, RCTs comparing placebo or each intervention and clinical studies on the effects of combinations of intervention are necessary for almost all CQs. In particular, the establishment of evidence for cancer patients is required for domperidone and mirtazapine for nausea and vomiting, CART and Denver peritoneovenous shunts for malignant ascites, and rikkunshito for anorexia, all of which could not be concluded. There is also a need to determine the optimal dose, frequency, and administration route (oral, injection, rectal, etc.) and when to recommend each intervention. Furthermore, there is a need to establish the methodology of clinical trials for gastrointestinal symptoms in patients with advanced cancer, especially a consensus on appropriate outcomes to determine the response of interventions. In addition, continuous guideline updates are required to improve the quality of gastrointestinal symptom management in cancer patients.

Footnotes

Acknowledgments

The authors thank the Japanese Society of Gastroenterology, Japanese Society of Clinical Oncology, Japanese Society of Medical Oncology, Japan Primary Care Association, Japanese Society of Cancer Nursing, and Japanese Society for Pharmaceutical Palliative Care and Sciences for their cooperation and advice during the development of these recommendation statements. This work was funded by the Japanese Society for Palliative Medicine.

Author Disclosure Statement

No competing financial interests exist.

References

Walsh

, Davis

, Ripamonti

, et al.: 2016 Updated MASCC/ESMO consensus recommendations: Management of nausea and vomiting in advanced cancer. Support Care Cancer, 2017; 25:333–340.

Stephenson

, Davies

: An assessment of aetiology-based guidelines for the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer, 2006; 14:348–353.

Laval

, Marcelin-Benazech

, Guirimand

, et al.: Recommendations for bowel obstruction with peritoneal carcinomatosis. J Pain Symptom Manage, 2014; 48:75–91.

Ripamonti

, Twycross

, Baines

, et al.: Clinical-practice recommendations for the management of bowel obstruction in patients with end-stage cancer. Support Care Cancer, 2001; 9:223–233.

Smith

, Jayson

: The current and future management of malignant ascites. Clinical Oncol (R Coll Radiol), 2003; 15:59–72.

Cavazzoni

, Bugiantella

, Graziosi

, et al.: Malignant ascites: Pathophysiology and treatment. Int J Clin Oncol, 2013; 18:1–9.

Larkin

, Sykes

, Centeno

, et al.: The management of constipation in palliative care: Clinical practice recommendations. Palliat Med, 2008; 22:796–807.

Staats

, Markowitz

, Schein

: Incidence of constipation associated with long-acting opioid therapy: A comparative study. South Med J, 2004; 97:129–134.

, Lorenz

, Naeim

, et al.: Evidence-based recommendations for cancer fatigue, anorexia, depression, and dyspnea. J Clin Oncol, 2008; 26:3886–3895.

10.

Vainio

, Auvinen

: Prevalence of symptoms among patients with advanced cancer: An international collaborative study. Symptom Prevalence Group. J Pain Symptom Manage, 1996; 12:3–10.

11.

Collis

, Mather

: Nausea and vomiting in palliative care. BMJ, 2015; 351:h6249.

12.

Dans

, Smith

, Back

, et al.: NCCN guidelines insights: Palliative care, version 2.2017. J Natl Compr Canc Netw, 2017; 15:989–997.

13.

Davis

, Hallerberg

: A systematic review of the treatment of nausea and/or vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manage, 2010; 39:756–767.

14.

Levy

, Smith

, Alvarez-Perez

, et al.: Palliative care version 1.2016. J Natl Compr Canc Netw, 2016; 14:82–113.

15.

Larkin

, Cherny

, La Carpia

, et al.: Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. Ann Oncol, 2018; 29:iv111–iv125.

16.

Sande

, Laird

BJA

, Fallon

: The management of opioid-induced nausea and vomiting in patients with cancer: A systematic review. J Palliat Med, 2018. DOI: 10.1089/jpm.2018.0260.

17.

The Japanese Society for Palliative Medicine, ed Clinical Guideline for Gastrointestinal Symptoms in Cancer Patients. Tokyo, Japan: Kanehara & Co., Ltd, 2011.

18.

Oxford Textbook of Palliative Medicine, 5th ed. Cherny

, Fallon

, Kaasa

, Portenoy

, et al. (eds). Oxford, United Kingdom: Oxford University Press, 2015.

19.

The Rand/UCLA Appropriateness Method User's Manual. Fitch

, Bernstein

, Aguilar

, et al. (eds). Santa Monica, CA: RAND Corporation, 2001.

20.

Guyatt

, Oxman

, Vist

, et al.: GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 2008; 336:924–926.

21.

Lichter

: Results of antiemetic management in terminal illness. J Palliat Care, 1993; 9:19–21.

22.

Bentley

, Boyd

: Use of clinical pictures in the management of nausea and vomiting: A prospective audit. Palliat Med, 2001; 15:247–253.

23.

Imai

, Ikenaga

, Tamura

, et al.: Effectiveness of the etiology-based antiemetic recommendations by a palliative care team for nausea in cancer patients. Palliat Care Res, 2014; 9:108–113.[Only available in Japanese]

24.

Hardy

, Skerman

, Glare

, et al.: A randomized open-label study of guideline-driven antiemetic therapy versus single agent antiemetic therapy in patients with advanced cancer and nausea not related to anticancer treatment. BMC Cancer, 2018; 18:510.

25.

Bruera

, Belzile

, Neumann

, et al.: A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage, 2000; 19:427–435.

26.

Hardy

, Daly

, McQuade

, et al.: A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer, 2002; 10:231–236.

27.

Johannes

, Varas-Lorenzo

, McQuay

, et al.: Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: A nested case-control study. Pharmacoepidemiol Drug Saf, 2010; 19:881–888.

28.

Arana

, Johannes

, McQuay

, et al.: Risk of out-of-hospital sudden cardiac death in users of domperidone, proton pump inhibitors, or metoclopramide: A population-based nested case-control study. Drug Saf, 2015; 38:1187–1199.

29.

van Noord

, Dieleman

, van Herpen

, et al.: Domperidone and ventricular arrhythmia or sudden cardiac death: A population-based case-control study in the Netherlands. Drug Saf, 2010; 33:1003–1014.

30.

Hardy

, O'Shea

, White

, et al.: The efficacy of haloperidol in the management of nausea and vomiting in patients with cancer. J Pain Symptom Manage, 2010; 40:111–116.

31.

Murray-Brown

, Dorman

: Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev, 2015:CD006271.

32.

Imai

, Ikenaga

, Kodama

, et al.: Sublingually administered scopolamine for nausea in terminally ill cancer patients. Support Care Cancer, 2013; 21:2777–2781.

33.

Ferris

, Kerr

, Sone

, Marcuzzi

: Transdermal scopolamine use in the control of narcotic-induced nausea. J Pain Symptom Manage, 1991; 6:389–393.

34.

Tolen

, McMath

, Alt

, et al.: Initial selection of antiemetics in end-of-life care: A retrospective analysis. Int J Pharm Compd, 2006; 10:147–153.

35.

Mystakidou

, Befon

, Liossi

, Vlachos

: Comparison of tropisetron and chlorpromazine combinations in the control of nausea and vomiting of patients with advanced cancer. J Pain Symptom Manage, 1998; 15:176–184.

36.

Mystakidou

, Befon

, Liossi

, Vlachos

: Comparison of the efficacy and safety of tropisetron, metoclopramide, and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer, 1998; 83:1214–1223.

37.

Eisenchlas

, Garrigue

, Junin

, De Simone

: Low-dose levomepromazine in refractory emesis in advanced cancer patients: An open-label study. Palliat Med, 2005; 19:71–75.

38.

Kennett

, Hardy

, Shah

, A'Hern

: An open study of methotrimeprazine in the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer, 2005; 13:715–721.

39.

Tagami

, Mawatari

, Abe

, et al.: Perospirone exhibits antiemetic efficacy against opioid-induced nausea in patients with advanced cancer. J Palliat Med, 2015; 18:823–824.

40.

Okamoto

, Tsuneto

, Matsuda

, et al.: A retrospective chart review of the antiemetic effectiveness of risperidone in refractory opioid-induced nausea and vomiting in advanced cancer patients. J Pain Symptom Manage, 2007; 34:217–222.

41.

Passik

, Lundberg

, Kirsh

, et al.: A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage, 2002; 23:526–532.

42.

Yennurajalingam

, Frisbee-Hume

, Palmer

, et al.: Reduction of cancer-related fatigue with dexamethasone: A double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol, 2013; 31:3076–3082.

43.

Bruera

, Moyano

, Sala

, et al.: Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: A randomized controlled trial. J Pain Symptom Manage, 2004; 28:381–388.

44.

Kim

, Shin

, Kim

, et al.: Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry Clin Neurosci, 2008; 62:75–83.

45.

Aramaki

, Arai

, Inaba

, et al.: Phase II study of percutaneous transesophageal gastrotubing for patients with malignant gastrointestinal obstruction; JIVROSG-0205. J Vasc Interv Radiol, 2013; 24:1011–1017.

46.

Issaka

, Shapiro

, Parikh

, et al.: Palliative venting percutaneous endoscopic gastrostomy tube is safe and effective in patients with malignant obstruction. Surg Endosc, 2014; 28:1668–1673.

47.

Kawata

, Kakushima

, Tanaka

, et al.: Percutaneous endoscopic gastrostomy for decompression of malignant bowel obstruction. Dig Endosc, 2014; 26:208–213.

48.

Vashi

, Dahlk

, Vashi

, Gupta

: Percutaneous endoscopic gastrostomy tube occlusion in malignant peritoneal carcinomatosis-induced bowel obstruction. Eur J Gastroenterol Hepatol, 2011; 23:1069–1073.

49.

Zucchi

, Fornasarig

, Martella

, et al.: Decompressive percutaneous endoscopic gastrostomy in advanced cancer patients with small-bowel obstruction is feasible and effective: A large prospective study. Support Care Cancer, 2016; 24:2877–2882.

50.

Hardy

, Ling

, Mansi

, et al.: Pitfalls in placebo-controlled trials in palliative care: Dexamethasone for the palliation of malignant bowel obstruction. Palliat Med, 1998; 12:437–442.

51.

Laval

, Girardier

, Lassauniere

, et al.: The use of steroids in the management of inoperable intestinal obstruction in terminal cancer patients: Do they remove the obstruction?. Palliat Med, 2000; 14:3–10.

52.

Currow

, Quinn

, Agar

, et al.: Double-blind, placebo-controlled, randomized trial of octreotide in malignant bowel obstruction. J Pain Symptom Manage, 2015; 49:814–821.

53.

Laval

, Rousselot

, Toussaint-Martel

, et al.: SALTO: A randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction. Bull Cancer, 2012; 99:E1–E9.

54.

Peng

, Wang

, Li

, et al.: Randomized clinical trial comparing octreotide and scopolamine butylbromide in symptom control of patients with inoperable bowel obstruction due to advanced ovarian cancer. World J Surg Oncol, 2015; 13:50.

55.

Mercadante

, Ripamonti

, Casuccio

, et al.: Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer, 2000; 8:188–191.

56.

Mystakidou

, Tsilika

, Kalaidopoulou

, et al.: Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: A randomized, double-blind, controlled clinical trial. Anticancer Res, 2002; 22:1187–1192.

57.

Ripamonti

, Mercadante

, Groff

, et al.: Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: A prospective randomized trial. J Pain Symptom Manage, 2000; 19:23–34.

58.

Clark

, Lam

, Currow

: Reducing gastric secretions—A role for histamine 2 antagonists or proton pump inhibitors in malignant bowel obstruction?. Support Care Cancer, 2009; 17:1463–1468.

59.

Baines

, Oliver

, Carter

: Medical management of intestinal obstruction in patients with advanced malignant disease. A clinical and pathological study. Lancet, 1985; 2:990–993.

60.

Fainsinger

, Spachynski

, Hanson

, Bruera

: Symptom control in terminally ill patients with malignant bowel obstruction (MBO). J Pain Symptom Manage, 1994; 9:12–18.

61.

Kaneishi

, Kawabata

, Morita

: Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manage, 2012; 44:604–607.

62.

Tuca

, Roca

, Sala

, et al.: Efficacy of granisetron in the antiemetic control of nonsurgical intestinal obstruction in advanced cancer: A phase II clinical trial. J Pain Symptom Manage, 2009; 37:259–270.

63.

Ventafridda

, Ripamonti

, Caraceni

, et al.: The management of inoperable gastrointestinal obstruction in terminal cancer patients. Tumori, 1990; 76:389–393.

64.

Greenway

, Johnson

, Williams

: Control of malignant ascites with spironolactone. Br J Surg, 1982; 69:441–442.

65.

Mitsuhashi

, Nemoto

, Satoh

, et al.: Effect of tolvaptan on ascites due to malignancy. Gan To Kagaku Ryoho, 2015; 42:201–205. [Available in Japanese only.]

66.

Pockros

, Esrason

, Nguyen

, et al.: Mobilization of malignant ascites with diuretics is dependent on ascitic fluid characteristics. Gastroenterology, 1992; 103:1302–1306.

67.

Belfort

, Stevens

, DeHaek

, et al.: A new approach to the management of malignant ascites: A permanently implanted abdominal drain. Eur J Surg Oncol, 1990; 16:47–53.

68.

Courtney

, Nemcek

Jr , Rosenberg

, et al.: Prospective evaluation of the PleurX catheter when used to treat recurrent ascites associated with malignancy. J Vasc Interv Radiol, 2008; 19:1723–1731.

69.

Mercadante

, Intravaia

, Ferrera

, et al.: Peritoneal catheter for continuous drainage of ascites in advanced cancer patients. Support Care Cancer, 2008; 16:975–978.

70.

O'Neill

, Weissleder

, Gervais

, et al.: Tunneled peritoneal catheter placement under sonographic and fluoroscopic guidance in the palliative treatment of malignant ascites. AJR Am J Roentgenol, 2001; 177:615–618.

71.

Ross

, Kessler

, Clair

, et al.: Sonographically guided paracentesis for palliation of symptomatic malignant ascites. AJR Am J Roentgenol, 1989; 153:1309–1311.

72.

Savin

, Kirsch

, Romano

, et al.: Peritoneal ports for treatment of intractable ascites. J Vasc Interv Radiol, 2005; 16:363–368.

73.

Wong

, Cake

, Kachuik

, Amjadi

: Indwelling peritoneal catheters for managing malignancy-associated ascites. J Palliat Care, 2015; 31:243–249.

74.

McNamara

: Paracentesis—An effective method of symptom control in the palliative care setting?. Palliat Med, 2000; 14:62–64.

75.

Ito

, Hanafusa

, Iwase

, et al.: Effects of cell-free and concentrated ascites reinfusion therapy (CART) on symptom relief of malignancy-related ascites. Int J Clin Oncol, 2015; 20:623–628.

76.

Sugawara

, Sone

, Arai

, et al.: Radiological insertion of Denver peritoneovenous shunts for malignant refractory ascites: A retrospective multicenter study (JIVROSG-0809). Cardiovasc Intervent Radiol, 2011; 34:980–988.

77.

Wickremesekera

, Stubbs

: Peritoneovenous shunting for malignant ascites. N Z Med J, 1997; 110:33–35.

78.

Won

, Choi

, Ko

, et al.: Percutaneous peritoneovenous shunt for treatment of refractory ascites. J Vasc Interv Radiol, 2008; 19:1717–1722.

79.

Zanon

, Grosso

, Apra

, et al.: Palliative treatment of malignant refractory ascites by positioning of Denver peritoneovenous shunt. Tumori, 2002; 88:123–127.

80.

Agra

, Sacristan

, Gonzalez

, et al.: Efficacy of senna versus lactulose in terminal cancer patients treated with opioids. J Pain Symptom Manage, 1998; 15:1–7.

81.

Wirz

, Nadstawek

, Elsen

, et al.: Laxative management in ambulatory cancer patients on opioid therapy: A prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose. Eur J Cancer Care (Engl), 2012; 21:131–140.

82.

Candy

, Jones

, Larkin

, et al.: Laxatives for the management of constipation in people receiving palliative care. Cochrane Database Syst Rev, 2015:Cd003448.

83.

Cryer

, Katz

, Vallejo

, et al.: A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain. Pain Med, 2014; 15:1825–1834.

84.

Jamal

, Adams

, Jansen

, Webster

: A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain. Am J Gastroenterol, 2015; 110:725–732.

85.

Fukudo

, Hongo

, Kaneko

, et al.: Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation. Clin Gastroenterol Hepatol, 2015; 13:294–301.

86.

Marciniak

, Toledo

, Lee

, et al.: Lubiprostone vs Senna in postoperative orthopedic surgery patients with opioid-induced constipation: A double-blind, active-comparator trial. World J Gastroenterol, 2014; 20:16323–16333.

87.

Paulsen

, Klepstad

, Rosland

, et al.: Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: A randomized, placebo-controlled, double-blind trial. J Clin Oncol, 2014; 32:3221–3228.

88.

Bruera

, Roca

, Cedaro

, et al.: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep, 1985; 69:751–754.

89.

Della Cuna

, Pellegrini

, Piazzi

: Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: A placebo-controlled, multicenter study. The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol, 1989; 25:1817–1821.

90.

Moertel

, Schutt

, Reitemeier

, Hahn

: Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer, 1974; 33:1607–1609.

91.

Popiela

, Lucchi

, Giongo

: Methylprednisolone as palliative therapy for female terminal cancer patients. The Methylprednisolone Female Preterminal Cancer Study Group. Eur J Cancer Clin Oncol, 1989; 25:1823–1829.

92.

Wilson

, Plourde

, Marshall

, et al.: Long-term safety and clinical effectiveness of controlled-release metoclopramide in cancer-associated dyspepsia syndrome: A multicentre evaluation. J Palliat Care, 2002; 18:84–91.

93.

Nelson

, Walsh

: Metoclopramide in anorexia caused by cancer-associated dyspepsia syndrome (CADS). J Palliat Care, 1993; 9:14–18.

94.

Takiguchi

, Hiura

, Takahashi

, et al.: Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy. Gastric Cancer, 2013; 16:167–174.

95.

Fearon

, Barber

, Moses

, et al.: Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol, 2006; 24:3401–3407.

96.

Dewey

, Baughan

, Dean

, et al.: Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev, 2007:Cd004597.

97.

Bruera

, Ernst

, Hagen

, et al.: Effectiveness of megestrol acetate in patients with advanced cancer: A randomized, double-blind, crossover study. Cancer Prev Control, 1998; 2:74–78.

98.

Bruera

, Macmillan

, Kuehn

, et al.: A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer, 1990; 66:1279–1282.

99.

Chow

, Machin

, Chen

, et al.: Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J Cancer, 2011; 105:945–952.

100.

De Conno

, Martini

, Zecca

, et al.: Megestrol acetate for anorexia in patients with far-advanced cancer: A double-blind controlled clinical trial. Eur J Cancer, 1998; 34:1705–1709.

101.

Feliu

, Gonzalez-Baron

, Berrocal

, et al.: Usefulness of megestrol acetate in cancer cachexia and anorexia. A placebo-controlled study. Am J Clin Oncol, 1992; 15:436–440.

102.

Loprinzi

, Kugler

, Sloan

, et al.: Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol, 1999; 17:3299–3306.

103.

Ruiz Garcia

, Lopez-Briz

, Carbonell Sanchis

, et al.: Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev, 2013:Cd004310.

104.

Downer

, Joel

, Allbright

, et al.: A double blind placebo controlled trial of medroxyprogesterone acetate (MPA) in cancer cachexia. Br J Cancer, 1993; 67:1102–1105.

105.

Kornek

, Schenk

, Ludwig

, et al.: Placebo-controlled trial of medroxy–progesterone acetate in gastrointestinal malignancies and cachexia. Oncol Res Treat, 1996; 19:164–168.

106.

Simons

, Aaronson

, Vansteenkiste

, et al.: Effects of medroxyprogesterone acetate on appetite, weight, and quality of life in advanced-stage non-hormone-sensitive cancer: A placebo-controlled multicenter study. J Clin Oncol, 1996; 14:1077–1084.

107.

Tominaga

, Abe

, Ohshima

, et al.: Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer, 1994; 30A:959–964.