2016 updated MASCC/ESMO consensus recommendations: Anticipatory nausea and vomiting in children and adults receiving chemotherapy.

PURPOSE: We aimed to update the 2011 recommendations for the prevention and treatment of anticipatory nausea and vomiting in children and adults receiving chemotherapy. METHODS: The original systematic literature search was updated. Randomized studies were included in the evidence to support this guideline if they as follows: were primary studies published in a journal in full text (i.e., abstracts, letters, book chapters, and dissertations were excluded); published in English; evaluated an intervention for the prevention or treatment of anticipatory nausea and vomiting; reported the proportion of patients experiencing complete control of anticipatory nausea and vomiting consistently and; included at least ten participants per study arm for comparative studies and at least ten participants overall for noncomparative studies. RESULTS: Eighty-eight new citations were identified. Of these, nine were brought to full-text screening; none met inclusion criteria. The guideline panel continues to recommend that anticipatory nausea and vomiting are best prevented through optimization of acute and delayed phase chemotherapy-induced nausea and vomiting control. Benzodiazepines and behavioral therapies, in particular progressive muscle relaxation training, systematic desensitization and hypnosis, continue to be recommended for the treatment of anticipatory nausea and vomiting. CONCLUSIONS: No new information regarding interventions aimed at treating or preventing ANV that met criteria for inclusion in this systematic review was identified. The 2015 MASCC recommendations affirm the content of the 2009 MASCC recommendations for the prevention and treatment of anticipatory nausea and vomiting.

Anticipatory nausea and vomiting due to chemotherapy.

As a specific variation of chemotherapy-induced nausea and vomiting, anticipatory nausea and vomiting (ANV) appears particularly linked to psychological processes. The three predominant factors related to ANV are classical conditioning; demographic and treatment-related factors; and anxiety or negative expectancies. Laboratory models have provided some support for these underlying mechanisms for ANV. ANV may be treated with medical or pharmacological interventions, including benzodiazepines and other psychotropic medications. However, behavioral treatments, including systematic desensitization, remain first line options for addressing ANV. Some complementary treatment approaches have shown promise in reducing ANV symptoms. Additional research into these approaches is needed. This review will address the underlying models of ANV and provide a discussion of these various treatment options.

Lipopolysaccharide (LPS) blocks the acquisition of LiCl-induced gaping in a rodent model of anticipatory nausea.

The effects of systemic treatment with lipopolysaccharide (LPS) on conditioned gaping in a rodent model of anticipatory nausea were examined. Stimulation of the immune system has been found to enhance, impair, or have no effect on various learning and memory tasks. The development of anticipatory nausea is formed through a classically conditioned response to a context that has been paired previously with toxin-induced nausea and/or vomiting. Rats display a distinctive conditioned gaping response when injected with a nausea-inducing drug such as LiCl. In the present study, male Long-Evans rats were injected intraperitoneally with LPS (200microg/kg) or saline (NaCl) followed 90min later by an injection of the toxin LiCl or saline before being placed in a distinctive context on four conditioning days (72h apart). On the condition test day, rats (n=6/group) were placed in the distinctive context in a drug-free state and behavioral responses were videotaped. Rats given LPS followed by LiCl were found to have significantly fewer gaping responses when compared to rats given NaCl followed by LiCl. All groups were also found to have similar levels of spontaneous ingestive behaviors suggesting that the decrease in gaping was not due to motor impairment. The present results suggest that activation of the immune system with LPS administration significantly impairs the acquisition of anticipatory nausea.

The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat.

RATIONALE: Anticipatory nausea (AN) experienced by chemotherapy patients is resistant to current anti-nausea treatments. In this study, the effect of manipulation of the endocannabinoid (EC) system on a rat model of nausea (conditioned gaping) was determined. OBJECTIVE: The potential of cannabidiol (CBD) and the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (URB) to reduce conditioned gaping in rats were evaluated. MATERIALS AND METHODS: In each experiment, rats received four conditioning trials in which they were injected with lithium chloride immediately before placement in a distinctive odor-laced context. During testing, in experiment 1, rats were injected with vehicle (VEH), 1, 5 or 10 mg/kg CBD 30 min before placement in the context previously paired with nausea and in experiment 2, rats were injected with VEH, 0.1 or 0.3 mg/kg URB 2 h before placement in the context. Additional groups evaluated the ability of the CB(1) antagonist/inverse agonist, SR141716A, to reverse the suppressive effects of URB. Experiment 3 measured the potential of URB to interfere with the establishment of conditioned gaping. RESULTS: When administered before testing, CBD (1 and 5, but not 10 mg/kg) and URB (0.3, but not 0.1 mg/kg) suppressed conditioned gaping. The effect of URB was reversed by pre-treatment with the CB(1) antagonist/inverse agonist, SR141716A. When administered before conditioning, URB also interfered with the establishment of conditioned gaping. CONCLUSIONS: Manipulations of the EC system may have therapeutic potential in the treatment of AN.

[Substance P and anticancer drug-induced emesis].

BACKGROUND: Cytotoxic drug-induced emesis is the side effect most feared by cancer patients. The Acute emesis has become well controlled by the emergence appearance of 5-HT3 receptor antagonist, but control of delayed emesis (DE) is insufficient. The mechanism of DE is different from acute emesis,and the existence of a mediator different from serotonin is contemplated. There were some reports suggesting the role of substance P (SP) and its receptor, neurokinin receptor 1 (NK 1), in the development of emesis. AIM: We investigated the relationship between DE and SP in patients treated with anticancer agents. PATIENTS AND METHOD: Digestive cancer and breast cancer patients, who were administered cytotoxic agents, were the objects of this study. We measured plasma levels of SP for 20 cases on the day before administration of anticancer agents and for five days after administration. RESULT: Plasma levels of SP increased significantly on the first and third days after administration. In the patient who experienced DE, the difference in plasma levels on the day before and the first day after chemotherapy was higher than that of who never experienced. CONCLUSION: The plasma levels of SP were transiently increased by chemotherapy. The difference in plasma levels between the day before and the first day after chemotherapy is important.

Behavioral interventions in treating anticipatory nausea and vomiting.

Anticipatory nausea and vomiting (ANV) is associated with a significant reduction in the quality of life for many chemotherapy patients. The use of 5-hydroxytryptamine type 3 receptor antagonists provides some relief for chemotherapy-induced nausea and vomiting, but does not seem to control ANV. Nonpharmacologic approaches, which include behavioral interventions, may provide the greatest promise in relieving symptoms. Little evidence supports the use of complementary and alternative methods, such as acupuncture and acupressure, in relieving ANV. Behavioral interventions, especially progressive muscle relaxation training and systematic desensitization, should be considered important methods for preventing and treating ANV.

Pavlovian conditioning of nausea and vomiting.

Cancer patients undergoing cytotoxic drug treatment often experience side-effects, the most distressing being nausea and vomiting. Despite antiemetic drugs, 25-30% of the chemotherapy patients report these side-effects when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea and anticipatory vomiting. The present paper summarizes the evidence that anticipatory vomiting is acquired by Pavlovian conditioning, and, consequently, may be alleviated by conditioning techniques. To explore the mechanisms that induce and alleviate conditioned nausea and vomiting further, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea was demonstrated. Cortisol and tumor-necrosis factor-alpha were elevated as endocrine and immunological correlates of nausea. Data in the rotation-induced motion sickness model indicated that gender is an important moderator variable to be considered in further studies. The paper concludes with a review of applications of the demonstrated conditioning principles as interventions to ameliorate distressing anticipatory nausea or anticipatory vomiting in cancer patients undergoing chemotherapy.

Overshadowing and latent inhibition of context aversion conditioning in the rat.

A review is presented of experimental studies, using rats as the subjects, that were designed to establish an animal model of the clinical phenomenon of anticipatory nausea. Experiments 1 and 2 demonstrated that pairing a distinctive context with an illness-inducing injection of lithium chloride endowed the context with new properties, consistent with the proposal that classical conditioning had established an association between the context as the conditioned stimulus and nausea as the unconditioned stimulus. The conditioned response to the context constitutes a form of anticipatory nausea. Experiment 3 examined overshadowing, showing that the presence of a novel salient cue (a flavour) during context conditioning reduced the magnitude of the aversion conditioned to the context. Experiments 4-7 examined the effects of giving exposure to the context prior to conditioning. They demonstrated a latent inhibition effect, that is, a reduction in the magnitude of the aversion in pre-exposed animals. It is suggested that these ways of modulating conditioned aversions could form the basis of interventions for use in the chemotherapy clinic. Anticipatory nausea is assumed to be a consequence of the formation of an association between the cues that constitute the clinic and the drug-induced nausea experienced in their presence. By restricting the development of this association, latent inhibition and overshadowing procedures should be effective in alleviating the problem of anticipatory nausea.

The continuing problem of post chemotherapy nausea and vomiting: contributions of classical conditioning.

Despite continuing improvements in antiemetic therapies, nausea and vomiting following chemotherapy treatments for cancer remain significant clinical problems for many patients. The role of classical conditioning in patients' anticipatory nausea is well known, but little attention has been paid to possible conditioning effects on post treatment nausea. The present study statistically examined the contribution of anticipatory (conditioned) nausea to patients' subsequent post treatment nausea. Forty early stage breast cancer patients who developed anticipatory nausea were analyzed. Results revealed a significant correlation between the intensity of anticipatory nausea in the clinic prior to their treatment infusion and subsequent post treatment nausea during the 24 h after the infusion. These results provide support for the hypothesis that, once established, conditioned nausea may contribute to the severity of subsequent post treatment nausea in patients receiving repeated cycles of chemotherapy for cancer. The results suggest the importance of considering the contribution of conditioning process to nausea and other post treatment side effects.

[Retrospective analysis of tegafur/uracil (UFT) plus oral leucovorin (LV) regimen in patients with advanced colorectal cancer].

The clinical efficacy and safety of tegafur/uracil (UFT) plus oral Leucovorin (LV) regimen for advanced or metastatic colorectal cancer were studied retrospectively. From September 2003 to March 2005, 82 patients were treated with UFT (300 mg/m(2)/day)/LV (75 mg/day) at our institute. The objective overall response rate was 14. 8% (95% confidence interval, 5.3 to 24.3%) in 54 evaluable patients. The response rate was 33.3% for previously untreated patients and 5.5% for previously treated patients, respectively. Grade 3 or more severe adverse reactions such as diarrhea or liver function abnormalities were only 7.3%. In 28 previously untreated patients,the median survival was 25.8 months with 1-and 2-year survival rates of 88.0% and 60.5%, respectively. This retrospective study demonstrated the reproducible activity and safety of UFT/LV for advanced or metastatic colorectal cancer in clinical practice.

Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: An animal model of anticipatory nausea and vomiting.

Chemotherapy patients report not only acute nausea and vomiting during the treatment itself, but also report anticipatory nausea and vomiting upon re-exposure to the cues associated with the treatment. We present a model of anticipatory nausea based on the emetic reactions of the Suncus murinus (musk shrew). Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with each of the principal cannabinoids found in marijuana, Delta(9)-tetrahydrocannabinol or cannabidiol, at a dose that did not suppress general activity. On the other hand, pretreatment with a dose of ondansetron (a 5-HT(3) antagonist) that interferes with acute vomiting in this species, did not suppress the expression of conditioned retching during re-exposure to the lithium-paired context. These results support anecdotal claims that marijuana, but not ondansetron, may suppress the expression of anticipatory nausea.

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer.

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-naïve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-naïve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.

Efficacy of progressive muscle relaxation training and guided imagery in reducing chemotherapy side effects in patients with breast cancer and in improving their quality of life.

GOALS: This study was designed to assess the effectiveness of progressive muscle relaxation training (PMRT) and guided imagery (GI) in reducing the anticipatory nausea and vomiting (ANV) and postchemotherapy nausea and vomiting (PNV) of patients with breast cancer and to measure their effects on the patients' quality of life (QoL). PATIENTS AND METHODS: Thirty chemotherapy-naive patients with breast cancer were randomized to the PMRT and GI group and 30 to the control group. Before each of six cycles of adjuvant chemotherapy, each patient was administered a self-report Multiple Affect Adjective Checklist (MAACL), and incidents of ANV and PNV for the first three postchemotherapy days were recorded. All patients were administered the Functional Assessment of Cancer Therapy-Breast (FACT-B) at baseline and after 3 and 6 months. RESULTS: We found that the PMRT and GI group was significantly less anxious, depressive, and hostile than the control group. We also found that the PMRT and GI group experienced significantly less ANV and PNV and that 6 months after CT, the QoL of the PMRT and GI group was higher than that of the control group. CONCLUSION: These results indicate that PMRT and GI were associated with both the improvements in ANV and PNV and in the QoL of patients with breast cancer.

Anticipatory nausea and vomiting.

Anticipatory nausea and vomiting (ANV) is not only a learned response but can occur without prior exposure to chemotherapy depending on patient emotional distress and expectations. The best method to avoid development or reinforcement of ANV is to avoid both vomiting and nausea from the first exposure to chemotherapy. If ANV develops, benzodiazepines have been documented to help in adult patients, and several psychological techniques are also of help, including systematic desensitization. The evidence on which these conclusions are based is reviewed in this article.

The efficacy of behavioral interventions for cancer treatment-related side effects.

The use of increasingly aggressive methods of cancer treatment (e.g., cytotoxic doses of chemotherapy and total body irradiation) has resulted in the need for more effective management of pain, nausea, and other aversive side effects. One of the most promising approaches is nonpharmacologic intervention based on behavioral research and theory. The purpose of this article is to review the efficacy of behavioral intervention methods in controlling aversive side effects of cancer treatments. Sixty-seven published studies were identified for review. Results indicated that: (1) behavioral intervention can effectively control anticipatory nausea and vomiting in adult and pediatric patients undergoing cancer chemotherapy. However, evidence for the efficacy of behavioral intervention to control post-chemotherapy nausea and vomiting is mixed; (2) behavioral intervention integrating several behavioral techniques can decrease levels of anxiety and distress associated with invasive treatments and cancer diagnosis; and (3) although a variety of behavioral methods have been shown to reduce acute treatment-related pain, not all behavioral techniques are equally effective. Hypnotic-like methods involving relaxation, suggestion, and imagery appear to have the greatest impact on cancer-related pain management. The use of behavioral theory and techniques has an important place in the care of patients undergoing invasive cancer treatments.

Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV).

Little is understood about effective countermeasures to the expression of anticipatory nausea and vomiting (ANV) in chemotherapy patients. We present a model of ANV based on the emetic reactions of the Suncus murinus (musk shrew). Following two pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with THC at a dose that did not suppress general activity. This provides the first experimental evidence in support of anecdotal reports that THC suppresses ANV.

[Prevention and treatment of the side effects of cancer chemotherapy].

Management of the side effects of chemotherapy in cancer patients is important because side effects can affect the tolerability and continuation of therapy, in addition to lowering the quality of life of patients. A significant efficacy of serotonin receptor antagonists against nausea and vomiting due to cancer chemotherapy, and granulocyte colony-stimulating factor against neutropenia secondary to chemotherapy, has been recently demonstrated. New chemoprotective drugs have been developed, such as amifostine for cisplatin-induced nephrotoxicity and neurotoxicity, and dexrazoxane for cardiac toxicity due to anthracyclines. Antiviral agents including lamivudine and interferons suppress virus replication, preventing the development of fulminant hepatitis during chemotherapy in cancer patients who have chronic hepatitis B infection. Various supportive therapies have resulted in the advance of cancer chemotherapy.

Efficacy and tolerability of tropisetron in the prevention of cisplatin-induced nausea and vomiting in advanced non-small cell lung cancer.

The efficacy and tolerability of tropisetron were studied in an open trial comprising a total of 30 patients with advanced non-small cell lung cancer undergoing high-dose, cisplatin-based chemotherapy (cisplatin dosage 100 mg/m2). Patients received tropisetron 5 mg intravenous infusions for 15 min on day 1. followed by 5 mg tropisetron taken orally in the morning on days 2 6. All treated patients were assessed during the entire treatment period (6 days). Acute nausea and vomiting were evaluated during the 24 h after chemotherapy. Delayed nausea and vomiting were evaluated during days 2-6 after chemotherapy. Response to tropisetron was graded as: complete control, major control, minor control and failure for nausea or vomiting. Rates for complete plus major control of acute nausea and vomiting in cycles 1-5 were 77%, 81%, 86%, 67% and 75%, respectively. Rates for complete plus major control of delayed nausea and vomiting in cycles 1-5 were 87%, 76%, 86%, 78% and 75%, respectively. Adverse reactions were mainly headache and diarrhea, but both reactions were mild and are common in most patients treated with this type of antiemetic agent. It is concluded that tropisetron is an effective drug for the prevention of side effects of highly emetogenic drugs such as cisplatin. The dosage and schedule of tropisetron reported here can prevent both acute and delayed nausea and vomiting.

Postoperative complications in patients of esophageal cancer after neoadjuvant chemotherapy.

We examined the effects of neoadjuvant chemotherapy on surgery by evaluating postoperative complications in 50 patients who had undergone neoadjuvant chemotherapy (Group A) and in 108 patients who had undergone surgery without neoadjuvant chemotherapy (Group B). Toxicity of grade 3 by chemotherapy were WBC in 3 patients (6%), alopecia in 3 patients (6%), and anorexia in 22 patients (44%). There were 4 patients with anastomotic leakage (8%) (all in minor), 5 patients with infection of wound (10%), 6 patients with arrhythmia (12%), no patients with postoperative bleeding, 2 patients with respiratory complications (4%), and no patients who died due to complications in Group A. In Group B, there were 13 patients with anastomotic leakage (13%) (all in minor), 12 patients with infection of the wound (11%), 11 patients with arrhythmia (10%), 2 patients with postoperative bleeding (2%), 8 patients with respiratory complications (7%), and 2 patients who died due to complications (2%). There was no significant difference in the incidence of postoperative complications between the patients who had undergone surgery after neoadjuvant chemotherapy, such as CDDP + 5FU therapy and FAP therapy, and the patients who had undergone surgery without neoadjuvant chemotherapy, in patients who had been diagnosed as being able to undergo relative non-curative resection or better, who had Ccr 60 ml/min or more and no severe complication, and whose stomach could be used for reconstruction of the esophagus, on the condition that surgery would be performed on NC patients at the end of first-course treatment.