Efficacy of Granisetron in the Antiemetic Control of Nonsurgical Intestinal Obstruction in Advanced Cancer: A Phase II Clinical Trial

Transcription

1 Vol. 37 No. 2 February 2009 Journal of Pain and Symptom Management 259 Clinical Note Efficacy of Granisetron in the Antiemetic Control of Nonsurgical Intestinal Obstruction in Advanced Cancer: A Phase II Clinical Trial Albert Tuca, MD, Rosa Roca, MD, Carme Sala, MD, Josep Porta, MD, PhD, Gala Serrano, MD, Jesús González-Barboteo, MD, and Xavier Gómez-Batiste, MD, PhD Instituto Catalán de Oncología (A.T., J.P., G.S., J.G.-B., X.G.-B.), L Hospitalet, Barcelona; Hospital de Santa Caterina (R.R.), Girona; and Hospital de Sant Llàtzer (C.S.), Terrassa, Barcelona, Spain Abstract The objective of this study was to assess antiemetic efficacy of granisetron in inoperable intestinal obstruction caused by advanced cancer. The study was open, prospective, and multicentered. We assessed 24 patients (mean age: 61.3 years; 10 males, 14 females) with intestinal obstruction who were refractory to previous antiemetics. Obstruction involved the upper intestine in six patients, the lower intestine in three, and was at multiple levels in 15. Daily treatment included intravenous granisetron (3 mg) and dexamethasone (8 mg); nasogastric drainage was not allowed. Subcutaneous haloperidol was available as rescue therapy. A numeric scale was used to evaluate nausea, pain, asthenia, and anorexia at baseline visit and every 24 hours up to the completion of four days of treatment (final visit). Treatment failure was defined as nausea >4 on the numeric scale, vomiting 2/day or more, and rescue therapy with haloperidol at 5 mg/day or more. Of the 24 patients, 23 were evaluable for efficacy. Evaluation pre- vs. post-treatment indicated a significant decrease in the severity of nausea (score 6.9 vs. 0.8; P < 0.001), number of episodes of vomiting (5.3 vs. 1.0; P < 0.001), and abdominal pain (score 4.4 vs. 1.2; P < 0.001). Nausea and vomiting control was achieved in 86.9% of patients. Although there was a trend toward greater efficacy in the lower and multiple levels of obstruction, the differences were not statistically significant owing, probably, to small sample size. We conclude that granisetron may be highly efficacious in the control of emesis resulting from intestinal obstruction caused by metastatic cancer, and can be used effectively in patients refractory to other antiemetics. J Pain Symptom Manage 2009;37:259e270. Ó 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Advanced cancer, intestinal obstruction, antiemetics, 5-HT 3 receptor antagonists, granisetron The study was supported, in part, by a grant from Roche Farma SA. The funding body was not involved in the collection and interpretation of data, or in the decision to publish. Address correspondence to: Albert Tuca, MD, Servei de Cures Palliatives, Hospital Duran y Reynals, Institut Ó 2009 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Catalan de Oncología, Av. Gran Vía s/n, Km 2, L Hospitalet, Barcelona, Spain. atuca@iconcologia.net Accepted for publication: February 1, /09/$esee front matter doi: /j.jpainsymman

2 260 Tuca et al. Vol. 37 No. 2 February 2009 Introduction Malignant bowel obstruction (MBO) is a common complication in advanced cancer, especially in patients with abdominal or pelvic tumors. The overall frequency of MBO in cancer patients has been estimated as between 3% and 15%; between 5% and 42% of patients with ovarian cancer, and between 4% and 24% of patients with colorectal cancer develop the complication. 1e5 MBO provokes very severe symptoms, which are frequently difficult to control, and are associated with a median life expectancy of three months. 36 Palliative surgery is the only alternative intended to restore the continuity of the bowel lumen. Many patients with advanced cancer are not eligible for surgery because of technical difficulties that preclude intestinal transit or a deteriorated general status. 8e25,34,35 Conservative medical treatment in inoperable MBO includes gastric venting through nasogastric or gastrostomy tube, no oral intake, intravenous hydration, and parenterally administered antiemetic drugs. The objective is to redress the electrolyte imbalance, to reduce intestinal distension, to control symptoms, and in some cases, to facilitate the spontaneous resolution of occlusive process. Adequate control of nausea and vomiting can be achieved in more than 80% of the cases when gastric aspiration tube is maintained together with no oral intake. In about 30% of cases, a spontaneous resolution of occlusion is observed within a period of between five and eight days from the start of conservative treatment, especially if the condition is a subocclusive crisis. Nevertheless, the reobstruction index is 50% or more. 6,7,23,34, When palliative surgery is not possible and there has not been spontaneous resolution, persistent intestinal obstruction provokes a fast and progressive impairment of general status and very severe symptoms. Baines et al. demonstrated in 1985 that palliative treatment based on the rational use of analgesics, antiemetics, antisecretory medications, and corticoids can control the persistent symptoms without nasogastric tube drainage, and in some cases, with a continuation of minimum food intake. 1e3,26,27,36,37 The majority of investigators accept that haloperidol is the first-choice antiemetic drug because of the potent central anti-dopaminergic action. Prokinetic drugs, such as metoclopramide, are useful but may paradoxically increase colic pain. Antisecretory drugs reduce endoluminal flow of water and sodium, assisting in the control of nausea, abdominal distension, and colic pain. The anticholinergics (such as hyoscine) are the preferred antisecretory drugs. Octreotide, a synthetic analog of somatostatin, also possesses a potent antisecretory effect and can be used as a second-line treatment, in combination or not, with an anticholinergic agent. Octreotide has greater potency than anticholinergics, and according to the results of some clinical trials, 28e33,37 can be effective when there is no adequate response to hyoscine. The use of corticoids also is particularly recommended given their antiemetic action and their anti-inflammatory effect with reduction of intestinal edema. In addition, corticosteroids are the unique class of drugs, according to data from clinical trials evaluated in meta-analyses, which can improve the index of spontaneous resolution of MBO. 4,5 Chemical or mechanical stimulation (intestinal distension) of the gut lumen provokes an excessive release of serotonin (5-hydroxytryptamine) by enterochromaffin cells. The high level of serotonin activates 5-hydroxytryptamine (5-HT) 3 receptors on the vagal primary afferent neurons, which are connected with brainstem neurons involved in the vomiting reflex. 43,44,52e54 It is well known that selective 5-HT 3 receptor antagonists are highly effective against emesis induced by cancer chemotherapy, radiotherapy, or anesthesia. 8e12,38e42 Data about the use of these drugs in palliative care are very limited. Some published studies suggest a high effectiveness of these drugs in antiemetic control of nausea unrelated to cancer chemotherapy in advanced and terminal cancer patients. 45e51 None of these studies addressed specifically the usefulness of 5-HT 3 receptor antagonists in MBO. Based on clinical experience and the increased levels of serotonin owing to intestinal distension, we hypothesized that a 5-HT 3 receptor antagonist may be useful in the control of emesis resulting from intestinal obstruction caused by advanced cancer. The principal objective of this Phase II study was to determine the antiemetic efficacy of granisetron in the control of nausea and vomiting provoked by

3 Vol. 37 No. 2 February 2009 Granisetron as an Intestinal Obstruction Antiemetic 261 inoperable intestinal occlusion of malignant origin. Secondary objectives were the determination of antiemetic response according to the site of occlusion and the evaluation of the analgesic control related to the grade of antiemetic efficacy of the study drug. Materials and Methods The purpose of the study was to evaluate the antiemetic efficacy of a 5-HT 3 receptor antagonist in patients with inoperable intestinal obstruction of malignant origin. A multi-center, prospective, analytical, open-label (noncomparative) clinical trial was designed to explore the variables of symptom control at baseline visit and after experimental therapeutic intervention. Given that, as yet, there is a paucity of scientific evidence on the antiemetic efficacy of 5-HT 3 receptor antagonists in MBO, it was not possible to design a randomized comparative study without the previous step of a Phase II clinical trial. Care Setting The patient recruitment and trial development were carried out in palliative care units (PCU) of three different hospitals: Catalan Cancer Institute (Hospital Duran i Reynals, L Hospitalet, Barcelona), Fundació Sant Llàtzer (Terrassa, Barcelona), and Hospital Santa Caterina (Girona). All these PCUs were composed of a complete multidisciplinary team devoted to maintaining the best possible symptom control of advanced cancer patients. Study coordination was centralized in the Catalan Cancer Institute. Patients Patients admitted to the PCUs who had inoperable intestinal obstruction owing to advanced cancer were screened for eligibility. The study was proposed successively to all patients according to inclusion and exclusion criteria. The inclusion criteria for study entry were age 18 years or more; diagnosis of advanced cancer; clinical and radiological diagnosis of intestinal obstruction; no indication for palliative surgery, assessed by a surgeon, oncologist, and palliative care specialist; no contraindication for corticoids; cognitive status (evaluated clinically) indicating that the patient understood the study and its consequences; absence of clinical history of intolerance to 5-HT 3 receptor antagonists; and written informed consent for participation in the trial. The exclusion criteria were possibility of palliative surgery after conservative treatment; mental or cognitive impairment; antecedents of intolerance to corticoids or 5-HT 3 receptor antagonists; and inclusion in other clinical trials in a period of at least four weeks. Study Treatment The patients started the experimental treatment during the first 72 hours after admission to the PCU (within 24 hours after they signed informed consent). The experimental treatment scheme was: nil by mouth; no insertion of nasogastric tube for aspiration; intravenous hydration with saline; granisetron (3 mg intravenously [i.v.] every 24 hours); and dexamethasone (4 mg i.v. every 12 hours). The option to administer haloperidol (2.5 mg subcutaneously) was retained for rescue therapy for those patients who experienced nausea or vomiting refractory to the experimental therapeutic scheme. Granisetron used in this study was stored, controlled, and labeled as a clinical trial drug in the Pharmacy Service of each hospital. The patients who had pain were treated with subcutaneous morphine at a minimum effective dose (5 mg every four hours). In those cases previously treated with strong opioids, the original opioid was substituted with morphine at a standard equianalgesic dose. Patients without pain were prescribed 5 mg of subcutaneous morphine on demand, as rescue treatment. All antiemetic treatments were suspended prior to the start of the trial. Because of their potential antiemetic effect, the anticholinergic drugs (e.g., hyoscine) were not included within the study protocol even if the patient had colic pain. Dexamethasone was included in the trial protocol despite its potential antiemetic effect, because it is the only drug that, according to meta-analyses, can facilitate the reversal of intestinal obstruction. The experimental treatment was maintained over 96 hours. If the patient had an adequate antiemetic response, the treatment was allowed to continue for a maximum of seven days, during which an antisecretory drug could be prescribed in combination.

4 262 Tuca et al. Vol. 37 No. 2 February 2009 Outcome data were collected at the baseline visit and every 24 hours during the study period (96 hours). Analysis of the difference in symptom severity between baseline and end of study was used to determine the efficacy of treatment. Data Collection and Methods of Assessment At baseline, relevant clinical data were collected (age, gender, specific cancer diagnosis, Karnofsky Performance Status [KPS], obstruction level, symptom severity, number of vomiting episodes in last 24 hours, analgesic and antiemetic drugs). The intestinal obstruction level was classified as upper, lower, and multiple levels (more than one level or diagnosis of peritoneal carcinomatosis), based on clinical and radiological data. The symptom severity was assessed using a numerical scale (0e10). During the clinical trial, rating of each symptom (nausea, continuous pain, colic pain, anorexia, and asthenia), number of vomiting episodes, and need for antiemetic or analgesic rescue doses in the last 24 hours were recorded every day. The subjective impression of response expressed by the attending physician was recorded for each case. The response to trial scheme was also evaluated according to previously established criteria of response or failure. Consensus definition of inadequate antiemetic response was: rating of nausea of more than 4; number of episodes of vomiting of 2 or more; and consumption of haloperidol as antiemetic rescue at 5 mg/day or more. The patients who did not develop adequate antiemetic control according to these criteria were recorded as treatment failures. In such cases, the experimental scheme was replaced by best possible care for the control of symptoms at the discretion of the attending physician. Adverse effects and possible toxicity of therapy were recorded every 24 hours during the clinical trial and in the follow-up period. Efficacy Evaluation and Statistical Analysis To assure the best possible clinical trial monitoring, data collection, storage, and analysis were controlled by a research team external to each PCU. Antiemetic efficacy was established by comparing symptom severity recorded at the baseline visit with the values obtained every 24 hours until the end of four days of the clinical trial. It was also evaluated as the rate of patients who met the criteria of adequate control and the subjective impression of the clinician. All data were analyzed as globally and as stratified according to the level of intestinal obstruction. The Wilcoxon test for paired samples was used to compare these variables. Symptom severity and antiemetic response according to obstruction level (lower, upper, multiple levels) were analyzed with the Kruskal-Wallis test for independent samples. Ethical Considerations The antiemetic drug in the study is theoretically equal or superior to standard treatment and does not compromise the spontaneous resolution of the intestinal obstruction. The principal investigator of each center was permanently on call in order to establish an accurate case follow-up and assure study withdrawal if the patient refused to continue. Trial protocol included a guideline for rescue treatment with antiemetic standard drugs in the case of no response to the experimental therapeutic scheme. Criteria for failure of the experimental treatment were established. The experimental scheme was substituted for standard antiemetic treatment in nonresponsive cases according to these criteria. A document was designed containing the information for the patients and this accompanied the informed consent document. The protocol for the study and documentation for the clinical trial were evaluated and approved by the Ethics Committees for Clinical Investigation of the participating centers. Results There were 24 patients recruited. Twentythree finished the trial and were valid for response evaluation. One patient declined to continue treatment during the first day of the trial, without side effects related to the treatment, and he was not valid for response evaluation. Ten patients were male (41.7%) and 14 were female (58.3%) (Table 1). The mean age was 61.3 years (standard deviation [SD] 13.0; range 40e83). All the patients had advanced cancerd14 with digestive tract cancer (58.3%), six with gynecological cancer (25.0%), and four with other different

5 Vol. 37 No. 2 February 2009 Granisetron as an Intestinal Obstruction Antiemetic 263 Table 1 Characteristics of the Patients Included in the Trial Characteristics n (%) No. of patients Total 24 Patients who finished trial 23 (95.8) Age, years (mean SD, range) , 40e83 Gender Male 10 (42) Female 14 (58) Cancer diagnosis Total 24 (100) Digestive tract 14 (58.3) Gynecology 6 (25.0) Others 4 (16.7) Site of obstruction Upper intestinal tract 6 (25.0) Lower intestinal tract 3 (12.5) Multiple levels 15 (62.5) Karnofsky index 70% 3 (12.5) 60% 5 (20.8) 50% 6 (25.0) 40% 6 (25.0) 30% 4 (16.7) Admission from Emergency service 8 (33.3) Palliative care outpatient clinic 6 (25.0) Medical oncology service 6 (25.0) Surgery service 4 (16.7) localizations (16.7%). All patients received specific cancer treatment previously. There was a clear clinical and radiological diagnosis of intestinal obstruction in all cases. At the moment of trial inclusion, all patients were not candidates for more specific cancer treatments or palliative surgery. Lower intestinal obstruction was diagnosed in three patients (12.5%), upper obstruction in six patients (25.0%), and multiple levels or peritoneal carcinomatosis in 15 patients (62.5%). Baseline performance status varied between 30% and 70% on the KPS: three patients, 70%; five, 60%; six, 50%; six, 40%; and four, 30% (66.7% of patients had KPS of 50% or less). In all cases, a maximum period of 72 hours had passed since diagnosis of bowel obstruction. Eight patients (33.3%) were admitted to the PCU from the Emergency Service, six (25.0%) from the outpatient clinic of the Palliative Service, six (25.0%) from the Medical Oncology Service, and four (16.7%) from the Surgery Service. All patients had inadequate control of nausea and vomiting at the time of inclusion in the trial, despite treatment with standard antiemetics in most cases (Table 2). Twenty-three patients (96.0%) had received antiemetic drugs prior to trial inclusion. The standard treatment prescribed was: haloperidol in 13 patients (54.2%), chlorpromazine in one (4.2%), metoclopramide in eight (33.3%), hyoscine butylbromide in three (12.5%), octreotide in one (4.2%), dexamethasone in nine (37.5%), methylprednisolone in one (4.2%), and ondansetron in three (12.5%). Overall, the patients had received 1.6 antiemetic drugs per patient previous to the trial inclusion. Eleven patients (45.8%) were treated with only one antiemetic, eight (33.3%) with two, and four (16.6%) with three antiemetic drugs simultaneously. To prevent confounding the evaluation of efficacy in the three patients who had received ondansetron, this drug was suspended during a wash-out period of at least 72 hours prior to entry into the clinical trial, with the explicit consent of the patients. All patients had abdominal pain on entry into the trial, and all received analgesics at fixed doses. Seven (29.2%) were treated with non-opioid analgesics, one (4.2%) with a socalled weak opioid, and 16 (66.6%) with a strong opioid. Morphine was prescribed for those patients treated previously with a non- Treatment Table 2 Treatment Prior to Inclusion in the Present Trial (n ¼ 24) No. of Patients % Drugs with antiemetic action Drug type Haloperidol Chlorpromazine Metoclopramide Hyoscine butylbromide Octreotide Dexamethasone Methylprednisolone Ondansetron Antiemetic drugs per patient No drugs 1 4,2 One drug Two drugs More than two drugs Analgesic treatment Drug type Nonopioid Weak opioid Strong opioid

6 264 Tuca et al. Vol. 37 No. 2 February 2009 opioid or weak opioid analgesic (Table 1). Subcutaneous morphine at standard equianalgesic doses was indicated for those patients treated at the baseline visit with a strong opioid. The substitution was done without incident in any of the cases. Baseline Visit The mean severity of nausea at the baseline visit was 6.9 (SD 1.7; range 3e10). The mean number of episodes of vomiting during the 24- hour period before entry into the trial was 5.3 (SD 2.9; range 1e13). At the baseline visit, the mean severity of continuous pain was 4.4 (SD 3.2; range 0e10) and colic pain was 3.3 (SD 3.6; range 0e9.9). Asthenia and anorexia were 6.8 (SD 2.2; range 0e10) and 6.7 (SD 2.7; range 0e10), respectively. First Day of Trial Once the first day of the trial had been completed, a dramatic reduction was observed in all the symptom variables, with the exception of asthenia and anorexia. During this period, the mean scores were 2.4 (SD 2.8; range 0e8) for nausea, 1.9 (SD 3.1; range 0e8) for colic pain, 1.4 (SD 2.0; range 0e8) for continuous pain, 7.0 (SD 2.0) for asthenia, and 6.7 (SD 2.3) for anorexia. The number of episodes of vomiting was reduced by a mean of 1.0 (SD 1.9) episode per patient. Seventeen patients (73.9%) did not need antiemetic rescue treatment, and six patients (26.1%) were treated with haloperidol, in all cases with a dose lower than 10 mg/day (first day mean dose of haloperidol per patient of 3.5 mg [SD 2.5]). According to response criteria, 21 patients (91.3%) had adequate antiemetic control, and two patients (8.7%) were considered treatment failures. There were no reported adverse effects caused by trial medication. Second Day of Trial Twenty-one patients continued in the clinical trial. At the second follow-up visit at 48 hours, the symptom response was maintained. The mean ratings were 1.3 (SD 1.9; range 0e4) for nausea, 1.4 (SD 2.3; range 0e6) for colic pain, 1.2 (SD 2.2; range 0e7) for continuous pain, 7.1 (SD 2.2) for asthenia and 6.7 (SD 2.3) for anorexia. The mean of the number of episodes of vomiting was 0.5 (SD 1.0) episodes per patient. Fifteen patients (71.4%) did not need antiemetic rescue treatment, and six patients (28.6%) were treated with haloperidol, in all cases with a dose lower than 5 mg/day (second day mean dose of haloperidol per patient of 2.8 mg [SD 1.9]). According to response criteria, 21 patients (91.3%) had adequate antiemetic control on the second day of the trial. There were no reported adverse effects caused by trial medication. Third Day of Trial Twenty-one patients continued in the clinical trial. The mean scores were 0.9 (SD 1.6; range 0e4) for nausea, 0.9 (SD 1.9; range 0e6) for colic pain, 1.7 (SD 2.1; range 0e7) for continuous pain, 7.1 (SD 2.4) for asthenia, and 6.5 (SD 2.4) for anorexia. The mean of episodes of vomiting was 0.7 (SD 1.2) episodes per patient. Fifteen patients (71.4%) needed no antiemetic rescue treatment, and six patients (28.6%) were treated with haloperidol, in all cases with a dose lower than 5 mg/day (mean dose 2.6 mg [SD 1.4]). According to the response criteria, 21 patients (91.3%) had adequate antiemetic control. One patient developed headache, which could be attributed to the drug. This potentially drug-related adverse effect spontaneously resolved and did not require modification of treatment. Final Visit of Trial At the final visit of the study (96 hours from the start of the treatment), the reductions in the severity of nausea, colic pain, and continuous pain were maintained. Twenty-one patients finished the trial. The mean scores were 0.8 (SD 1.9; range 0e8) for nausea, 0.4 (SD 1.0; range 0e3) for colic pain, 1.2 (SD 2.2; range 0e7) for continuous pain, 7.0 (SD 2.5) for asthenia, and 6.4 (SD 2.8) for anorexia. The mean of the episodes of vomiting was 0.9 (SD 2.1) episodes per patient (range 0e9). Fifteen patients (71.4%) did not need antiemetic rescue treatment, and six patients (28.6%) were treated with haloperidol, in all cases with a dose lower than 10 mg/day (mean dose of haloperidol 4.3 mg [SD 2.4]). According to response criteria, 20 patients (86.9%) had adequate antiemetic control, and one patient was considered a treatment failure. There

7 Vol. 37 No. 2 February 2009 Granisetron as an Intestinal Obstruction Antiemetic 265 were no reported adverse effects owing to trial medication. Follow-Up Data Twenty patients continued granisetron for at least seven days more. During the first 10 days of the follow-up period, four patients (20.0%) had spontaneous resolution of the MBO. Nine patients (45.0%) maintained oral liquid intake without complete recuperation of digestive transit. Survival after the MBO diagnosis was 43.5% at one month and 21.7% at three months. Global Evaluation and Statistical Analysis Overall, 20 patients (83.3%) had an adequate antiemetic response to the study treatment (Table 3, Fig. 1). Three patients (12.5%) were considered treatment failures, two on the first day of the trial and one at the last visit (96 hours). The subjective assessment of the attending physician of overall symptom response was satisfactory in 20 patients, coinciding fully with response criteria previously established by the research team (Fig. 2). According to the use of rescue antiemetic drug, we observed a complete antiemetic response (no rescue drug) in 14 patients (58.3%) and a partial response (haloperidol as rescue dose in a dose lower than 5 mg/day) in six patients (25.0%). The analysis of efficacy was established comparing the symptom variables at the start with those at the end of the trial period (96 hours) using the Wilcoxon test for paired samples. Also, the differences between the variables in the follow-up visits at 24, 48 and 72 hours were analyzed to assess the speed of resolution of the symptoms and their consolidation over the subsequent days. Nausea and the number Table 3 Overall Response to Clinical Trial Treatment Patients n % Total patients included Number evaluable for efficacy Response evaluation Failure to trial treatment Adequate control of nausea and vomiting Complete response (no rescue treatment) Partial response (requirement of rescue treatment) Baseline Day1 Day 2 Day 3 Final Control Nausea Colic Pain Continous Pain Anorexia Asthenia Fig 1. Evolution of nausea, anorexia, asthenia, colic and continuous pain during trial. of episodes of vomiting underwent a reduction (P < 0.001) between the baseline and the follow-up visit at 24 hours, and were maintained at follow-up at 48 and 72 hours, with the final visit at 96 hours. The continuous pain and colic pain also underwent improvement at 24 hours (P < 0.05), and was statistically highly significant at 96 hours (P < 0.001). The mean scores for asthenia and anorexia were stable and did not show statistically significant differences (Table 4). On stratification of the study sample according to levels of occlusion (upper, lower, and multiple), we observed that an upper intestinal occlusion was associated with a greater mean severity in all of the variables. The responses, according to the pre-established criteria, were satisfactory in four of six cases (67%) of upper intestine occlusion, in all (100%) cases of lower intestine occlusion, and in 13 of 15 cases (87%) of multiple-level occlusion. As such, there was a greater symptom response in those patients with an occlusion at the lower and multiple intestinal levels. However, analyzing Baseline Day 1 Day 2 Day 3 Final Control Rescue drugs No adequate emesis control Fig 2. Evolution of number of patients without adequate emesis control and number of patients who needed rescue doses during trial.

8 266 Tuca et al. Vol. 37 No. 2 February 2009 these data using the Kruskal-Wallis test for independent samples, the differences were not statistically significant, owing probably to the small patient sample and the tendency for the occlusions to be grouped in the multiplelevel category. Discussion Peristalsis is the result of a series of local reflexes, which includes the contraction of intestinal muscle above a stimulus and relaxation of muscle below this stimulus. Mucosal or mechanical distension provokes the release of 5- HT by enterochromaffin cells, which stimulates intrinsic enteric afferent interneurons. Above the stimulated area, ascending cholinergic interneurons relay the signal to excitatory motor neurons containing acetylcholine and substance P. The result is the peristaltic contraction of intestinal circumferential muscles. Below the mechanical or mucosal stimulus, descending cholinergic interneurons activate inhibitory motor neurons containing nitric oxide, vasoactive intestinal polypeptide (VIP) and adenosine triphosphate (ATP), provoking relaxation of these muscles. In digestive obstruction, a drastic distension stimulus is extended to the intestinal area proximal to the obstruction level. The release of 5-HT activates secretomotor neurons (VIP) causing vasodilatation and hypersecretion by crypt cells, and also activates motor neurons causing giant peristaltic contractions. The stimulation of vagal primary afferent neurons, which are connected with brainstem neurons, is directly involved in the vomiting reflex. Selective antagonists of 5-HT 3 receptors inhibit release of 5-HT, block activation of vagal primary afferent neurons, and reduce stimulation of the vomiting center. 43,44,53 It is well known that selective 5-HT 3 receptor antagonists are highly effective against emesis induced by cancer chemotherapy, radiotherapy, or anesthesia. 8e12,38e42 Selective 5-HT 3 receptor antagonists are seldom used for emesis control in advanced cancer patients who are no longer receiving cancer chemotherapy or radiotherapy. Clinical reports about the use of 5-HT 3 receptor antagonists in palliative care are very limited. 45e51 Between 1992 and 1998, there were several clinical notes published that Table 4 Symptom Changes with Trial Treatment: Efficacy Results Trial Day: Baseline 24 hours P 48 hours P 72 hours P 96 hours P Symptom severity Nausea (mean score SD) < < < <0.001 No. of vomiting episodes (mean SD) < < < <0.001 Colic pain (mean score SD) < < < <0.001 Continuous pain (mean score SD) < < < <0.001 Anorexia (mean score SD) NS NS NS NS Asthenia (mean score SD) NS NS NS NS Antiemetic rescue treatment Antiemetic drug rescue, n (%) e 6 (25.0) e 6 (25.0) e 6 (25.0) e 6 (25.0) e Haloperidol (mean dose SD mg/day) e e e e e Adverse side effect, n (%) e 0 (0) e 0 (0) e 1 (4.3) e 0 (0) e Patients following trial, n (%) 23 (95.8) 21 (87.5) e 21 (87.5) 21 (87.5) e e e Criteria of symptom control Adequate control, n (%) e 21 (87.5) e 21 (87.5) e 21 (87.5) e 20 (83.3) e No adequate control, n (%) e 2 (8.3) e - e e 1 (4.2) e

9 Vol. 37 No. 2 February 2009 Granisetron as an Intestinal Obstruction Antiemetic 267 suggested a high effectiveness of these drugs in the antiemetic control of nausea unrelated to cancer chemotherapy. In some cases, they were administered through the subcutaneous route. 45,46 Currow et al. and Tuca 49,50 published two observational descriptive studies, in acquired immunodeficiency syndrome (AIDS) patients and terminal cancer patients, respectively, demonstrating a rate of overall effectiveness of more than 60% in those cases in which there had not been an adequate control of emesis with standard treatment. 50 The study also demonstrated that the most difficult situation to control was nausea and vomiting resulting from MBO. Nevertheless, 5-HT 3 receptor antagonists achieved a satisfactory emesis control in more than 55% of cases of MBO. In 1998, Mystakidou et al. published a randomized clinical trial comparing seven different antiemetic treatments, in monotherapy or in combinations, in advanced cancer patients with emesis not related to chemotherapy or radiotherapy and not responding to standard treatment. 51 In this study, the patients who had nausea and vomiting owing to MBO were excluded. Tropisetron (another 5HT 3 receptor antagonist) formed a part of five of these seven treatment schedules in monotherapy or in combination with metoclopramide, chlorpromazine, and dexamethasone. The conclusion was that the antagonists of serotonin receptors were more efficacious than the standard treatment, given that all of the schemes that had included tropisetron showed significant differences in the control of nausea compared with the control group that had regimens of metoclopramide plus dexamethasone or chlorpromazine plus dexamethasone. The present trial represents the first study exploring the efficacy of 5-HT 3 receptor antagonists in inoperable MBO. The sociodemographic data obtained in this study (distribution by age and gender) and cancer origin, mainly digestive and gynecological tumors, correspond to the natural history of the diseases and are similar to other series in palliative care patients. The inclusion of patients into this clinical trial was especially difficult because patients with MBO present a very impaired general status and frequently have cognitive failure. The need for urgent intervention and the admission of patients in emergency or surgery departments add to the difficulty because conservative treatment received in these services usually includes nasogastric tubes for aspiration, which, in the present study, was an exclusion criterion. The majority of patients included in the trial had been treated previously by specialist teams with appropriate antiemetic (96%) and analgesic drugs (100%). Given that all patients included in the clinical trial fulfilled inclusion criteria (persistent nausea and vomiting), we could consider that, indeed, the patients were refractory to standard treatment. The results of the present trial show a significant reduction of scores for nausea and number of vomiting episodes in the majority of patients (Figs. 1 and 2). The emesis control was drastic and statistically significant from the first day of treatment and the response was maintained during the three days of the trial. The requirement for rescue antiemetic therapy (haloperidol) was slight, and a very low dose was required. According to antiemetic rescue requirements, we can consider that 14 patients (58.3%) had a complete antiemetic response (no rescue doses), and six patients (25.0%) had a partial response (need for haloperidol rescue with a dose of more than 5 mg/day). Given the excellent antiemetic control achieved, the need for nasogastric tubes was avoided in all the patients who responded to trial treatment. As was expected, the severity of the asthenia and anorexia was not modified. The intensity of the pain was reduced during the trial despite there being no changes in the previously established equianalgesic dose of the opioid drugs. This phenomenon suggests that the good antiemetic control achieved and the reduction of stimulation of ascending cholinergic interneurons mediated by 5-HT 3 receptor antagonists could assist in the reduction of distension and abdominal contractions, reducing pain as a consequence. The efficacy evaluation based on the previously established consensus criteria coincides with subjective impressions of the attending physicians, showing a satisfactory response in 20 patients (86.9%). Only three patients (12.5%) had inadequate emesis control and were considered treatment failures. The safety profile was excellent. Only one patient complained of slight headache, which could be attributed to the drug. This adverse

10 268 Tuca et al. Vol. 37 No. 2 February 2009 phenomenon resolved during the treatment schedule and did not require the patient to be withdrawn from the trial. The analyses of the data confirm that granisetron is a highly efficacious and safe drug for use in the control of emesis resulting from malignant inoperable intestinal obstruction. The absence of significant pharmacodynamic differences between the 5-HT 3 receptor antagonists suggests that the antiemetic efficacy can be extended, within the present clinical situation, to all drugs in this group. The excellent emesis control in patients who have not responded to adequate medication previously administered suggests that selective 5-HT 3 receptor antagonists are more potent than standard antiemetic treatment. Further studies, including controlled Phase III clinical trials, are warranted to explore the probable superiority of the 5-HT 3 receptor antagonists compared with standard drugs with respect to efficacy in monotherapy, and in combination with other pharmacological agents, such as anticholinergics and somatostatin analogs. References 1. Ripamonti C. Management of bowel obstruction in advanced cancer patients. J Pain Symptom Manage 1994;49:193e Ripamonti C, De Conno F, Vantafridda V, et al. Management of bowel obstruction in advanced and terminal cancer patients. Ann Oncol 1993;4:15e Ripamonti C, Twycross R, Baines M, et al. Clinical practice recommendations for management of bowel obstruction in patients with end-stage cancer. Support Care Cancer 2001;9:223e Feuer DJ, Bradley KE. Corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev 2000;2. CD Feuer DJ, Bradley KE. Systematic review and meta-analysis of corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecologic and gastrointestinal cancers. Ann Oncol 1999;10:1035e Miller G, Boman J, Shrier I, Gordon PH. Readmission for small-bowel obstruction in the early postoperative period: etiology and outcome. Can J Surg 2002;45:255e Parker MC, Baines MJ. Intestinal obstruction in patients with advanced malignant disease. Br J Surg 1996;83:1e2. 8. Lund B, Hansen M, Lundvall F, et al. Intestinal obstruction in patients with advanced carcinoma of the ovaries treated with combination chemotherapy. Surg Gynecol Obstretics 1989;169:213e Rubin SC, Hoskins WJ, Benjamin I, Lewis JL. Palliative surgery for intestinal obstruction in advanced ovarian cancer. Gynecol Oncol 1989;34: 16e Tunca JC, Buchler DA, Mack EA, et al. The management of ovarian-cancer-caused bowel obstruction. Gynecol Oncol 1981;12:186e Castaldo TW, Petrilli ES, Ballon SC, Lagasse LD. Intestinal operations in patients with ovarian carcinoma. Am J Obstet Gynecol 1981;139:80e Piver MS, Barlow JJ, Lele SB, Frank A. Survival after ovarian cancer-induced intestinal obstruction. Gynecol Oncol 1982;13:44e Ripamonti C, Panzeri C, Groff L, et al. The role of somatostatin and octreotide in bowel obstruction: pre-clinical and clinical results. Tumori 2001; 87:1e Krebs HB, Goplerud DR. Mechanical intestinal obstruction in patients with gynecologic disease: a review of 368 patients. Am J Obstet Gynecol 1987;157:577e Clarke-Pearson DL, Chin NO, DeLong ER, et al. Surgical management of intestinal obstruction in ovarian cancer. I. Clinical features, postoperative complications, and survival. Gynecol Oncol 1987; 26:11e Beattie GJ, Leonard R, Smyth JF. Bowel obstruction in ovarian carcinoma: a retrospective study and review of the literature. Palliat Med 1989;3: 275e Spears H, Petrelli NJ, Herrera L, Mittelman A. Treatment of bowel obstruction after operation for colorectal carcinoma. Am J Surg 1988;155:383e Pictus D, Marx MV, Weyman PJ. Chronic intestinal obstruction: value of percutaneous gastrostomy tube placement. Am J Radiol 1988;150:295e Van Oojen B, van der Burg MEL, ASTh Planting, et al. Surgical treatment of gastric drainage only for intestinal obstruction in patients with carcinoma of the ovary or peritoneal carcinomatosis of other origin. Surg Gynecol Obstet 1993; 176:469e Jong P, Sturgeon J, Jamieson CG. Benefit of palliative surgery for bowel obstruction in advanced ovarian cancer. Can J Surg 1995;38(5):454e Sun X, Li X, Li H. Management of intestinal obstruction in advanced ovarian cancer: an analysis of 57 cases. Chung Hua Chung Liu Tsa Chih 1995;17: 39e Redman CWE, Shafi MI, Ambrose S, et al. Survival following intestinal obstruction in ovarian cancer. Eur J Surg Oncol 1988;14:383e386.

11 Vol. 37 No. 2 February 2009 Granisetron as an Intestinal Obstruction Antiemetic Buther JA, Cameron BL, Morrow M, et al. Small bowel obstruction in patients with a prior history of cancer. Am J Surg 1991;162:624e Woolfson RG, Jennings K, Whalen GF. Management of bowel obstruction in patients with abdominal cancer. Arch Surg 1997;132:1093e Chan A, Woodruff RK. Intestinal obstruction in patients with widespread intra-abdominal malignancy. J Pain Symptom Manage 1992;7:339e Ripamonti CI, Easson AM, Gerdes H. Management of malignant bowel obstruction. Eur J Cancer 2008;44(8):1105e Ventafridda V, Ripamonti C, Caraceni A, et al. The management of inoperable gastrointestinal obstruction in terminal cancer patients. Tumori 1990; 76:389e Ripamonti C, Mercadante S, Groff L, et al. Role of octreotide, scopolamine butylbromide and hydration in symptom control of patients with inoperable bowel obstruction having a nasogastric tube: a prospective, randomized clinical trial. J Pain Symptom Manage 2000;19:23e Mercadante S, Ripamonti C, Casuccio A, et al. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 2000;8:188e De Conno F, Caraceni A, Zecca E, et al. Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 1991;6:484e Mercadante S, Kargar J, Nicolosi G. Octreotide may prevent definitive intestinal obstruction. J Pain Symptom Manage 1997;13:352e Mulvihill SJ, Pappas TN, Fonkalsrud EW, Debas HT. The effect of somatostatin on experimental intestinal obstruction. Ann Surg 1988;207:169e Mercadante S, Ferrera P, Villari P, Marrazzo A. Aggressive pharmacological treatment for reversing malignant bowel obstruction. J Pain Symptom Manage 2004;28:412e Lau PW, Lorentz TG. Results of surgery for malignant bowel obstruction in advanced, unresectable, recurrent colorectal cancer. Dis Colon Rectum 1993;36:61e Helyer L, Easson AM. Surgical approaches to malignant bowel obstruction. J Support Oncol 2008;6(3):105e Baines M, Oliver DJ, Carter RL. Medical management of intestinal obstruction in patients with advanced malignant disease. Lancet 1985;2:990e Mercadante S, Spoldi E, Caraceni A, Naddaloni S, Simoneti MT. Octeotride in relieving gastrointestinal symptoms due to bowel obstruction. Palliat Med 1993;7:295e del Gilglio A, Soares HP, Caparroz C, Castro PC. Granisteron is equivalent to ondansetron for prophylaxis of chemotherapy induced nausea and vomiting, results of meta-analysis of randomized clinical trials. Cancer 2000;89:2301e Henzi J, Walder B, Tramer MR. Dexamethasone for prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000;90:186e Figueredo E, Canosa L. Prophylactic ondansetron for postoperative emesis, meta-analysis of its effectiveness in patient with previous history of postoperative nausea and vomiting. Eur J Anaesthesiol 1999;16:556e Figueredo E, Canosa L. Prevention or treatment of postoperative vomiting using ondansetron? A mathematical assessment. J Clin Anesth 1999;11: 24e Tramer MR, Reynolds DJ, Stoner NS, Moore RA, Mc Quay HJ. Efficacy of antagonists 5 HT3 receptors in radiotherapy-induced nausea and vomiting, a quantitative systematic review. Eur J Cancer 1998;34:1836e Hutchinson SMW, Beattie G, Shearing CH. Increased serotonin excretion in patients with ovarian carcinoma and intestinal obstruction. Palliat Med 1995;9:67e Jiménez García A, Balongo García R, Alconero FF, et al. Intestinal wall damage in simple ileus in rabbits: immune modulator role of somatostatin. Hepatogastroenterology 2004;58:1030e Mulvenna PM, Regnard CF. Subcutaneous ondansetron [letter]. Lancet 1992;339: Nicholson GA, Evans C, Mansi J. Ondansetron in intractable nauseas and vomiting. [letter]. Lancet 1992;339: Cole MC, Robinson F, Harvey L, Trethowan K, Murdoch V. Successful control of intractable nausea and vomiting requiring combined ondansetron and haloperidol in patients with advanced cancer. J Pain Symptom Manage 1994;9:48e Mercadante S, Sarpio M, Seretta R. Ondansetron in nausea and vomiting induced by spinal morphine. J Pain Symptom Manage 1998;16:259e Currow DC, Coughlan M, Fardell B, Cooney NJ. Use of ondansetron in palliative medicine. J Pain Symptom Manage 1997;13:302e Tuca A. Effectiveness of selective antagonist of 5 HT3 receptors in nausea and vomiting not induced by cancer chemotherapy. [Spanish]. Med Pal 2000; 7:62e Mystakidou K, Befon S, Liossi C, Viachos L. Comparison of the efficacy and safety of tropisetron, metoclopramide and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer 1998;83:1214e1223.

12 270 Tuca et al. Vol. 37 No. 2 February Lindley C, Blower P. Oral serotonin type 3-receptor antagonist for prevention of chemotherapy-induced emesis. Am J Health Syst Pharm 2000; 15:1685e Goyal RK, Hirano I. Enteric nervous system. N Engl J Med 1996;334(17):1106e Cubeddu LX, Hoffman IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 1990;322: 810e816.