Long-Acting Octreotide for the Treatment and Symptomatic Relief of Bowel Obstruction in Advanced Ovarian Cancer

Transcription

1 Vol. 30 No. 6 December 2005 Journal of Pain and Symptom Management 563 Clinical Note Long-Acting Octreotide for the Treatment and Symptomatic Relief of Bowel Obstruction in Advanced Ovarian Cancer Ursula A. Matulonis, MD, Michael V. Seiden, MD, PhD, Maria Roche, NP, Carolyn Krasner, MD, Arlan F. Fuller, MD, Tina Atkinson, B.A., Alice Kornblith, PhD, and Richard Penson, MD Division of Medical Oncology (U.A.M., T.A., A.K.), Dana-Farber Cancer Institute, Boston; and the Divisions of Hematology and Oncology (M.V.S., M.R., C.K., A.F.F., R.P.) and Gynecologic Oncology (M.V.S., M.R., C.K., A.F.F., R.P.), Massachusetts General Hospital, Boston, Massachusetts, USA Abstract Symptoms of malignant bowel obstruction in patients with recurrent ovarian cancer lead to a poor quality of life. Sandostatin LAR Ò Depot (LAR) (Novartis Pharmaceuticals Corp., East Hanover, NJ) is an intramuscular, monthly administered, long-acting form of octreotide. LAR s safety and utility were evaluated in a pilot study enrolling 15 advanced ovarian cancer patients with bowel dysfunction. Once safety with subcutaneous (SQ) octreotide was assessed, patients were given 30 mg LAR on Day 1 and octreotide SQ for 2 weeks. Of 13 evaluable patients, three patients had a major response to LAR treatment with reduction in bowel obstruction, two had a minor response, four had no response, and four had progressive. Three patients remained on LAR for more than 9 months. No significant toxicities were attributable to octreotide or LAR. Because three patients received nine or more monthly injections of LAR, possible direct antitumor effects of LAR or synergy with chemotherapy needs to be explored. J Pain Symptom Manage 2005;30: Ó 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Long-acting octreotide, ovarian cancer, bowel obstruction Introduction Bowel obstruction and of chronic intermittent obstruction or ileus are common complications in patients with recurrent cancer of the ovary and peritoneum, and are reported in up to 42% of patients. 1,2 Once Address reprint requests to: Ursula A. Matulonis, MD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Accepted for publication: May 26, Ó 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. a malignant bowel obstruction (MBO) occurs, median survival is approximately 3 months. 3 Etiologies of MBO in ovarian cancer include extrinsic occlusion of the lumen, malignant infiltration of mesentery and intestinal muscle and serosal surfaces, and intraluminal obstruction Secondary intestinal immobility resulting from opioids and certain antiemetics also plays a role in MBO. Bowel obstruction results in an accumulation of gastric, pancreatic, and biliary secretions; reduced absorption of water and sodium; and an increase in water and sodium secretion because of increased gastric /05/$--see front matter doi: /j.jpainsymman

2 564 Matulonis et al. Vol. 30 No. 6 December 2005 distension This pathophysiology results in vomiting, nausea, pain, esophagitis, constipation, and/or diarrhea. The clinical picture of MBO can vary greatly from patient to patient depending on the location of the obstruction, whether there are single versus multiple points of obstruction, the mechanism of obstruction, exacerbating medications, and the extent and sites of tumor recurrence. Many patients with ovarian cancer will not be eligible for surgery because of the presence of diffuse intraperitoneal carcinomatosis, multiple partial bowel obstruction points, ascites, and/or previous radiotherapy, or because of their overall functional status. 10,11 Palliative therapies to treat bowel obstruction in patients who are deemed nonsurgical candidates include gastric venting via placement of a nasogastric or gastrostomy tube, or medications such as anticholinergic drugs; analgesics; steroids; antiemetics; smooth muscle relaxants such as atropine, scopolamine, or loperamide; and somatostatin and its analogs. 6, Somatostatin and its analogs (octreotide and vapreotide) have been used either alone or in combination to alleviate the from an MBO in ovarian cancer and other malignancies. 13,16,17 Somatostatin inhibits hormones such as glucagon and insulin, reduces acid secretion, slows intestinal mobility, decreases bile flow, and reduces splanchnic blood flow. 18 Octreotide exerts actions similar to somatostatin, but has a longer half-life and more potently inhibits growth hormone, glucagon, and insulin. Octreotide suppresses luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH) and inhibits release of gastrin, secretin, vasoactive intestinal peptide, motilin, and pancreatic polypeptide Sandostatin LAR Ò Depot (LAR) (Novartis Pharmaceuticals Corp., East Hanover, NJ), a long-acting depot form of octreotide that is administered intramuscularly once per month, consists of microspheres of the biodegradable polymer, poly(dl-lactide-co-glycolide glucose). 21 One intramuscular (IM) injection of LAR leads to an initial octreotide peak one hour later, followed by decreased concentrations over the next one to two weeks and an increase from Days 14 to 42, with levels falling thereafter. 22 LAR has not been evaluated in MBO but has been tested at different dose levels in carcinoid syndrome as an alternative to the shortacting subcutaneous (SQ) form. 15 Steady-state octreotide levels were reached by Week 8 for the 20 and 30 mg doses of LAR, and by Week 12 for the 10 mg group. The drug was well tolerated, regardless of the dose of LAR, and efficacy (control of flushing) was better controlled at doses above 20 mg. This is the first study to use LAR in patients with recurrent ovarian cancer who have signs and/or of inoperable bowel obstruction. The objectives of this pilot study were to assess the effectiveness of LAR in improving the of inoperable bowel obstruction and to measure toxicities. Methods Patients were enrolled from the Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Brigham and Women s Hospital, all in Boston, Massachusetts, between 2002 and All patients signed a written, informed consent approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board, which has authority over all cancer studies at the above-mentioned institutions. Eligibility criteria included a diagnosis of documented recurrence of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer and the presence of a bowel obstruction or a chronic intermittent bowel obstruction based on a compilation of clinical signs,, and/or radiographic evidence. The obstruction could not be surgically correctable, as assessed by the patient s gynecologic oncology surgeon. Furthermore, patients could not have had prior use of somatostatin or its analogs and must have had a total bilirubin #1.5 g/dl, life expectancy greater than 2 months, and ability to give written informed consent. Radiographic confirmation of obstruction was not required for entry into the study. If radiographic evidence of bowel obstruction was made, this was either performed through plain radiography or CT scan. Patients could concomitantly receive systemic chemotherapy; patients were also eligible if they were on hospice. Patients were not allowed to participate if they had a current history of diabetes mellitus requiring insulin or antihyperglycemic agents, clinically significant EKG (electrocardiogram) abnormalities, a family history of a prolonged QT-interval syndrome, history of

3 Vol. 30 No. 6 December 2005 Long-Acting Octreotide Use in Bowel Obstruction 565 carcinoid, pancreatitis, or active biliary disease, receipt of other investigational agents on a protocol within 30 days of study entry, or untreated hypothyroidism. After informed consent was obtained, patients were immediately given a single test dose of 100 mg of octreotide delivered subcutaneously and then observed for 60 minutes. If signs of intolerance such as hypotension, hypertension, chest pain, shortness of breath, or anaphylactic reaction occurred, patients were removed from the study and received no further octreotide or LAR. If the patient tolerated SQ octreotide, he/ she immediately received 30 mg LAR delivered intramuscularly in the buttock. In addition, during the initial two weeks of therapy, patients self-administered 100 mg of octreotide subcutaneously three times per day to achieve immediate therapeutic levels. Patient logs and unused octreotide were used to confirm octreotide use. Patients were allowed to use lidocaine/prilocaine cream (AstraZeneca Pharmaceuticals LP, Wilmington, DE) preinjection to ameliorate injection pain. If patients were on home hospice, they were allowed to receive LAR at home, with the injection being performed by a registered nurse. Patients continued on IM LAR at a dose of 30 mg until one of the following occurred: 1) clear progression of or intolerability of LAR or octreotide, 2) the patient opted out of the study or the physician opted to remove the patient from the study, or 3) any Grade 3 or 4 toxicity by Common Toxicity Criteria (CTC) directly related to either octreotide or LAR. Patients were asked to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the OV28 pretreatment and once monthly at the time of the LAR injection visit. The EORTC QLQ-C30 and the OV28 are validated surveys used to measure quality of life in cancer patients (QLQ-C30) and specifically in ovarian cancer patients (OV28). 23,24 Measurement on Therapy Symptom responses to octreotide and LAR use were measured by the most significant change in while on study and were scored as follows: major response, significant clinical benefit resulting in significant reduction or resolution of (i.e., significant or complete resolution of nausea/ vomiting and/or ability to remove nasogastric tube); minor response, minor reduction in that fell between a major reduction and no change; no change, were neither significantly clinically improved nor worse; and progression, of nausea/vomiting worsened following LAR treatment. Results Fifteen patients were enrolled into this pilot study. All patients had a diagnosis of recurrent epithelial ovarian cancer. Table 1 lists the patients ages at the time of study entry, number of lines of prior chemotherapy, whether the patient was on chemotherapy, predominant sites of ovarian cancer as assessed by CT scanning, by patient report, and radiographic findings if radiography was performed. The mean age of patients was 61 years. The mean number of prior chemotherapies at the time of entry into the study was 5.6, with a range of Patient 8 is not included in any assessments since she withdrew consent prior to receiving any treatment because of rapidly progressing cancer. One patient (no. 1) developed hives after receiving the test dose of SQ octreotide; this reaction cleared quickly with oral diphenhydramine. This patient was removed from the trial, and she received no further SQ octreotide or LAR. Of the 14 patients enrolled in the study who received some treatment, seven patients had a documented small bowel obstruction (SBO) or partial SBO radiographically. One of these patients did not receive LAR because of an allergic reaction to octreotide (no. 1). The remaining seven patients either had no radiographic evidence of a bowel obstruction (five patients) or did not have radiographic studies done (two patients). Sites of cancer recurrence were determined by CT scanning, and most patients had peritoneal metastases as the predominant site of disease (Table 1). Nausea and vomiting were the most common complaints, and patients are listed in Table 1. Table 2 reviews the treatment history, best symptom response to LAR therapy on study, and survival (measured from day of starting treatment on study). Of the 13 patients who received at least one dose of LAR, four patients received only one

4 566 Matulonis et al. Vol. 30 No. 6 December 2005 Table 1 Patient Characteristics Patient No. Age at Time of Study Entry # of Lines of Prior Chemotherapy (Including at Time of Enrollment) Was Patient Receiving Chemotherapy While on Study? Predominant Sites of Cancer Predominant Symptoms Radiographic Findings Yes Pl, per N/V/abd pain SBO Yes Per, asc N/V No SBO Yes Pl, omen, per N/V/abd pain No SBO Yes Pl, per V/con/early sat No SBO Yes Pl, per N/V/bl/abd pain No SBO Yes Pl, per N/V/abd pain No SBO Yes Per N/V/abd pain SBO Yes Liver mets V/abd pain/bl/con Partial SBO Yes Pl, per N/V/bl X-ray not performed Yes Per, asc, nodal V/con/abd pain Partial SBO No Pl, per, nodal Alternating diarrhea/con SBO Yes Pl, per N/V/abd pain, bl X-ray not performed No Per V/bl/abd pain SBO No Per Int N/V SBO Pl ¼ pleural; per ¼ peritoneal; asc ¼ ascites; omen ¼ omental; N ¼ nausea; V ¼ vomiting; bl ¼ bloating; con ¼ constipation; int ¼ intermittent; abd ¼ abdominal; sat ¼ satiety; SBO ¼ small bowel obstruction. injection of LAR. One of those four patients (no. 15) received all 42 injections of SQ octreotide, while the others received 30 (no. 5), seven (no. 13), and four (no. 10) doses. The four patients who received only a single LAR injection discontinued study treatment because of progression of their original, suggesting lack of efficacy of octreotide Table 2 Length of Time on Study, Response to Treatment, and Survival Patient No. Months on Study #ofsq Injections # of LAR Injections Reasons for Removal from Study Best Clinical Response to SQ Octreotide/LAR # of Days between Study Entry and Death Reaction to SQ Not assessable 853þ octreotide Progression of Minor 273 and cancer Progression of cancer Major Progression of cancer No response Progression of Progression Progression of cancer/ Minor Progression of No response 115 and cancer (12 on study Still on trial Major 484þ and 3 off study) Progression of Progression Still on trial Major 321þ Progression of No change Progression of Progression Progression of No change Progression of disease/ Progression 15

5 Vol. 30 No. 6 December 2005 Long-Acting Octreotide Use in Bowel Obstruction 567 and LAR. Patient 15 had the shortest survival on study and had therapy stopped because of rapidly progressing ovarian cancer. Nine patients received more than one injection of LAR. All of these patients received two full weeks (42 doses) of SQ octreotide. Of these nine patients, three patients (nos. 3, 9, and 11) had a major response to treatment, and two of these patients remain on LAR for 15þ months (no. 9) and 10þ months (no. 11). Of these three patients, two (nos. 9 and 11) had a partial SBO on radiography. Two patients had a minor response to therapy, and one patient remained on study for 9 months before significant cancer progression. Four patients had no change in their. Of the 13 patients who received LAR, three patients were not actively receiving chemotherapy during study treatment. None of the three patients who were not receiving chemotherapy had a response to LAR. Among the 13 patients who received at least one dose of LAR, mean survival was 226 days, median survival was 89 days, and two patients are alive at 853þ and 484þ days. Toxicities were graded from 1 through 4 by CTC. Table 3 lists toxicities that were determined to definitely, probably, or possibly relate to LAR. No Grade 3 or 4 toxicities thought to be related to LAR occurred. Two patients who remain on long-term LAR reported pain at the injection site often extending into the buttock that lasted several days. Quality-of-life scores as measured by the EORTC QLQ-C30 and the OV28 23,24 were measured pretreatment and once monthly at the time of the LAR injection visit. There were Table 3 Toxicities Related to LAR or SQ Octreotide per Cycle per Patient Toxicity Grade 1 (n) Grade 2 (n) Pain at injection site 2 0 Constipation 1 0 Dyspepsia 1 0 Flatulence 0 1 GI (other) 1 0 Elevation of alkaline 0 1 phosphatase Elevation of SGOT 1 1 Abdominal pain/cramping 1 1 Headache 1 0 Myalgia 1 0 Dyspnea 0 3 Gallstones 0 0 no significant differences among the QOL scores, specifically the QLQ-C30, OV28, and the abdominal subscale of the OV28, regardless of response to LAR. Discussion This pilot study represents the first use of LAR in recurrent ovarian cancer patients with surgically inoperable bowel obstruction or of chronic bowel obstruction. Although the mean survival on therapy was only 3 months and thus comparable to prior literature, it is notable that three patients were on LAR for 9 months or greater, and two of these patients still remain on study, with one patient receiving 15 months of therapy. Of the 13 evaluable patients, three patients had a major response to study treatment, two had a minor response, four experienced no change in, and four patients worsened on treatment. There were no Grade 3 or 4 toxicities directly related to LAR, and the most frequently reported side effect was pain at the injection site. Several studies, both prospective nonrandomized and randomized, have documented the efficacy of octreotide in patients with MBO. 6,16,17 Mangili et al. 16 tested octreotide from 300 to 600 mg per day as either an SQ bolus or a continuous infusion. Thirteen patients were enrolled, and all had obstruction present based on clinical signs and confirmed by plain abdominal radiography. Some patients were given nasogastric tube drainage (eight patients), and others were given additional drugs such as metoclopramide, morphine, and haloperidol. Complete relief of occurred within 3.07 days, and vomiting stopped within 2--3 days of starting treatment in most patients. Mean survival from discharge was 15 days (range days). Mercadante 17 examined octreotide in 14 patients with MBO secondary to various cancers and also used octreotide from 0.3 to 0.6 mg per day via SQ bolus or continuous SQ infusion. Vomiting was controlled in 12 patients and reduced in two. The drug was well tolerated. Patients also received additional medications to reduce of bowel obstruction, such as haloperidol and analgesics. In the largest study of the use of octreotide in MBO, Riley and Fallon 25 examined 24 patients

6 568 Matulonis et al. Vol. 30 No. 6 December 2005 with various cancers who had intractable vomiting as a result of bowel obstruction that was unresponsive to a combination of antiemetics, steroids, and/or nasogastric tube drainage for 24 hours. Fourteen of the 24 had no further vomiting, and four patients showed improvement. Six patients did not respond. Larger studies thus demonstrate that not all patients will respond to octreotide even in the setting of radiographically-proven obstruction. A 68-patient trial that randomized patients with MBO to either chlorpromazine and hyoscine butylbromide or octreotide revealed significant improvement in nausea and vomiting within 3 days of starting treatment in the patients receiving octreotide. 26 Patients also received opioids in addition to chlorpromazine. There was no difference in pain control between the two groups. Our study differed from previously published studies of octreotide use in MBO in that bowel obstruction was defined by the clinical constellation of nausea, vomiting, constipation, abdominal pain, and decreased oral intake regardless of whether bowel obstruction was documented radiographically. In our study, only seven of 13 evaluable patients had documented partial or complete bowel obstruction. Response to octreotide and LAR may vary depending on sites of obstruction (diffuse bowel obstruction or ileus versus acute SBO), primary cancer type, route of administration of octreotide and LAR, and the mechanism of obstruction. Patients who have acute bowel obstruction that is documented on radiography may respond better to octreotide because of the drug s ability to reduce secretion of water, sodium, and chloride, and increase absorption of water, than patients with intermittent of bowel slowing that mimic a partial, intermittent obstruction. Larger trials of octreotide are needed in patients with MBO to define which patient subgroups can derive maximum benefit from LAR and for what reasons. Furthermore, it is not known whether the primary cancer type has any effect on the efficacy of octreotide as palliation or before a bowel obstruction occurs. LAR has certain attractive advantages in the management of MBO. SQ-administered octreotide has more limited absorption in patients with edema and low peripheral blood flow, making an IM injection possibly better absorbed. Because LAR does not reach therapeutic levels until at least 14 days after injection, patients will require SQ short-acting octreotide to provide adequate drug levels until LAR levels become therapeutic. This initial SQ course may also provide an expeditious mechanism for discerning which patients will be octreotide responsive since most studies confirm that improve in responding patients within 3 days of initiation of octreotide. Octreotide and, more recently, LAR have been associated with cancer regression, including ovarian cancer. 27 Three patients on our trial received nine or more doses of monthly LAR, raising the possibility that LAR may have contributed to cancer regression. Somatostatin and its five receptors have been found in brain, pancreatic D cells, intestinal/gastric epithelium, salivary glands, intestinal myenteric neurons, and a variety of human cancers including adenocarcinomas of the breast, ovary, prostate, kidney, colon, islet tumors, carcinoids, and lymphomas. 28 Other roles for octreotide have yet to be examined fully, such as direct antitumor effects, modulation of the GnRH and LH-releasing hormone pathways, and possible synergy with chemotherapy. In addition, whether or not improved chemotherapymanagement and/or prophylactic use of octreotide may prevent or delay bowel obstructions is not known. Because our trial has demonstrated the safety and tolerability of LAR in patients with advanced and recurrent ovarian cancer with documented bowel obstruction or of bowel obstruction, a larger Phase II trial is needed to test the effects of LAR on palliation of of MBO. Evaluating the potential of LAR to add to the effectiveness of chemotherapy will likely require a large Phase III trial in a carefully defined patient population. References 1. Beattie GJ, Leonard R, Smyth JF. Bowel obstruction in ovarian carcinoma: a retrospective study and review of the literature. J Palliat Care 1989;3: Tunca JC, Buchler DA, Mack EA, et al. The management of ovarian-cancer-caused bowel obstruction. Gynecol Oncol 1981;12:

7 Vol. 30 No. 6 December 2005 Long-Acting Octreotide Use in Bowel Obstruction Baines M, Oliver DJ, Carter RL. Medical management of intestinal obstruction in patients with advanced malignant disease: a clinical and pathological study. Lancet 1985;2: Dvoretsky PM, Richards KA, Angel C, et al. Distribution of disease at autopsy in 100 women with ovarian cancer. Hum Pathol 1988;19: Feuer DJ, Broadley DE, Shepherd JH, Barton DPJ. Systemic review of surgery in malignant bowel obstruction in advanced gynecological and gastrointestinal surgery. Gynecol Oncol 1999;75: Jatoi A, Podratz KC, Gill P, Hartmann LC. Pathophysiology and palliation of inoperable bowel obstruction in patients with ovarian cancer. Support Oncol 2004;2: Ripamonti C, Panzeri C, Groff L, Galeazzi G, Boffi R. The role of somatostatin and octreotide in bowel obstruction: pre-clinical and clinical results. Tumori 2001;87: Wright HK, O Brien JJ, Tilson MD. Water absorption in experimental closed segment obstruction of the ileum in man. Am J Surg 1971;121: Shields R. The absorption and secretion of fluid and electrolytes by the obstructed bowel. Br J Surg 1965;52: Piver MS, Barlow JJ, Lele SB, Frank A. Survival after ovarian cancer induced intestinal obstruction. Gynecol Oncol 1982;13: Castaldo TW, Petrilli ED, Ballon SC, Lagasse LD. Intestinal operations in patients with ovarian cancer. Am J Obstet Gynecol 1981;139: Ripamonti C, Bruera E. Palliative management of malignant bowel obstruction. Int J Gynecol Cancer 2002;12: Mercadante S, Ferrera P, Villari P, Marrazzo A. Aggressive pharmacological treatment for reversing malignant bowel obstruction. J Pain Symptom Manage 2004;28: Tsahalina E, Woolas RP, Carter PG, et al. Gastrostomy tubes in patients with recurrent gynecological cancer and intestinal obstruction. BJOG 1999;106: Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999;17: Mangili G, Franchi M, Mariani A, et al. Octreotide in the management of bowel obstruction in terminal ovarian cancer. Gynecol Oncol 1996;61: Mercadante S. The role of octreotide in palliative care. J Pain Symptom Manage 1994;9: Reichlin S. Medical progress: somatostatin. N Engl J Med 1983;309: Reichlin S. Medical progress (Part 2). N Engl J Med 1983;309: Fallon MT. The physiology of somatostatin and its synthetic analogue, octreotide. Eur J Palliat Care 1994;1: Product insert, LAR octreotide. 22. Scarpignato C, Pelosini I. Somatostatin analogs for cancer treatment and diagnosis: an overview. Chemotherapy 2001;47(Suppl 2): Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85: Cull A, Howat S, Greimel E, et al. A development of the European Organization for Research and Treatment of Cancer Questionnaire module to assess the quality of life of ovarian cancer patients in clinical trials. A progress report. Eur J Cancer 2001;37: Riley J, Fallon MT. Octreotide in terminal bowel obstruction of the gastrointestinal tract. Eur J Palliat Care 1994;1: Mystakidou K, Tsilika E, Kalaidopoulou O, et al. Comparison of octreotide administration versus conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double-blind, controlled study. Anticancer Res 2002;22: Jones RH, Reubi J-C, Millan D, Vasey P. Octreotide: an active agent in epithelial ovarian carcinoma? Lancet Oncol 2004;5: Bousquet C, Puente E, Buscall L, Vaysse N, Susini C. Antiproliferative effect of somatostatin and analogs. Chemotherapy 2001;47(Suppl 2):