Octreotide in the Management of Bowel Obstruction in Terminal Ovarian Cancer

GYNECOLOGIC ONCOLOGY ARTICLE NO.

61, 345–348 (1996)

0154

Octreotide in the Management of Bowel Obstruction in Terminal Ovarian Cancer GIORGIA MANGILI, M.D.,1 MASSIMO FRANCHI, M.D.,* ANDREA MARIANI, M.D., FLAVIA ZANABONI, M.D.,* EMANUELA RABAIOTTI, M.D., LUIGI FRIGERIO, M.D., PIER FRANCESCO BOLIS, M.D.,* AND AUGUSTO FERRARI, M.D. Department of Obstetrics and Gynecology, S. Raffaele Hospital, University of Milan, Milan, Italy; and *Department of Obstetrics and Gynecology, Hospital of Varese, University of Varese, Varese, Italy Received July 10, 1995

Intestinal obstruction is a common and distressing clinical complication in ovarian cancer. The aim of our study was to assess vomit control in terminal ovarian cancer patients with inoperable gastrointestinal obstruction, using a symptomatic pharmacological treatment with octreotide which obviates the need for nasogastric tube placement. We studied 13 patients, all of whom had advanced ovarian cancer FIGO stage IIIc. Seven patients were treated in the Gynecology Department of S. Raffaele Hospital, at the University of Milan, and 6 were managed in the University of Varese Hospital. Octreotide was administered at doses starting with 0.3 up to 0.6 mg (mean 0.44 mg) a day by subcutaneous bolus or continuous infusion. Octreotide controlled vomiting in all cases to grade 0 on the WHO emesis scale. Complete relief of symptoms was achieved within 3.07 days (range 1–6 days). Vomiting stopped within 2–3 days of starting treatment in most patients. In 8 patients with a nasogastric tube, drainage decreased from 2000 to under 100 ml/day after the start of octreotide treatment. No side effects were reported. All patients died with minimal distress or pain. q 1996 Academic Press, Inc.

INTRODUCTION

Intestinal obstruction is a common and distressing clinical complication in ovarian cancer and is reported in 5.5–42% of terminal patients [1–3]. Vomiting secondary to bowel obstruction is a great problem in these patients. Not all cancer patients with intestinal obstruction are fit for surgery: from 6.2 to 50% may be inoperable [2, 4– 7]. Conventional primary treatment consists of nasogastric suction and intravenous fluid supplementation or placement of a venting gastrostomy, but these approaches often require hospitalization, in addition to causing immobility and discomfort. 1 To whom correspondence should be addressed at H S. Raffaele, Istituto di Ricovero e Cura a Carattere Scientifico, Clinica Ostetrico Ginecologica, Universita` degli Studi di Milano, Via Olgettina 60, 20132 Milano, Italy. Fax: 00 39 2 2641 3592.

Baines et al. [8] published the first study on a pharmacological approach in treating nausea, vomiting, pain, and other symptoms due to inoperable bowel obstruction in advanced cancer, thereby avoiding the nasogastric tube and intravenous hydration. Various drugs and administration routes are possible. Haloperidol is considered the drug of first choice in relieving pain or vomiting [9]. Somatostatin and its analogs (octreotide and vapreotide) are new drugs under study to control symptoms due to gastrointestinal obstruction. They inhibit the release and activity of gastrointestinal hormones [10]. These drugs also modulate gastrointestinal function by reducing gastric acid secretion, slowing intestinal motility, decreasing bile flow, increasing mucus production, and reducing splanchnic blood flow [10–12]. The aim of this study was to evaluate the efficacy of a symptomatic pharmacological treatment with octreotide in controlling vomiting of terminal ovarian cancer patients with inoperable gastrointestinal obstruction, in order to obviate the need for nasogastric tube placement. METHODS

From January 1992 to May 1994 13 patients with abdominal recurrence of advanced ovarian cancer FIGO stage IIIc [13, 14] entered the study. Mean age of patients was 57.4 years (range 16–77 years). Seven patients were treated in the Gynecology Department of S. Raffaele Hospital, at the University of Milan, and 6 were managed in the Gynecologic Department of Varese University. All underwent surgery and primary- and second-line chemotherapy, and the neoplasia was no longer responsive to treatment. Eleven carcinomas were serous, 1 was a small-cell carcinoma, and 1 was a mucinous carcinoma. All cases were assessed according to WHO classification [15]. The diagnosis of gastrointestinal obstruction was made on the basis of clinical signs and confirmed by plain abdominal

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0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.

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radiography. These patients were terminally ill and surgery was done in only two cases (Nos. 3 and 8), after the diagnosis of obstruction, but without achieving total relief of symptoms. The patients’ characteristics are summarized in Table 1. Ten had ascites. Eight patients underwent nasogastric drainage and 6 received parenteral nutrition. Five complained of more than 10 episodes of vomiting daily. Parenteral hydration and nasogastric tubes were suspended when possible. Octreotide (Longastatina, Italfarmaco, Milan) was administered at a starting dose of 0.3 up to 0.6 mg (mean 0.44 mg) a day by subcutaneous bolus or continuous infusion (24 hr continuous iv infusion was used only in patient nos. 6 and 7). Other drugs were administered as necessary (Table 1). In some cases octreotide was used in first-line therapy, but it was mainly started after conventional therapies for intestinal obstruction (i.e., metoclopramide and haloperidol). The dosage of the drug was changed day by day until the symptoms were under control. The initial dosage was 300 mg/day in all patients. In five responding patients treatment was not changed. In eight patients the final treatment dosage was increased (Table 1). In four (nos. 2, 3, 5, and 13) of these patients we escalated the dosage with an increment of 300 mg, in the other four patients (nos. 6, 7, 9, and 10) with an increment of 100 mg. In relieving pain we used common analgesics; morphine was used only in patient no. 3. Episodes of vomiting (or the volume of gastric drainage in the presence of a nasogastric tube) were recorded (Table 1). Patients were also checked for side effects probably due to octreotide. RESULTS

Mean survival from the diagnosis of obstruction was 27.1 days (range 8–83 days). Octreotide controlled vomiting in all cases to grade 0 on the WHO emesis scale [16]. Complete relief of symptoms was achieved within 3 days (range 1–6 days). Vomiting stopped within 2–3 days of starting treatment in most patients. In eight patients with a nasogastric tube, mean initial production of nasogastric drainage was 1687.5 ml (range 2000–1000 ml) (Table 1). Nasogastric drainage was removed when it was decreased till under 50 ml/day and the patient achieved complete remission of vomiting. No side effects were reported. Three patients (nos. 5, 6, and 7) could resume oral intake for 64, 30, and 15 days, respectively, then they restarted vomiting and stopped the oral diet. All other patients remained on iv drips till the end. The nasogastric tube was removed from all these patients and symptoms were controlled. Colicky pain was controlled using common analgesics in association with octreotide. One patient (7.6%) treated with octreotide had necrosis of the small bowel wall above the obstruction, leading to an enterocutaneous fistula relieving the obstruction. The fistula

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developed 5 days after the diagnosis of obstruction and 3 days after octreotide administration. During treatment with octreotide the patient was on free fluids orally. Nasogastric tube produced 2000 ml on the first day of octreotide and 1200 ml when fistula developed. All patients died with minimal distress or pain. Eight of the 13 patients were discharged from the hospital and treated with octreotide at home. Mean survival from discharge was 15 days (range 4–32). DISCUSSION

Vomiting due to intestinal obstruction is a distressing symptom in patients with terminal ovarian cancer. Surgery cannot always control obstruction and symptoms in advanced cancer patients [3]. The most frequent reasons for which patients are inoperable are extensive tumor, multiple partial obstructions, and impossibility of surgical palliation. Surgery can lead to further complications in a large percentage of cases, and postoperative survival tends to be very short [6]. A patient is considered a suitable candidate for surgery when she has a life expectancy of more than 2 months [9]. Prognostic criteria have been established which help in selecting patients likely to benefit from surgical intervention [17]. They are sometimes subjective in accordance with each institution’s surgical experience and depend on the single patient’s general conditions. They are summarized in Table 2. Prolonged nasogastric suction and intravenous fluids for symptomatic treatment of inoperable patients is not recommended [9]. During long-term drainage a nasogastric tube can interfere with coughing to clear pulmonary secretions and may be associated with nasal cartilage erosion, otitis media, aspiration pneumonia, esophagitis, and bleeding [18]. The nasogastric tube is sometimes even more unpleasant for the patient than the basic condition itself. Medical treatments help rest the intestine by reducing the stimulation from bowel distension and secretions [11]. Standard medical management of inoperable intestinal obstruction consists of H2 receptor blockers, antispasmodics, and antiemetics together with analgesics for pain [19]. Octreotide is a long-acting octapeptide, with a more powerful effect and less influence on insulin secretion than somatostatin [20]. It inhibits secretion of growth hormone, gastrin, secretion, vasoactive intestinal peptide, pancreatic polypeptide, insulin, and glucagon and directly blocks the secretion of gastric acid, pepsin, pancreatic enzyme, bicarbonate, intestinal epithelial electrolytes, and water [11]. It has a half-life of about 1.5 hr after different intravenous or subcutaneous doses and can be given on a twice daily or more frequent basis by subcutaneous infusion, being rapidly absorbed by this route. The median initial dosage to control vomiting is usually 300 mg/day (100 mg 1 3/day). The characteristics of this drug encourage the develop-

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IIIc

IIIc

IIIc

IIIc

IIIc

IIIc

8

9

10

11

12

13

Mucinous

Serous

Serous

Serous

Serous

Serous

Serous

54

77

63

62

50

60

48

57

64

62 64 16 70

13

37

29

40

13

8

83

52

65

14 42 13 12 No

M

SI

SI

M

SI

M

C

No

No

No

No

No

Yes

No

No

C / fistula SI

No No Yes No

SI M M D

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

No

Yes Yes No Yes 1 3 2 3 3 5 2 ú10 ú10

S/X

S/X S/X S/X S/X S/X S/X S/X

ú10 ú10 1 ú10

S/X

S/X S/X S/X S

Y

N

N

Y

N

N

Y

Y

Y

Y Y Y N

1000

/

/

2000

/

/

1900

1000

2000

2000 2000 1600 /

1 1 1 1

3 3 3 3

mg mg mg mg

0.2 1 3 mg

0.1 1 3 mg

0.1 1 3 mg

0.1 1 5 mg

0.1 1 4 mg

0.1 1 3 mg

0.1 1 5 mg

0.1 1 5 mg

0.2 1 3 mg

0.1 0.2 0.2 0.1

Maximal dose octreotidea

2

6

2

3

4

4

5

11

3

1 1 2 2

No. days of octreotide treatment to complete remission

Haloperidol SC Ranitidine IV

/

/

/

Ranitidine IV

/

Ranitidine IV

/

Ranitidine IV

Ranitidine IV Ranitidine IV Morphine SC /

Other drugs

Note. S, symptoms; X, X ray; Y, yes; N, no; D, duodenal; SI, small intestine; C, colon; M, multiple; NG, nasogastric; SC, subcutaneously; IV, intravenously. a All started with 0.3 mg/day.

IIIc

Serous

7

Serous

IIIc

IIIc

5

Serous Serous Small cell Serous

IIIc IIIC IIIc IIIc

1 2 3 4

Initial daily No. days from Surgery production diagnosis of after No. daily of NG obstruction to Site of diagnosis of episodes of NG drainage Patient Stage Histotype Age death obstruction obstruction Ascites Diagnosis vomiting tube (ml)

TABLE 1 Characteristics of Ovarian Cancer Patients with Intestinal Obstruction

8

No discharge

No discharge

8

No discharge

No discharge

18

23

20

7 32 4 No discharge

No. days from discharge to death

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TABLE 2 Poor Prognostic Factors for Surgery in Patients with Bowel Obstruction

5.

Poor prognostic factors 6. 1 2 3 4 5 6

Intestinal motility problems due to diffuse intraperitoneal carcinomatosis Age over 65 years in association with cachexia Ascites requiring frequent paracentesis Previous radiotherapy of the abdomen or pelvis Palpable intra-abdominal masses and liver involvement or distant metastases, pleural effusion, or pulmonary metastases Multiple partial bowel obstruction with prolonged passage time on X-ray examination Note. From Ripamonti et al. [17].

7.

8.

9. 10. 11.

ment of its clinical use in palliative home care. Various authors [11, 12, 16, 21–24] describe its use in palliative care. It has been suggested [21] that when symptoms are not controlled by conventional antiemetics, octreotide should be started at a dose of 0.3 mg a day subcutaneously and titrated until the desired effect is obtained. As it is expensive, its cost–benefit ratio must be carefully considered, especially for prolonged treatment [9, 21], bearing in mind that this treatment does permit home care, avoiding costs of hospitalization, and, potentially, a better quality of life. The average survival after the diagnosis of obstruction in our patients was similar to that reported by Isbister et al. [25]. We found only 1 of 13 cases (no. 5) with necrosis of the bowel wall above the obstruction (7.6%), compared with 1 of 6 cases (16.6%) described by Stiefel and Morant [26] in patients treated with vapreotide. We consider the necrosis of the bowel wall as a blowout due to distention. We do not know if regression of vomiting in patient no. 5 was due only to octreotide or to the formation of the fistula, or possibly both. In the patients treated in this study octreotide controlled vomiting due to bowel obstruction, confirming previous reports of efficacy, without important side effects [9, 16, 21, 22, 24]. REFERENCES

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21.

22.

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26.

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