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Case:

Ms JB is a 32 year old woman with type 1 diabetes who underwent a living related donor renal transplant and a subsequent pancreas transplant. Unfortunately, both transplants were complicated by rejection and graft failure requiring re-initiation of hemodialysis in 2007. Since that time she has suffered with constant, intractable nausea with multiple episodes of vomiting throughout each day. Her symptoms were initially thought related to diabetic gastroparesis but they did not respond to metoclopramide, erythromycin or pylorus muscle botulinum toxin injections. An electrical gastric stimulator was to be placed but was aborted when a gastric emptying study was normal. Extensive workup, including laboratory studies, endoscopy, CNS imaging and abdominal imaging, was unrevealing. She received little or no benefit from adequate trials of domperidone, prochlorperazine, ondansetron, oral granisetron, promethazine, trimethobenzamide, scopolamine, mirtazapine, dronabinol, pancreatic enzymes and a proton pump inhibitor.

She underwent voluntary admission to a psychiatric hospital for treatment of any possible contributing eating disorder without any improvement. Since 2007, she has had more than 40 admissions to the hospital for nausea and vomiting. A feeding J-tube was placed to maintain adequate nutrition in 2008. She presented to the Palliative Care clinic in 2010 for further management of her nausea and vomiting. After a complete history and physical, the etiology of her symptoms remained somewhat elusive. She had nausea before her transplant and it had resolved when the kidney was working then recurred when it failed so the final conclusion was that her symptoms may be due to a poorly defined metabolic process related to her renal failure. Olanzapine was initiated on the first visit for refractory nausea and vomiting and the patient was referred to psychology and psychiatry to help with coping and to address underlying depression and anxiety. At the subsequent visit she noted some benefit so the olanzapine dose was increased and a granisetron transdermal patch was added. At the next visit her symptoms had improved dramatically with a clear temporal relation to starting the granisetron patch. She was only vomiting once or twice in the morning and was relatively asymptomatic through the day. In her first clinic visit she had vomited multiple times through the visit and appeared miserable.


At this visit she was asymptomatic, neatly dressed, wearing makeup and was thrilled at this new level of symptom control which was allowing her to re-engage her life.

Discussion: There were many factors that likely contributed to the dramatic improvement in Ms JB’s refractory nausea and vomiting. Better psychiatric care through the palliative care psychologist and psychiatrist almost certainly played a role in her overall clinical turn-around. The close attention, serial visits and supportive counseling she received in the Palliative Care clinic could also have been therapeutic. Up-titration of her olanzapine also likely was helpful. Olanzapine is an atypical antipsychotic that works on multiple receptors including dopaminergic, serotonergic, adrenergic, histaminergic and muscarinic receptors. Of particular interest is its antagonism of 5HT2 receptors which are located in the vomiting center and are not well targeted by other traditional antiemetics. Multiple small trials have demonstrated efficacy of olanzapine for chemotherapy-induced nausea and vomiting.¹ Many palliative care practitioners are now also starting to use olanzapine for refractory nausea and vomiting in patients with advanced cancer and other life-limiting conditions.^2-4

Even with all of these possible contributors to her improvement, there still seemed to be a clear benefit that came with initiation of the granisetron patch. While intravenous and oral granisetron have been available for some time, transdermal granisetron (Sancuso©) is a relatively new addition to the practitioner’s toolbox for difficult to control nausea and vomiting. Transdermal granisetron was approved by the FDA for chemotherapy-induced nausea and vomiting (CINV) in September of 2008 based largely on a trial of 582 patients receiving multi-day moderately or highly emetogenic chemotherapy. Patients received either oral or transdermal granisetron and achieved equally good control of their symptoms with either method (approximately 60% in each group achieving complete symptom control). The most common side effect in both groups was constipation.⁵ The patch is an 8x6cm clear, plastic-backed patch and is worn for 7 days. Pharmacokinectic studies suggest that the patch delivers a dose equivalent to 2 mg of oral granisetron each day it is worn.⁶

It is thought to exert its antiemetic effect through antagonism of 5HT3 receptors in the gut and chemoreceptor trigger zone.⁷ Experience with the patch outside of CINV, however, is limited. This case suggests that transdermal granisetron may have a role in other cases of refractory nausea and vomiting. It is unclear why the transdermal form of the drug worked so much better than the oral version for Ms JB. It could reflect absorption issues, especially if she was unable to keep the pills down. It could also reflect compliance issues and may bring into question the adequacy of her prior trial of oral granisetron. Whatever the mechanism, however, the result was dramatic. Further study of this agent in settings other than CINV is clearly needed. Hopefully these results can be replicated and other patients with difficult-to-control nausea and vomiting can achieve life-changing results similar to those achieved by Ms. JB.

References:
1. Navari RM, Einhorn LH, Loehrer PJ Sr, Passik SD, Vinson J, McClean J, Chowhan N, Hanna NH; Johnson CS (2007). A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Supportive Care in Cancer, 15 (11), 1285-91 PMID: 17375339

2.  Srivastava M, Brito-Dellan N, Davis MP, Leach M, Lagman R (2003). Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. Journal of Pain and Symptom Management, 25 (6), 578-82 PMID: 12782438

3.  Jackson WC, Tavernier L (2003). Olanzapine for intractable nausea in palliative care patients. Journal of Palliative Medicine, 6 (2), 251-5 PMID: 12854942

4.  Passik SD, Lundberg J, Kirsh KL, Theobald D, Donaghy K, Holtsclaw E, Cooper M, & Dugan W (2002). A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. Journal of Pain and Symptom Management, 23 (6), 526-32 PMID: 12067777

5.  Boccia RV, Gordan LN, Clark G, Howell JD, Grunberg SM, on behalf of the Sancuso Study Group (2010). Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Supportive Care in Cancer PMID: 20835873

6.  Howell J, Smeets J, Drenth HJ, & Gill D (2009). Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting. Journal of Oncology Pharmacy Practice, 15 (4), 223-31 PMID: 19304880

7. Wood, G., Shega, J., Lynch, B., & Von Roenn, J. (2007). Management of Intractable Nausea and Vomiting in Patients at the End of Life: "I Was Feeling Nauseous All of the Time . . . Nothing Was Working" JAMA: The Journal of the American Medical Association, 298 (10), 1196-1207 DOI: 10.1001/jama.298.10.1196

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Case

Mr BT is a 57 year old man with stage IV laryngeal squamous cell carcinoma, status post radiation and chemotherapy who is now thought to have no evidence of metastases or recurrence. He was followed in a palliative care clinic for chronic musculoskeletal pain and was referred to a new palliative care physician when his prior physician left the practice. Upon presentation to the new physician, the patient complained mainly of painful gynecomastia (excessive growth of breasts in a male) without galactorrhea (spontaneous flow of milk from the nipple) for the past several months. Besides some unrelated knee pain, his examination was remarkable only for bilateral tender gynecomastia. He had not undergone any endocrinological lab studies and a recent PET/CT of the head/neck/chest/abdomen/pelvis was unremarkable. Upon review of his medications, the only possible culprit was metoclopramide which had been started approximately one year prior for nausea. The nausea had since resolved but he was still taking the medication since it was prescribed on a scheduled basis. The metoclopramide was discontinued and several labs were ordered in consultation with endocrinology including testosterone, prolactin, TSH, free T4, FSH, LH, estradiol and HCG. Lab workup was largely unrevealing although most, including the prolactin level, were drawn after the metoclopramide was discontinued. Over the several months following metoclopramide discontinuation the patient’s gynecomastia resolved without any recurrence of his nausea.

Discussion

This case, although relatively simple, is important for two major reasons. First, it reminds us of a rare but significant side effect of a medicine commonly used in Palliative Care. Second, and perhaps more importantly, it highlights the dangers of polypharmacy in the Palliative Care setting.

Metoclopramide is a Dopamine type 2 (D2) receptor antagonist and is used as an antiemetic and prokinetic agent. In addition to these effects, it also reliably increases prolactin levels through its action on the D2 receptor. Dopamine normally inhibits pituitary secretion of prolactin. Metoclopramide administration blocks this inhibition resulting in increased prolactin levels.1 This effect has been used as both a research tool and as a clinical test. Symptomatic gynecomastia from elevated prolactin in patients taking metoclopramide, however, is rare, although it has been reported.² Galactorrhea has also been reported. In fact, metoclopramide has been used to augment lactation in breast-feeding women.³ Upon serologic testing, prolactin levels will generally be elevated in metoclopramideinduced gynecomastia. Discontinuation of the drug generally results in resolution of the symptoms.

Since metoclopramide is generally considered a first line antiemetic and is frequently used in clinical Palliative Care practice, this case serves as useful reminder of this rare but significant side effect. The equally or more important message from this case, however, is the need for careful medication management in this vulnerable population.⁴ Going back to Cicely Saunders, one of the guiding principles of Palliative Care is the scheduled administration of medications to provide continuous symptom control. Recent literature reinforces this concept in the management of nausea and vomiting.⁵ In addition, it is suggested to not only use scheduled antiemetics but to add second and third antiemetics as needed instead of stopping one and starting another. While this method has been shown to provide effective relief of symptoms, it can expose the patient to a high risk of side effects if the practitioner fails to taper the medications after the emetic impulse has resolved. This patient had no recurrence of his nausea with discontinuation of his metoclopramide, suggesting that he could have been spared the development of gynecomastia if the metoclopramide had been tapered earlier.

This case also reinforces one of the most basic but important principles in medicine: symptoms which emerge after initiation of a medication are most likely caused by that medication. Because of the serious and progressive nature of the illnesses encountered in Palliative Care, it can be easy to assume that all clinical deterioration is due to worsening of the underlying disease. This case reminds us of the importance of a solid understanding of medication adverse effects and the need for a constant vigilance for these outcomes. Fortunately for Mr BT, the culprit medication was discovered and the symptoms resolved with discontinuation, thereby allowing him to get back to enjoying his life after what appears to be a very successful initial treatment of his serious underlying cancer.

References:
1. Macullum RW, Sowers JR, Hershman JM, Sturdevant RAL. Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab. 1976;43:1148-1152.

2. Madani S, Tolia V. Gynecomastia with metoclopramide use in pediatric patients. J Clin Gastroenterol. 1997;24:79-81.

3. Ehrenkranz RA, Ackerman BA. Metoclopramide effect on faltering milk production by mothers of premature infants. Pediatrics. 1986;78:614-620.

4. Bernard SA, Bruera E. Drug interactions in palliative care. J Clin Oncol. 2000;18:1780-1799.

5. Wood GJ, Shega JW, Lynch B, Von Roenn JH. Management of intractable nausea and vomiting at the end of life: “I was feeling nauseous all of the time…nothing was working”. JAMA. 20087;298:1196-1207

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Case:

Ms BB is a 57 year old woman with fallopian tube cancer with multiple mesenteric and peritoneal metastases and a history of large and small bowel obstructions. She presented with nausea, vomiting, and abdominal distention. She was found to have another bowel obstruction and had an NG tube placed with improvement in her symptoms. She then went to the OR for an exploratory laparotomy. She was found to have massive carcinomatosis and ascites and it was felt that a debulking was not possible so a venting gastrostomy tube (g-tube) was placed and the operation was aborted.

Palliative care was consulted to assist with postoperative nausea and vomiting. Despite placement of the venting gtube, the patient had persistent nausea and held a basin next to her during the interview to catch her frequent episodes of emesis. She was despondent because the surgeons had told her that the g-tube was working well and draining large amounts of fluid but that it was unable to keep up. Antiemetics were not helpful. The patient thought that there was nothing left to do and that she would have to live the rest of her life with this level of discomfort. A trial of octreotide 0.1mg subcutaneously three times daily was initiated in addition to continued drainage by her venting gtube. She was also given around-the-clock intravenous haloperidol and PRN intravenous ondansetron. By the next day, her g-tube output had decreased and her nausea and vomiting had resolved. Her pain was controlled with a hydromorphone PCA. She was eventually able to be discharged home with plans to follow up with her outpatient oncologist to consider next steps. With her symptoms controlled, she was able to move past her initial distress and talk openly about her hopes for the future and how she wanted to spend the time she had left.

Discussion:

Malignant bowel obstruction can occur with any cancer but is most commonly associated with advanced ovarian cancer, where it occurs in up to 50% of patients. It generally indicates a poor prognosis and carries a heavy symptom burden predominated by nausea, vomiting and abdominal pain. Patients with carcinomatosis, like Ms BB, are generally not candidates for surgical correction of the obstruction or endoscopic stenting. Fortunately, medical management can be very effective. Abdominal pain is treated with opioids and nausea is treated with metoclopramide in partial obstructions and haloperidol in complete obstructions. Corticosteroids are also often used for help in symptom control and because there is some indication that they may promote resolution of the obstruction presumably by decreasing inflammation and promoting salt and water absorption. Gastrointestinal secretions can be controlled with anticholinergics (such as scopolamine) and/or somatostatin analogues (such as octreotide).

Two prospective, randomized controlled trials suggest octreotide is superior to scopolamine. Octreotide works by inhibiting the release of several gastrointestinal hormones thereby reducing secretions, slowing motility, increasing water and electrolyte absorption, and reducing bile and splanchnic blood flow. It is generally dosed 0.1-0.3mg subcutaneously TID. Some palliative care units will use continuous infusions at higher doses with anecdotal success.

Current guidelines suggest placing a venting g-tube if medical management is unsuccessful. A venting g-tube is similar to a traditional g-tube but is used solely for drainage of the gastrointestinal secretions and the liquids taken by mouth that are unable to bypass the obstruction. This drainage prevents the backup of these fluids that would normally stretch the viscus and stimulate vomiting. As experience with this intervention increases, many clinicians advocate g-tube placement early in the treatment algorithm because it can provide more complete relief of vomiting and allow more extensive pleasure feeding. Venting g-tubes can, however, place the patient at greater risk for electrolyte imbalances.

Most guidelines and many clinicians consider venting g-tube placement and medical management with octreotide/ anticholinergics as two separate treatment pathways. This case highlights the fact that, occasionally, both may be needed simultaneously. Although Ms BB’s venting g-tube was draining effectively, she still experienced severe nausea and vomiting, and it was not until octreotide was added to the regimen that her symptoms became controlled. This scenario is borne out in some of the data regarding venting g-tubes.

In one series of patients with gynecological malignancy and upper intestinal obstruction, 4 in 31 had incomplete resolution of their symptoms with placement of a venting g-tube alone. All 4 had complete symptom relief when octreotide was added to the regimen. Clinicians need to be aware that venting gastrostomy tubes and medical management with octreotide/anticholinergics are not mutually exclusive treatment algorithms and a small percentage of patients will require both for adequate symptom control. Fortunately, as was the case with Ms BB, this approach can allow almost all patients with malignant bowel obstruction to regain some measure of comfort.

References:

1. Ripamonti CI, Easson AM, Gerdes H. Management of malignant bowel obstruction. Eur J Cancer (2008). doi:10.1016/j.ejca.2008.02.028

2. Campagnutta E et al. Palliative treatment of upper intestinal obstruction by gynecological malignancy: the usefulness of percutaneous endoscopic gastrostomy. Gynecologic Oncology. 1996;62:103-105. doi:10.1006/gyno.1996.0197

3. Ripamonti CI et al. Clinical-practice recommendations for the management of bowel obstruction in patients with endstage cancer. Support Care Cancer. 2001; 9:223-233. doi:10.1007/s005200000198