EDITORIAL

Thomas R. Spitzer, MD, Associate Professor of Medicine, Harvard Medical School, Director, Bone Marrow Transplantation Program and Deputy Division Chief, Hematology/Oncology, Massachusetts General Hospital, Boston

The potential of bone marrow transplantation has been realized for a variety of malignant and non-malignant life-threatening disorders of the bone marrow or immune system. Historically, however, these therapies have been associated with profound nausea and vomiting. Retrospective analyses of patients receiving total body irradiation (TBI) as preparative therapy for bone marrow transplantation have shown that emesis following this therapy is universal despite a number of different antiemetic therapies. Patients often required heavy sedation, which interfered with their radiation treatments, and suffered from early nutritional problems, usually necessitating the early use of parenteral nutrition.

Nausea and vomiting, while generally not as abrupt and severe as that associated with TBI, occurs in the majority of patients who receive single fraction or fractionated abdominal irradiation (Feyer et al.). Emesis is considerably more common in patients who receive irradiation to a large field or upper half body irradiation (as apposed to lower body irradiation). Irradiation injury to the GI tract with the release of serotonin, and subsequent activation of peripheral and central 5-HT3 receptors, is the likely common theme in the pathogenesis of TBI and abdominal irradiation-induced emesis.

The 5-HT3-receptor antagonist agents have constituted a dramatic advancement in the management of nausea and vomiting associated with total body and abdominal irradiation. As a result, patients undergoing bone marrow transplantation usually experience a minimum of emesis, are able to maintain their oral nutrition through the therapy, and maintain a generally better performance status heading into the rigorous post-transplant period. The implications of this therapy, beyond just patient comfort, are significant and potentially include the delivery of TBI on an outpatient basis. This may be particularly relevant for the use of non-myeloablative, sometimes TBI-based, regimens for allogeneic stem cell transplantation.

Granisetron HCl (Kytril®) has been shown in two studies, which are described in this report, to be effective in the prevention of nausea and vomiting following both total body irradiation and abdominal irradiation. The ease of once daily administration-with its favorable toxicity profile-make this therapy an ideal strategy to manage the most troubling acute toxicity of these irradiation therapies. Based on this experience, 5-HT3-receptor agonist therapy should be considered the standard of care for the prevention of nausea and vomiting following these emetogenic irradiation-based treatment regimens.

INTRODUCTION

Nausea and vomiting continue to be of significant concern in terms of the side effects of cancer treatment. Acute emesis is seen most frequently with radiotherapy, and prolonged emesis-lasting two to three days-is reported by up to 40 percent of patients (Feyer et al.).

Total body irradiation and irradiation of the upper part of the abdomen or whole abdomen are the most emetogenic radiotherapy regimens. These therapies are associated with nausea, vomiting, anorexia, and diarrhea. Such side effects hinder treatment, because patients must remain immobilized while receiving each fraction of irradiation.

TBI has become the standard procedure before bone marrow transplant (BMT). Traditional medications, such as dopamine antagonists, sedating antihistamines, phenothizines, corticosteroids, and benzodiazepines used to prevent TBI-induced nausea and vomiting are not only ineffective, but they cause serious side effects.

The majority of patients receiving abdominal radiation experience severe nausea and vomiting. Emesis persisting through radiotherapy can cause physiologic changes, including dehydration, electrolytic imbalance, and malnutrition, all of which hamper the quality of life and the final outcome of treatment. Nausea and vomiting can be controlled by a 5-HT3-receptor antagonist called granisetron HCl (Kytril®). The safety, efficacy, and ease of oral, once daily granisetron HCl has been described in two studies (Lanciano et al.; Spitzer et al.), as well as in a more inclusive study reported in Bone Marrow Transplantation (2000).

With irradiation of the abdomen or with TBI, serotonin (5-HT) is released from enterochromaffin cells in the lining of the gastrointestinal tract. The serotonin then binds to the 5-HT3-receptors in the vagal neurons, which are stimulated to transmit signals to the vomiting center in the brain. Granisetron HCl, taken prior to irradiation, binds to the 5-HT3-receptors in the vagal neurons, blocking the signal to the vomiting center.

Feyer et al. concluded that one of the basic principles of antiemetic therapy in radiotherapy should be, whenever appropriate, regular administration of antiemetics, rather than administration on demand. Antiemetics must be integrated into the planning of radiotherapy in order to improve the therapeutic outcome and, most importantly, the patient's quality of life.

SAFETY AND EFFICACY OF GRANISETRON HCL PRIOR TO ABDOMINAL IRRADIATION

In one study, it was determined that the administration of granisetron HCl-taken as two one-milligram Kytril® tablets-prior to upper abdominal radiation, is effective in preventing nausea and emesis attributed to irradiation (Lanciano et al.).

Patients in this study-a randomized, double-blind, parallel-group, placebo-controlled, intent-to-treat investigation of 260 evaluable adult patients with malignant disease-were scheduled to receive ten to 30 fractions (each 180-300 cGy per fraction) of upper abdominal radiation. Approximately half of the patients (n = 134) received granisetron HCl, and the other half (n = 126) received a placebo. Both of these groups were on the same dosage schedule-two milligrams (two one-milligram tablets) once daily, one hour prior to the start of radiotherapy and at the same time on non-radiation days, for up to five weeks.

Patients treated with granisetron HCl had a significantly longer time to the first emesis (35 days vs. nine days, p < 0.001) relative to those who received placebo. The median time to the first episode of nausea was 11 days for granisetron HCl-treated patients and one day for placebo-treated patients (p < 0.001). Further, the proportion of granisetron HCl patients with no emesis at 24 hours (93 percent; p < 0.0001) and after ten fractions (86 percent; p = 0.001) was greater than the placebo population (62 percent and 69 percent, respectively). The proportion of granisetron HCl patients with no nausea at 24 hours (79 percent; p < 0.0001) and after ten fractions (53 percent; p = 0.006) was also significantly superior to placebo (45 percent and 32 percent, respectively). In addition, granisetron HCl was superior to placebo in that 18 percent of patients were emesis-free; 17 percent had no or mild nausea, and 15 percent were nausea-free.

Patient-reported adverse events were mild to moderate in severity. The most frequent adverse events reported with granisetron HCl were diarrhea (28 percent), asthenia (25 percent), and constipation (19 percent). Nausea (after 20 fractions) also occurred (11 percent), but two patients reported nausea before they received 20 fractions.

Additionally, there were 30 granisetron HCl patients-and 56 placebo patients-that were withdrawn before completing the study due to the lack of efficacy. These patients required rescue medication.

SAFETY AND EFFICACY OF GRANISETRON HCL PRIOR TO TOTAL BODY IRRADIATION

The results of the prospective, randomized trial evaluating the efficacy of granisetron HCl in the prevention of TBI-induced emesis were recently reported by TR Spitzer, CJ Friedman, W Bushnell, SR Frankel, and J Raschko in Bone Marrow Transplantation (2000), in an article entitled "Double-blind, Randomized, Parallel-Group Study on the Efficacy and Safety of Oral Granisetron and Oral Ondansetron in the Prophylaxis of Nausea and Vomiting in Patients Receiving Hyperfractionated Total Body Irradiation."

In this randomized study, 34 TBI-treated patients scheduled for TBI received double-blind oral granisetron HCl (two milligrams, once daily, one hour before the first daily fraction of irradiation), or they received another 5-HT3-receptor antagonist, ondansetron (Zofran®) (eight milligrams, 1.5 hours prior to each fraction of irradiation, three times daily for three days, and then twice daily on day four). If needed, rescue antiemetic medication of the physician's choosing was permitted. The results were compared with an historical negative control group (n = 90) of patients who, prior to TBI, did not receive 5-HT3-receptor antagonists. All patients were scheduled to receive TBI-1320 cGy in 11 fractions (each 120 cGy) over four days.

The primary efficacy variable was the proportion of patients who had no emesis over the four-day study period. During the study, no emesis occurred in 33.3 percent of patients taking granisetron HCl, 26.7 percent of patients taking ondansetron, and zero percent (p < 0.01; intent-to-treat) of patients in the historical control group.

Secondary efficacy endpoints were also evaluated, which included the number of emetic episodes throughout the first 24 hours (day 0), the number of emetic episodes during the entire four-day study period, the proportion of patients with no emetic episodes on day 0, and the time to first emesis. The time to first emetic episode and number of vomiting episodes were recorded every 24 hours. Also evaluated were the number of patients who had no nausea and no rescue antiemetic medication.

During the first 24 hours (day 0), significantly more patients taking granisetron HCl (61.1 percent) or ondansetron (46.7 percent) had zero emetic episodes compared to the historical control group. Complete emetic control during the four treatment days was more frequent in patients taking granisetron HCl (27.8 percent) or ondansetron (26.7 percent) compared with the historical control group (zero percent; p < 0.01).

Zero out of 18 patients taking granisetron HCl had more than five emetic episodes during the four days, a significant difference compared to the historical control group (40/90; p < 0.01).

Granisetron HCl-treated patients also had significantly better nausea control on day 0, compared with ondansetron-treated patients and the historical control group.

The most frequently reported adverse event in both treatment groups was headache. The complaints varied with each of the two medications. Side effects attributed to granisetron HCl included diarrhea and asthenia. The most frequently reported complaints for those taking ondansetron included insomnia, peripheral edema, back pain, and rash. All adverse effects were similar to those reported in previous studies using 5-HT3-receptor antagonists, which further supported the safety of these medications.

Two severe adverse events occurred in the ondansetron group as well as in the granisetron HCl group. The ondansetron adverse events included one severe infection and one episode of severe nervousness. The adverse events in the granisetron group included severe headache. There was one withdrawal in the ondansetron group due to a heart arrythmia.

CONCLUSION

Age, gender, alcohol consumption, and previous experience are all recognized risk factors for emetogenic therapies (Feyer et al.). In a recent study, approximately 40 percent of patients receiving abdominal irradiation who did not receive antiemetic therapy prior to therapy experienced emesis and nausea (Feyer et al.).

The advantages of oral administration of granisetron HCl and ondansetron HCl prior to TBI vs. intravenous (IV) administration are clear in terms of the reduced costs and ease of administration, thus potentially allowing patients to be treated on an outpatient basis. In addition, oral administration of 5-HT3-receptor antagonists may allow the medication to be absorbed and act peripherally and in the central nervous system, as well as act locally in the gut to inhibit the emetogenic stimulus.

"In light of these data, 5-HT3-receptor antagonists and antiemetic therapy for patients receiving TBI represents the standard of care in the bone marrow transplant community," concluded Spitzer et al.

As abdominal irradiation and total body irradiation are the most highly emetogenic radiotherapies, the basic principles of antiemetic therapy prior to irradiation should include prophylaxis.

References

Feyer PC, Titlbach OJ. Aetiology of Radiation Induced Emesis. In: Perugia Consensus Conference on Antiemetic Therapy. Gralla RJ, Tonato M, Roila F (Eds), New York: Springer-Verlag, 1997.

Lanciano R, Sherman DM, Michalksi J, et al. The efficacy and safety of Kytril® tablets (2 mg) once daily in patients receiving at least 10 fractions of upper abdominal radiation for malignancy [abstract]. Int J Radiat Oncol Biol Phys. 1998;42:204. Presented at the American Society for Therapeutic Radiology and Oncology, 40th Annual Meeting, October 1998. Abstract 259.

Spitzer TR, Friedman CJ, Bushnell W, Frankel SR, Raschko J. Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation. Bone Marrow Transplant 2000;26;203-210.

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