Robert D. Ornitz

On the mechanism of radiation-induced emesis: The role of serotonin

PURPOSE The aim of this study was to determine the mechanism of action of radiation-induced emesis by determining the incidence of radiation-induced emesis following hemibody irradiation; the effects of specific antiemetics especially ondansetron, a 5-hydroxytryptamine receptor antagonist, and to determine the relationship between radiation-induced emesis and serotonin (5-hydroxytryptamine) through its active metabolite, 5-hydroxyindoleacetic acid (5-HIAA). METHODS AND MATERIALS Forty-one patients received 53 hemibody treatments of 5-8 Gy following intravenous hydration. The patients were divided into three groups according to prehemibody irradiation treatment: Group A: no pretreatment antiemetics, 30 patients; Group B: nonondansetron antiemetics (metoclopramide, dexamethasone, prochlorperazine), ten patients; and Group C: ondansetron, 13 patients. The incidence of radiation-induced emesis was determined prehemibody irradiation or baseline and at 1 h posthemibody irradiation in 38 patients and the results expressed as the percent change in 5-HIAA (ng/ug creatinine). RESULTS The incidence of radiation-induced emesis was 82% (14/17) following upper/mid hemibody irradiation and 15% (2/11) following lower hemibody irradiation in Group A; 50% (3/6) and 25% (1/4) following upper/mid and lower hemibody irradiation respectively, in Group B; and 0% (0/13) after upper/mid hemibody irradiation in Group C. The incidence of emesis was significantly different (p < 0.001) between the patients of Group A and C who received upper/mid hemibody irradiation. The percent change in 5-HIAA excretion following upper/mid hemibody irradiation were greatest in Group A and smallest in Group C (p < 0.002). The degree of change following lower hemibody irradiation (15% incidence of emesis) in Group A was lower than upper/mid hemibody irradiation of the same group. CONCLUSION The higher incidence of radiation-induced emesis following upper and mid hemibody irradiation in antiemetic naive patients compared to the incidence following lower hemibody irradiation suggests that the critical organ responsible for radiation sickness is in the abdomen. The control of emesis by ondansetron, a 5-HT3 receptor antagonist, attests to the efficacy of ondansetron in radiation-induced emesis and suggests a role for serotonin in mediating radiation-induced emesis. Finally, the parallel changes in 5-HIAA and the incidence of emesis provides additional evidence for a more direct role for serotonin in radiation-induced emesis.

Clinical observations of early and late normal tissue injury and tumor control in patients receiving fast neutron irradiation

Abstract The clinical experience of the first 211 patients treated at MANTA from October 1973 to May 1978 is described. Acute cutaneous, mucosal, gastrointestinal reactions and late effects including myelitis, damage to brain, bowel, soft tissue and mandibular necrosis are described. A review of tumor response data is also submitted.

Clinical observations of early and late normal tissue injury in patients receiving fast neutron irradiation

This communication describes early and late normal tissue effects in 177 patients treated totally or in part by 15 MeV neutrons from the Naval Research Laboratory Cyclotron in Washington, D.C. between October 1973 and December 1976. Late normal tissue reactions were found to be greater than would be expected from careful observation of the early clinical responses to neutron treatment. Neutron prescriptions must be written based on the late effect tolerance level experience which is being accumulated at several neutron therapy facilities.

Fast neutron irradiation for locally advanced pancreatic cancer

Abstract Nineteen patients with locally advanced pancreatic cancer and one patient with islet cell cancer were treated with 1700–1750 neutron rad alone or in combination with 5-flourouracil to exploit the theoretic advantages of higher linear energy of transfer, and lower oxygen enhancement ration of neutrons. Only 5 of 14 (36%) obtained partial tumor regression. The median survival for all patients with pancreatic cacer was 6 months, which is less than that reported with 5-flouracil and conventional photon irradiation. Gastrointestinal toxicity was considerable; hemprrhagic gastritis in five patients, colitis in two and esophagitis in one. One patient developed radiation myelitis. We therefore, caution any enthusiasm for this modality of therapy until clear evidence of a therapeutic advantage over photon therapy is controlled clinical trials.

Treatment experience: Locally advanced sarcomas with 15 MeV fast neutrons

Experience with ten evaluable osseous sarcomas and ten evaluable advanced soft tissue sarcomas treated with neutrons of a mean neutron energy of 15 MeV are described. Neutron irradiation with or without conventional megavoltage radiotherapy is an effective modality in the treatment of these patients. No correlation between response rate and grade or whether fast neutrons alone or combined with megavoltage radiotherapy was noted. Those patients receiving a neutron dose of 2195 neutron plus gamma rads or greater all had a complete response.

Treatment experience. Glioblastoma multiforme treated with 15 MeV fast neutrons

Thirty‐one patients with glioblastoma multiforme treated at the Middle Atlantic Neutron Therapy Association (MANTA) are reported. All but one patient completed a prescribed course of treatment, and most demonstrated clinical improvement. Mean survivals of 11.1 months for Grade III neutron‐treated patients and 6.8 months for Grade IV patients were obtained. Persistent tumor in seven of eight patients was confirmed by biopsy or autopsy.

Treatment experience with 15 MeV fast neutrons in the oral cavity and oropharynx

All 86 patients with squamous cell carcinoma of the oral cavity and oropharynx treated with fast neutrons at the Mid‐Atlantic Neutron Therapy facility at the Naval Research Laboratory (MANTA) from its inception in 1976 until closing in 1979, are reported. Patients generally had advanced disease or have failed or were failing conventional treatment prior to being treated at MANTA. The fixed horizontal beam parameters were suboptimal. Patients were treated by either neutrons alone or various combinations of neutrons and photons. In patients with T3 or T4 primary carcinomas treated with less than 2100 neutron rad, only 37% (3/11) had a complete response at the primary compared to 57% (24/42) treated to a higher dose. However, there was a significant evidence of radiation related complication. The latter was expected in a phase I/II trial of a new modality such as fast neutrons. Isocentric hospital based cyclotrons should offer some hope of improvement in the future.