Introduction 1 5 6 10 11 18 −1 −1 4 −1 −1 −1 −1 −1 −1 −1 −1 −1 −1 −1 −1 n n −1 −1 −1 −1 −1 −1 5 −1 −1 5 1 −1 −1 −1 −1 −1 −1 −1 −1 19 19 1 3 The aim of the present study was to investigate the safety of ATP administration at home in pre-terminal cancer patients. We hypothesized that side effects of ATP infusions would occur mainly during the first ATP infusion, especially during assessment of the MTD of ATP. We also hypothesized that the presence of cardiac disorders and/or lung cancer would lead to a lower MTD, and a higher frequency of side effects. Patients and methods Study population and design 20 Intervention 2 −1 −1 −1 −1 −1 −1 Since initiation of ATP infusions under medical supervision in a clinical setting would facilitate the treatment of possible side effects, the first two ATP infusions were given at the day care center of the participating hospitals. Based on evaluation of safety data in the first 22 patients, in view of the mild character of the noted side effects during the first two infusions in these patients, the Ethical Committee granted permission to administer only the first ATP infusion at the day care center and all subsequent infusions at home. The description below applies to the procedures in case of only one hospital infusion. At the end of the first infusion, the safety and tolerated dose of ATP was evaluated for each individual patient. Subsequent infusions were given at the patients’ home by an experienced and trained nurse of a specialized infusion team, usually embedded in the regional Community Care Organization. The MTD as determined during the first infusion at the day care center was also the maximum dose for this patient for the next infusions at home. The same rule was applied for subsequent home infusions, so that the infusion rate in any subsequent ATP infusion course was never higher than the MTD during the previous ATP infusion. Patients and their partners were instructed extensively regarding the infusion procedures; also, they were instructed to immediately call the involved infusion team in case of any side effects. Documentation of side effects and adverse events Side effects of ATP infusions 21 19 Statistical analysis t P Results Study population 1 Table 1 n   Number Percent (%) Age (years) a  Gender  Male 35 69  Female 16 31 b  1 33 65  2 18 35 Tumor type  Lung 21 41  Colon 8 16  Gastro-intestinal other 6 12  Prostate 5 10  Other 11 21 Presence of cardiac disorders 12 24 a b 1 n n n Fig. 1 Flow diagram of the study  −1 −1 −1 −1 −1 −1 Heart rate and blood pressure p p p p p p Side effects 2 Fig. 2 Reported side effects of ATP according to location (day care centre vs. home), time of reporting side effects (during vs. after the infusion), and person to whom the side effects were reported (nurse vs. researcher)  At the day care center, 63 side effects were reported in 95 infusions (0.66 side effect per infusion). Of these 63 side effects, 56 (89%) were reported to the nurse, of which 55 during the infusions and 1 afterwards; and 7 (11%) to the researcher when specifically asked for. At home, 129 side effects were reported in 171 infusions (0.75 side effect per infusion); of these, 82 (64%) were reported to the nurse, of which 41 during the infusions and 41 afterwards; and 47 (36%) to the researcher when specifically asked for. All side effects were transient and resolved within minutes after lowering the ATP infusion rate. In a total of 99 infusions, one or more side effects were reported by patients. In the 51 infusions with one or more side effects reported during ATP administration, the infusion was stopped in 13 infusions (25%), lowered in 30 infusions (59%) and not changed in 8 infusions (16%). Of the latter eight infusions, the side effects had already disappeared before lowering the infusion rate in four infusions, whereas in three infusions the side effects had already been present before the start of the ATP infusions; in one infusion, extravasation occurred, and the ATP infusion was temporarily interrupted. In 48 out of the total of 99 infusions with one or more side effects, the side effects were reported by patients to the nurse or researcher only after completion of the infusion, and the infusion rate was therefore not adapted. 2 Table 2 Side effects during a total of 266 intravenous ATP cycles in 51 patients; CTC-grading No side effects Side effects according to CTC grade Total side effects 1 2 3 4 CTC grade unspecified Number Percent of inf. (%) Cardiac ischemia 266 0 0 0 0 0 0 0 Chest discomfort 234 26 1 4 0 1 32 12 Dyspnea 230 35 1 0 0 0 36 14 Epistaxis 266 0 0 0 0 0 0 0 Flushing 258 8 0 0 0 0 8 3 Headache 252 11 2 0 0 1 14 5 Injection side reaction 261 5 0 0 0 0 5 2 Lightheadedness 254 9 2 0 1 0 12 5 Mood alteration-anxiety 262 4 0 0 0 0 4 2 Nausea 251 14 1 0 0 0 15 6 a 235 28 2 0 0 1 31 12 Palpitations 265 1 0 0 0 0 1 0 Sweating 260 2 3 0 0 1 6 2 Urge to take a deep breath 238 18 10 0 0 0 28 11 Total  161 22 4 1 4 192  In some courses more than one side effect was observed a −1 −1 Urge to breathe deeply, headache, sweating and cold shivering in one patient at the day care center (the same patient with the CTC 3 chest discomfort and CTC 4 lightheadedness) Sweating in one patient at the day care center at the end of the infusion, due to flushing the infusion line (violation of the administration protocol) Pain in the infusion arm (one patient) and dyspnea (one patient), both at the day care center Urge to breathe deeply, headache and sweating in one patient at home, during the period of stepwise increasing the infusion rate by the nurse Chest discomfort (once) and lightheadedness (twice) at home in two patients, who called the home nurse Out of these seven patients with CTC 2 side effects, two patients decided to stop the ATP infusions for the rest of the study. To the nurse after completion of the infusion, by three patients (four infusions) To the researcher when specifically asked for, by one patient (five infusions) These nine CTC 2 side effects (eight times urge to breathe deeply, once nausea), were probably not sufficiently serious to call the home nurse. All of these patients continued the ATP infusions. Timing of side effects 3 2 Fig. 3 Average number of side effects per ATP infusion in subsequent infusions  Effect of cardiac or lung disorders on MTD and frequency of side effects −1 −1 3 −1 −1 p −1 −1 p p p Table 3 The independent effect of the presence of cardiac disorders and/or lung cancer on MTD and frequency of side effects Mean No cardiac disorders and/or lung cancer Cardiac disorders Lung cancer MTD 48 ± 2 40 ± 3*** 44 ± 2* All side effects 0.71 ± 0.28 2.25 ± 0.49* 0.66 ± 0.34 Chest discomfort 0.14 ± 0.05 0.32 ± 0.09 0.12 ± 0.06 Urge to breathe deeply 0.08 ± 0.05 0.25 ± 0.08 0.09 ± 0.05 Nausea 0.06 ± 0.04 0.18 ± 0.07 0.03 ± 0.05 Lightheadedness 0.06 ± 0.04 0.14 ± 0.08 0.06 ± 0.05 Dyspnea 0.12 ± 0.05 0.35 ± 0.09 0.17 ± 0.06 Other 0.09 ± 0.06 0.42 ± 0.11** 0.05 ± 0.07 Reference group: patients with no cardiac disorders and/or lung cancer p p p Continuation of infusions after completion of the study −1 −1 −1 −1 −1 −1 p Discussion 19 22 19 19 19 4 5 19 Results showed that in 43 out of 51 infusions (84%) with side effects reported during ATP administration, the infusion rate was lowered or stopped according to protocol. Reasons for not lowering the infusion rate in eight infusions were the fact that in four infusions complaints disappeared automatically; in three infusions the reported complaints were already present before the start of the infusion; and in one infusion extravasation occurred with a temporary interruption of the ATP infusion. In 48 infusions with side effects, side effects had only been reported after completion of the concerned ATP infusion and the infusion rate was therefore not adapted. One potential explanation for this finding may be that patients were eager to receive ATP at the highest possible dose, as some patients expressed their worry that the potential effectiveness of ATP could fade in case of lowering the dose (similar to chemotherapy), despite our explicit explanation to patients prior to the study that there is currently no evidence that the efficacy of ATP would be better at higher ATP doses. Another possible explanation is that patients in our study population were used to experiencing far more serious complaints caused by progression of the disease and/or previous antitumor treatment. Results Side effects were not limited to the period of MTD assessment, nor were they limited to the first ATP infusion. The implication of this finding is that alertness with regard to potential side effects of ATP administration is necessary during all subsequent ATP infusions, and not just during the first infusion or MTD assessment. The lower MTD found in the presence of cardiac disorders or lung cancer indicates that patients with these disorders tolerate lower doses of ATP without side effects than patients without these disorders. Moreover, even at the lower MTD, side effects tend to be more frequent in the presence of cardiac disorders. Because all patients with presence of COPD also had cardiac disorders or lung cancer, this subgroup was not analyzed separately. 19