Омела белая Viscum album Mistletoe
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- Бұл бет үшін навигация:
- 3.1. Adverse Events
- 3.2. Mistletoe-Related Adverse Events
- 3.3. Gemcitabine-Related Adverse Events
- 3.4. Maximum Tolerated Dose and Dose Limiting Toxicities
- 3.5. Pharmacokinetics of Gemcitabine
- 3.6. Best Clinical Response to Treatment
- 3.7. Best Clinical Response according to Diagnosis
- 3.8. Survival Analyses
- 3.9. Jonckheere-Terpstra Trend Test Results for ANC Values across Increasing Dose Levels
- 3.10. Development of Mistletoe Lectin 3 IgG Antibodies and Cytokine Release
3. ResultsA total of 44 study participants were enrolled on this study; twenty patients were treated in stage I (mistletoe dose escalation phase) and 24 in stage II (gemcitabine dose escalation phase). The study population's demographic information is presented in Table 1(a). All patients had stage IV disease; the majority had received previous chemo-, hormonal, immunological, or radiation therapy, and 23% were chemotherapy-naïve. Patients' disease characteristics are listed in Table 1(b). 3.1. Adverse EventsA total of 706 discrete hematologic adverse events (AEs) were documented, occurring in 95% of study participants (Table 2(a)). The most common were low lymphocyte counts (for example, lymphopenia) (n = 200 events), anemia (n = 158), leukopenia (e.g., total WBC count) (n = 149), thrombocytopenia (n = 100), and neutropenia (e.g., low granulocyte or absolute neutrophil count) (n = 99). The majority (85%) of observed hematologic AEs were grade 1-2, 104 grade 3 (15%) and five grade 4 toxicities were observed. The grade 4 AEs included 1 neutropenia event (defined as an ANC < 500), 2 thrombocytopenia events (defined as platelet count < 25,000), and 2 lymphopenia events. A total of 570 nonhematologic AEs were recorded. The most common were hyperglycemia and hypoalbuminemia, followed by almost equal numbers of nausea and fatigue (Table 2(b)). Nonneutropenic fever and flu-like syndrome, which have been previously described with mistletoe treatment and are also known AEs associated with gemcitabine, were observed in 24 of 44 (55%) patients. More patients experienced these symptoms in stage II of the study (15/24) than in stage I (9/20). Only one grade 3 febrile event was observed during stage II, all other events were grade 2 or less. 3.2. Mistletoe-Related Adverse EventsMistletoe-related nonhematologic adverse events are represented in Table 3. A total of 112 adverse events were attributed to mistletoe treatment. The most common AEs attributed to mistletoe treatment were injection site reactions (42 events), localized induration (20 events), grade 1-2 nonneutropenic fever (22 events), and grade 1-2 flu-like symptoms (10 events). All of these AEs were expected as they had been documented as known mistletoe-related AEs in the Investigators' Brochure. Seventy-five events were grade 1, thirty-five were grade 2, and two events were grade 3. The two grade 3 events were cellulitis at the mistletoe injection site. 3.3. Gemcitabine-Related Adverse EventsA total of 473 hematologic AEs at least possibly related to gemcitabine were documented. Most commonly occurring number of events were leukopenia, thrombocytopenia, neutropenia, and anemia, which is consistent with the previously published data. Thirty patients developed a low WBC, and 28 paients developed thrombocytopenia. 30% of the low WBC events and close to 10% of the thrombocytopenic events were grade 3. A total of 249 nonhematologic events were attributed at least possibly to gemcitabine. The most common were nausea (n = 47) and vomiting (n = 31), followed by liver enzyme elevation (elevated AST n = 25; elevated ALT n = 20), nonneutropenic fever (n = 21), and fatigue (n = 19). Thirteen grade 3 events were recorded, most commonly vomiting (n = 3) and fatigue (n = 2). 3.4. Maximum Tolerated Dose and Dose Limiting ToxicitiesFive dose limiting toxicities (DLTs) were observed (Table 4). One study participant experienced grade 4 neutropenia at dose level 6 (mistletoe 250  mg/gemcitabine 900 mg/m2). An additional three participants enrolled onto this dose level did not subsequently experience a DLT. One study participant experienced grade 4 thrombocytopenia at dose level 7 (mistletoe 250 mg/gemcitabine 1180 mg/m2); three subsequent participants enrolled at this dose level did not experience a DLT. Three study participants experienced individual DLTs at dose level 9 (gemcitabine 1560 mg/m2 with 250 mg daily of mistletoe). These included grade 3 cellulitis at the mistletoe injection site, grade 4 acute renal failure, and grade 4 neutropenia. As per the protocol's study design, one dose level below the dose level at which 3 DLTs were reached was defined as the maximum tolerated dose. Thus, we achieved the MTD at dose level 8 (gemcitabine 1380 mg/m2 and mistletoe 250 mg).
3.5. Pharmacokinetics of GemcitabinePlasma concentrations of gemcitabine from patients treated during stage I were measured in nmol/mL. Fifteen of 20 patients treated in stage I had plasma samples obtained for analysis. Twelve patients had paired samples obtained during cycle 1 (without mistletoe) and cycle 3 (with mistletoe). The addition of mistletoe did not affect gemcitabine pharmacokinetics as measured during cycle 3 (cycle 3, day 8 of gemcitabine/mistletoe combination) compared to cycle 1 of treatment (gemcitabine alone on day 1 of treatment before mistletoe was added on day 8, P values ranging from 0.47 to 0.97; Table 5). 3.6. Best Clinical Response to TreatmentFigure 1(a) shows the best overall response. Of the 44 enrolled study patients, 33, completed at least 3 cyes of therapy. Of these 33, six percent (n = 2) had a partial response, 42% (n = 14) had stable disease, and 43% (n = 14) progressed on treatment. Nine percent (n = 3) were not evaluable for response. 3.7. Best Clinical Response according to DiagnosisBoth partial responses were observed in patients with pancreatic cancer. Three of 4 evaluable patients with NSCLC had stable disease, and 5/11 patients with breast cancer had stable disease (Figure 1(b)). Only 1 out of 8 patients with colorectal cancer had stable disease. 3.8. Survival AnalysesOf the 44 study participants, three participants died on study, 10 participants requested to terminate the study, 23 participants progressed while on study, one terminated the study due to a dose limiting toxicity, 6 left due to complicating disease issues which may be tied to progression, and one voluntarily withdrew. An attempt was made to follow study subjects once they terminated study treatment until death. At the study's last attempt to contact former participants, three were still alive and five others were lost to followup. A Kaplan Meier curve was used to illustrate time to death in Figure 2. The median time to death of any cause was approximately 200 days. 3.9. Jonckheere-Terpstra Trend Test Results for ANC Values across Increasing Dose LevelsWe prospectively followed ANC nadir and ANC maximum as one of the study outcomes, hypothesizing that the ANC may be influenced by mistletoe exposure. ANC values showed a trend for increase between baseline and cycle 2 in stage I (P = 0.06). When ANC maximum was measured, there was a significant trend (P = 0.034) for the maximum ANC level achieved in stage II during cycle 1. However, if patients were eliminated based on dexamethasone exposure, the trend for stage I diminished (P = 0.092) but was maintained for cycle 1 ANC maximum during stage II (P = 0.017). 3.10. Development of Mistletoe Lectin 3 IgG Antibodies and Cytokine ReleaseHelixor A extract is low in ML-1 and high in ML-3 content. Therefore, ML-3 content was followed. All study patients eventually developed mistletoe lectin 3 IgG antibodies. The formation of antibodies was higher at increasing doses of mistletoe. For stage II, when all patients were exposed to the same mistletoe regimen with increasing doses of gemcitabine, only IgG3 antibody levels increased with increasing doses of gemcitabine (data not shown). Cytokines were minimally affected by this combination regimen. |