Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Clinical pharmacology of nitrous oxide: an argument for its continued use.

We tested the hypothesis that the administration of nitrous oxide (N2O) causes major (e.g., myocardial infarction, neuronal injury, hypoxemia, infection, death) or minor (e.g., nausea, vomiting, headache, earache) untoward effects in patients requiring anesthesia for 1.5-4 h. Given the higher morbidity and mortality associated with aging, we also tested whether aging increased any untoward effect of N2O. Finally, we investigated whether the substitution of N2O for a fraction of the anesthesia supplied by isoflurane altered the latter's pharmacologic effects. We studied 270 patients scheduled for elective total hip arthroplasty (n = 100), carotid endarterectomy (n = 70), or transsphenoidal hypophysectomy (n = 100) who were randomly assigned within each surgical group to receive isoflurane with or without 60% N2O. Regardless of patient age, we found no difference in major or minor untoward outcomes between anesthetic groups, nor a trend to suggest that a larger data cohort would reveal a significant adverse effect of N2O. The addition of N2O administration decreased the isoflurane requirement for clinical anesthesia but did not alter most of the clinical variables measured in practice, including blood pressure, heart rate, rate of recovery from anesthesia, development of postoperative pain, patient satisfaction with anesthesia, or duration of anesthesia or of hospitalization. Patients given N2O were no more likely to dream during anesthesia, remember events during anesthesia, or be frightened by those events. Our results support the continued use of N2O to anesthetize patients for elective surgery.

Effect on outcome of prolonged exposure of patients to nitrous oxide.

Prolonged (several days or repeated) exposure to nitrous oxide (N2O) can cause injury or death. To assess whether relatively prolonged anesthesia with N2O in normal patients might similarly cause untoward effects, we investigated whether the addition of N2O to isoflurane anesthesia caused injury to patients having surgical resection of acoustic neuroma lasting approximately 10 h. Twenty-six patients undergoing surgical resection of acoustic neuroma were randomly assigned to a regimen that included or excluded N2O (50%-60%) during isoflurane anesthesia plus intravenous adjuvants. On average, slightly less isoflurane (0.24%) was used during anesthesia with N2O. We measured standard clinical variables (blood pressure, heart rate), oxygen saturation, neurologic status, pain, and the incidence and type of morbid outcomes. Exposure to N2O did not increase the incidence of morbid outcomes (including hepatic injury, infection, or hypoxemia), prolong hospitalization, or increase common postoperative complaints such as nausea, vomiting, coughing, or headache. Patients anesthetized with either regimen were equally satisfied with their anesthetic.

No finding of increased myocardial ischemia during or after carotid endarterectomy under anesthesia with nitrous oxide.

Nitrous oxide (N2O) has been implicated as a cause of myocardial ischemia. We investigated whether substitution of N2O for a portion of the anesthesia supplied by isoflurane increased myocardial ischemia in patients at risk for such ischemia. Seventy patients having carotid endarterectomies (63 patients) or other carotid surgery (seven patients) were prospectively, randomly assigned to an anesthetic regimen that included or excluded N2O. All other aspects of anesthetic management were similar, except for greater concentrations of oxygen and isoflurane in patients not given N2O. Perioperative monitoring for myocardial ischemia and infarction included 12- or 5-lead electrocardiography, transesophageal echocardiography, and creatine kinase isoenzyme levels. By transesophageal echocardiographic or electrocardiographic criteria, 44% of patients given oxygen but only 21% of those given N2O had myocardial ischemia intraoperatively (P = 0.065). Similarly, myocardial infarction, identified by changes in creatine kinase isoenzymes, occurred in only one patient given N2O but in three given oxygen (not significantly different). Thus we found no trend indicating a greater incidence of myocardial ischemia or infarction associated with the use of N2O.

Postoperative hypoxemia after nonabdominal surgery: a frequent event not caused by nitrous oxide.

We tested whether anesthesia that includes nitrous oxide (N2O) results in the development of intraoperative and postoperative pulmonary complications, including hypoxemia. We also tested whether aging contributes to the development of such complications, particularly when anesthesia includes N2O. We randomly allocated patients having total hip replacements, carotid endarterectomies, or transsphenoidal hypophysectomies (total n = 270) to an anesthetic regimen with and without N2O (stratified within surgical group). A heat-and-moisture exchanger was included in the anesthetic circuit of all patients. Patients were monitored perioperatively and for 1 wk after surgery using intermittent and continuous pulse oximetry to determine oxyhemoglobin saturation. Intraoperatively, mean oxygen (O2) saturations were lower in patients given N2O, particularly older patients. Hypoxemia (O2 saturation less than 86%) developed in five patients receiving N2O and in one receiving O2. This difference was not significant. Administration of N2O did not decrease postoperative O2 saturation, nor did it alter the incidence of postoperative hypoxemia, cough, or sputum production.

Nitrous oxide does not impair hepatic function in young or old surgical patients.

We investigated whether anesthesia including nitrous oxide (N2O) caused hepatic injury, and whether any adverse effect of N2O was affected by patient age. One hundred patients having total hip replacements were randomly assigned to a regimen that included or excluded N2O (50%-60%) during regional anesthesia supplemented with isoflurane and intravenous adjuvants. Using postoperative plasma levels of alanine aminotransferase, bilirubin, and alkaline phosphatase 1 and 3 days after surgery as indicators of hepatic impairment, we found no evidence that N2O causes hepatic injury in either young or old patients.

Effect of nitrous oxide on folate and vitamin B12 metabolism in patients.

Exposure to nitrous oxide (N2O) markedly enhances excretion of formic acid and formiminoglutamic acid (FIGLU) in the urine of rats, suggesting a disruption in the normal pathways of folic acid metabolism secondary to an N2O-induced inactivation of methionine synthase. We tested whether surgical patients (23 having total hip replacements and 26 having resection of acoustic neuromas) exposed to isoflurane alone or combined with N2O responded similarly. We found no increase in urinary formic acid and FIGLU in patients exposed to N2O for hip replacement, but a small, transient increase in the FIGLU-to-creatinine ratio in those undergoing resection of acoustic neuromas (mean duration of anesthesia = 9.3 h). This increase peaked at the end of anesthetic exposure and returned toward control levels by the first day after anesthesia and surgery. Low preoperative levels of red blood cell folate and low-normal levels of serum vitamin B12 did not predict an increase in formic acid or FIGLU in response to N2O. Although an occasional patient may prove highly susceptible to and develop signs of severe vitamin B12 and folic acid deficiency after exposure to N2O, our findings suggest that this is a rare event.

Hematologic effects of nitrous oxide in surgical patients.

Nitrous oxide can cause hematologic abnormalities, including death, if it is administered for several days. However, the adverse hematologic effects of its use for surgical anesthesia are unclear. Accordingly, we have studied the hematologic responses of patients undergoing procedures involving hematologic stress or prolonged anesthesia with and without nitrous oxide. We measured red cell count, hemoglobin concentration, mean red cell volume, reticulocyte count, platelet count, mean platelet volume, blood leukocyte level, and leukocyte differential in patients undergoing total hip arthroplasty or removal of an acoustic neuroma. Nitrous oxide did not affect the production of red blood cells or platelets. Nitrous oxide treatment was associated with an increase in postoperative leukocyte levels that was modestly but significantly smaller than that found in patients not given nitrous oxide. There was no evidence that this small decrease in maximal leukocytosis adversely affected clinical outcome.

Blood loss and blood transfusion.

Homologous, or banked, blood is chronically in short supply. In addition, it is associated with a number of significant risks, including transfusion-related infection with hepatitis and acquired immune deficiency syndrome (AIDS), transfusion reactions, and alloimmunization. Therefore, the benefits of reducing the dependence on banked blood are clear. Several techniques are being used to transfuse the patient's own blood during surgery. With the predeposit technique, a patient anticipating surgery donates blood during the month preceding operation. During or immediately following surgery, the patient's blood can be collected and reintroduced (whole blood salvage and reinfusion) or it can be collected, washed, and reinfused in the form of packed cells. Expanded use of these techniques and efforts to reduce blood loss during surgery can reduce the incidence of transfusion-related complications. In the future, synthetic blood substitutes may further reduce the need for homologous transfusions in surgical patients.

Helium-oxygen gas therapy. Use and availability for the emergency treatment of inoperable airway obstruction.

Inoperable obstruction of the upper airway due to extrinsic malignancy may present as respiratory failure. We treated such a patient for 48 hours with 80 percent: 20 percent helium-oxygen delivered by a nonrebreathing mask while chemotherapy and radiation therapy reduced the tumor size. The need for intubation, mechanical ventilation, and high risk surgical intervention was avoided through the use of this gas therapy. We then surveyed San Francisco Bay area hospitals and found that fewer than one half could provide this potentially lifesaving gas therapy in an emergency situation. Physiologic basis of helium-oxygen gas therapy is reviewed and recommendations made for its use and availability.

Serum progesterone levels in early imminent abortion.

Blood progesterone levels of 112 women in 5 to 10 weeks of gestation were analyzed. Of them, 58 women were admitted for voluntary surgical abortion (control group), while 54 patients showed clinical signs of imminent spontaneous abortion (study group). Mean progesterone levels by gestational age (5 to 10 weeks--control/study) were as follows: 49.4/33.4-54.2/36.5-57.8/39.8-68.2/46.2-83.4/69.1-99.8/98.9 nmol/l. These values were significantly lower in the 5 to 9-week spontaneous abortion patients compared to the controls. No significant difference was observed in the 10-week group. The authors consider progesterone assays as a useful screening method for progesterone deficiency among imminent abortion patients and providing basis for better knowledge of the physiological background and meaningful therapy of this pathological condition.