Perioperative Trials Research Articles

Don't Overrely on Small Perioperative Trials

Don't Overrely on Small Perioperative Trials

Pros and Cons of Composite Endpoints in Anesthesia Trials

Pros and Cons of Composite Endpoints in Anesthesia Trials

Treatment Options for Surgically Resectable Gastric Cancer

Surgery is the only curative therapy for gastric cancer. The standard recommendations for resectable gastric adenocarcinoma are free-margin surgery with at least D1 resection and the removal of a minimum of 15 lymph nodes. The overall 5-year survival rate for resected gastric patients remains poor due to locoregional recurrence. The results of a large North American study (Gastrointestinal Cancer Intergroup Trial INT 0116) reported that postoperative chemoradiotherapy conferred a survival advantage compared with surgery alone, which led to the regimen being adopted as a standard of care. More recently the MAGIC/UK Medical Research Council (MRC) trial demonstrated that perioperative chemotherapy resulted in an improvement in overall survival and progression free survival. Thus, two successful strategies are available to improve outcomes in patients with localized gastric cancer. This article reviews data on adjuvant and perioperative treatment modalities for gastric cancer. The article discusses ongoing randomized adjuvant and perioperative trials that are designed to optimize chemotherapy regimens and also investigate combinations of chemotherapy and biologic agents. It is important to understand the mechanisms or pathways involved in gastric cancer development and metastasis. Identification of novel molecules pivotal to tumor biology may lead to new therapeutic approaches for this malignancy.

Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer

The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.

Can Attenuation of the Perioperative Stress Response Prevent Intermediate or Long-term Cardiovascular Outcomes among Patients Undergoing Noncardiac Surgery?

Can Attenuation of the Perioperative Stress Response Prevent Intermediate or Long-term Cardiovascular Outcomes among Patients Undergoing Noncardiac Surgery?

Recent Advances in Anaesthesia and Intensive Care–Volume 24

First published in 1932 as Recent Advances in Anaesthesia and Analgesia (Including Oxygen Therapy), the book’s title has changed over the years culminating in this 24th edition, Recent Advances in Anaesthesia and Intensive Care. This well organized 250-page text includes topics of interest to both general and specialist anesthesia practitioners, as well as to practitioners with an interest in critical care. The following topics are covered in the book’s 13 chapters: the role of cardiopulmonary exercise testing in the preoperative evaluation of surgical patients, esophagectomy for cancer, vascular surgery, anesthesia for the elderly, deaths following anesthesia, pelvic and acetabular trauma, echocardiography, levosimendan, critical care outreach, critical care and biological disasters, evaluating clinical performance, non-technical skills and anesthesia, and simulators in anesthetic training to enhance patient safety. With its focus on up-to-date information and important concepts, the chapter regarding the role of cardiopulmonary exercise testing in the preoperative evaluation of surgical patients presents an excellent overview of the method to assess a patient with limited cardiopulmonary physiological reserve who requires major surgery. I found this chapter to be particularly interesting and relevant given the increasing severity of comorbid illnesses and complex surgical procedures, and the results of the recent POISE trial and other perioperative trials. This chapter will be a helpful guide for managing the complex surgical patient and for administering limited intensive care resources. I must admit I had a desire for more information and wished this chapter was lengthier and more detailed. The chapters dealing specifically with anesthesia in relation to esophagectomy, vascular surgery, pelvic trauma, and the elderly are well written up-to-date reviews. The focus of the chapter specific to medication is on levosimendan for the treatment of acute decompensating congestive heart failure. The chapter regarding advances in critical care medicine covers the expanding role of echocardiography from the operating room to the intensive care unit. It includes a discussion by critical care outreach and medical emergency teams regarding the controversy within the current literature, and it incorporates a review of severe acute respiratory syndrome and pandemic planning. The final three chapters evaluate clinical performance, reduction of harm, and simulation to enhance training. In summary, Recent Advances in Anaesthesia and Intensive Care encompasses a wide range of topics, from the pre-admission clinic, to the operating room, to the intensive care unit, to quality improvement. The book is directed more towards the anesthesiologist who is an intensivist rather than towards other medical specialties. Its focus is on preparing the critically ill patient for surgery, and it includes relevant sections for all persons involved with the critically ill patient, including medical emergency teams and those engaged in simulation. The chapters are short, easy to read, well researched, and well written. For a speedy and succinct read, this book would be an excellent addition to your library.

Perioperative or Adjuvant Therapy for Resectable Colorectal Hepatic Metastases

Perioperative or Adjuvant Therapy for Resectable Colorectal Hepatic Metastases

Results from the perioperative epidural trial pilot study

Results from the perioperative epidural trial pilot study

Fosfomycin: Use Beyond Urinary Tract and Gastrointestinal Infections

The shortage of new antimicrobial agents has made the scientific community reconsider the potential value of old antibiotics. A search of the literature was performed to compile relevant evidence regarding the effectiveness and safety of fosfomycin for the treatment of patients with gram-positive and/or gram-negative bacterial infections (excluding urinary tract infection and gastrointestinal infection). Of 1311 potentially relevant studies, 62 studies were reviewed in detail. Of 1604 patients with various gram-positive and gram-negative infections of various body sites (including pneumonia and other respiratory infections; osteomyelitis; meningitis; ear, nose, and throat infections; surgical infections; obstetric and gynecological infections; arthritis; septicemia; peritonitis; cervical lymphadenitis; eye infections; diabetic foot infections; and typhoid fever) being treated with fosfomycin alone or in combination with other antibiotics, cure was achieved in 1302 (81.1%) of the patients, and improvement was noted in 47 (2.9%). In comparative perioperative prophylaxis trials that included a total of 1212 patients (mainly patients undergoing colorectal surgery), the fosfomycin-metronidazole combination led to results that were similar to those achieved with the combination of other antibiotics (doxycycline, ampicillin, or cephalothin) and metronidazole. In an era in which there is a shortage of new antibiotics, fosfomycin might be considered to be an alternative treatment agent for infections caused by gram-positive and gram-negative bacteria, in addition to its traditional use in treating uncomplicated urinary tract and gastrointestinal infections. Further research on the in vitro antimicrobial activity of fosfomycin, especially against multidrug-resistant pathogens (such as extended-spectrum beta-lactamase-producing and/or metallo-beta-lactamase-producing enterobacteriaceae and Pseudomonas aeruginosa, and on the effectiveness and safety of the drug in the treatment of patients with such infections may be warranted.

Does Tight Heart Rate Control Improve Beta-Blocker Efficacy? An Updated Analysis of the Noncardiac Surgical Randomized Trials

Recent meta-analyses assessing the efficacy of perioperative beta-blockade trials have failed to show a reduction in postoperative morbidity and mortality. Tight control of heart rate (HR) has been suggested to improve these outcomes. Meta-analyses have not considered the influence of tight HR control on the efficacy of perioperative beta-blockade. Using previously published search strategies, we identified all randomized trials evaluating perioperative beta-blockers after noncardiac surgery. This search yielded 10 trials with 2176 patients. We used the data from these studies to correlate measures of HR control with major postoperative outcomes, primarily in-hospital myocardial infarction (MI). Odds ratio (OR) and 95% confidence intervals (CI) were calculated, and metaregression was performed correlating measures of HR control with MI. The combined results of all studies did not show a significant cardioprotective effect of beta-blockers, with considerable heterogeneity among the studies (OR = 0.76; 95% CI = 0.4-1.4; P = 0.38 heterogeneity: I(2) = 34%). However, grouping the trials on the basis of maximal HR showed that trials where the estimated maximal HR was <100 bpm were associated with cardioprotection (OR = 0.23; 95% CI = 0.08-0.65; P = 0.005) whereas trials where the estimated maximal HR was >100 bpm did not demonstrate cardioprotection (OR = 1.17; 95% CI = 0.79-1.80; P = 0.43) with no heterogeneity. Moreover, metaregression of the HR response to beta-blockade against the log OR of postoperative MI demonstrated a linear association between the effect of beta-blockade on the mean, maximal, and variation in HR and the OR of an MI (r(2) = 0.63; P < 0.001) where a larger effect of beta-blockers on HR was associated with a decreased incidence of postoperative MI. Across all studies, beta-blockade resulted in a reduction in postoperative HR (weighted mean difference: 8.6 bpm; 95% CI = -9.6 to -7.6; I(2) = 85.3%) with considerable heterogeneity. This large heterogeneity in HR response to beta-blockade was found to be related, in part, to the type of beta-blocker, specifically, metoprolol, and the concomitant use of calcium channel blockers. Calcium channel blocker use and beta-blockers other than metoprolol resulted in more effective control of HR. There was wide variability in the HR response to beta-blockade. Twenty-five percent of patients receiving beta-blockers had episodes when the HRs were more than 100 bpm, although 15% of placebo patients also had bradycardia, which would have required a dose reduction had they been administered beta-blockers. Finally, this analysis found that perioperative beta-blockade was associated with an increased incidence of bradycardia (OR = 3.49; 95% CI = 2.4-5.9) and congestive heart failure (OR = 1.68; 95% CI = 1.00-2.8). The trials that achieve the most effective control of HR are associated with a reduced incidence of postoperative MI, suggesting that effective control of HR is important for achieving cardioprotection. Second, this analysis demonstrates that administration of beta-blockers does not reliably decrease HRs in all patients, and may be associated with increased side effects. Judicious use of combination therapy with other drugs may be necessary to achieve effective postoperative control of HR.

Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: current evidence and future directions

Gabapentin and pregabalin bind to the alpha-2-delta calcium channel subunit and represent a novel analgesic drug class. The evidence base supporting their use for chronic neuropathic and early postsurgical pain is reviewed. Multiple, large, high-quality trials have demonstrated the safety and efficacy of gabapentin and pregabalin in neuropathic pain. Treatment-related improvement of pain and sleep positively impact upon quality of life. Sedation, dizziness and ataxia are important and relatively common adverse effects, however. Accumulating evidence indicates that gabapentin, and possibly pregabalin, also exert important effects following surgery. Multiple high-quality trials have demonstrated analgesic and opioid-sparing efficacy with gabapentin following various surgical procedures. Gabapentin and pregabalin reduce movement-evoked pain and this can lead to enhanced functional postoperative recovery. Postoperative opioid sparing is of questionable relevance since few trials have shown reduced opioid-related adverse effects. Sedation, dizziness and ataxia have been reported in only a few trials. Future larger-scale perioperative trials focused on safety assessment are needed, however. Gabapentin and pregabalin are efficacious treatments for neuropathic and postsurgical pain. Future research addressing several specific questions would serve to better delineate their optimal roles in treating these and other pain conditions.

Pro: Beta-Blockers Are Indicated for Patients at Risk for Cardiac Complications Undergoing Noncardiac Surgery

Pro: Beta-Blockers Are Indicated for Patients at Risk for Cardiac Complications Undergoing Noncardiac Surgery

What is the role of NSAIDs in pre-emptive analgesia?

NSAIDs inhibit the cyclo-oxygenase enzymes, and decrease peripheral and central prostaglandin production. In addition to reducing the inflammation that accompanies tissue injury, decreasing prostaglandin production attenuates the response of the peripheral and central components of the nervous system to noxious stimuli. Such a reduction in the response to pain can reduce the peripheral and central sensitisation induced by noxious stimuli, and reduce the pain experienced in response to subsequent noxious stimuli. These properties would seem to make NSAIDs ideal drugs to use in a pre-emptive fashion, where analgesics are administered prior to a noxious stimulus, such as surgery, with the expectation that reduction in peripheral and central sensitisation will lead to a decrease of pain.However, the available perioperative trials of pre-emptive NSAID use have yielded modest or equivocal results, and these may be due, in part, to controversy associated with the definition of pre-emptive analgesia and how to conduct the corresponding clinical trials. Although NSAIDs may have a limited ability by themselves to induce a pre-emptive analgesic effect, the available trials suggest how the perioperative use of these drugs may be made more effective. It is expected that NSAIDs will play an increasing role in multimodal analgesia and pain relief in general.

Factors influencing patients' willingness to participate in perioperative trials

European Society of Anaesthesiologists; 8th Annual Meeting with the Austrian International Congress; Vienna, Austria, 1-4 April 2000

Overview of randomized perioperative polychemotherapy trials in women with early-stage breast cancer.

To determine whether perioperative polychemotherapy (PeCT) can significantly prolong the overall survival of women with early-stage breast cancer. A meta-analysis that used updated individual patient data from all available randomized trials of PeCT, both published and unpublished, was conducted. Data on 6,093 patients (1,124 deaths and 1,912 recurrences) from five clinical trials were available (median follow-up duration, 5.3 years; maximum, 11.3 years). No significant effect of PeCT on overall survival was observed. However, patients who received PeCT had a significantly longer disease-free survival (hazards ratio [HR], 0.89; 95% confidence interval [CI], 0.82 to 0.98; P = .02). Time to local recurrence was significantly prolonged in the PeCT arm (HR, 0.68; 95% CI, 0.58 to 0.80; P < .0001). Likewise, there was a borderline significant difference in favor of PeCT in terms of time to distant metastases (HR, 0.90; 95% CI, 0.81 to 1.00; P = .05). Subgroup analyses suggest that node-negative women benefited the most from treatment. At present, there is no evidence that PeCT is able to prolong overall survival in patients with early-stage breast cancer; however, further follow-up evaluation is required. PeCT significantly prolongs disease-free survival, especially in node-negative women, which emphasizes once more the need for clinical trials in this subgroup.

The effect of adjuvant tamoxifen: The latest results from the Cancer Research Campaign adjuvant breast trial

The CRC Adjuvant Breast Trial, launched in 1980 to repeat both the Nolvadex Adjuvant Trial Organisation tamoxifen trial and the Scandinavian trial of perioperative cyclophosphamide trial, randomised 2230 stage I or II early breast cancer patients in a 2 × 2 factorial design to investigate the benefits of a short course of perioperative cyclophosphamide or tamoxifen daily for 2 years. At a median follow-up of 7.8 years, no significant benefit is noted for perioperative cyclophosphamide, however the main effect analysis for adjuvant tamoxifen demonstrates a significant improvement in disease-free survival which increases with time over the follow-up period. These results are in keeping with the World Overview of Trials of Adjuvant Tamoxifen. However, this study is unique, having a large number of node negative patients and over 500 premenopausal women in a comparison of tamoxifen and control. The relative risk reductions for the node negative patients for disease-free survival are greater than for node positive patients. This might suggest that the absolute benefit for adjuvant tamoxifen is similar in both groups of patients, bearing in mind the increase risk of relapse with node positive patients. No trend for interaction emerges according to age or menopausal status suggesting an identical benefit for pre and postmenopausal women. Similar relative risk reductions are seen when the data are stratified according to tumour size, suggesting a similar positive benefit may be seen for all patients irrespective of tumour size. Of particular interest is the incidence of contralateral breast cancer, the initial overall effect which emerged at the third year of follow-up ceases to be apparent. However subgroup analysis according to menopausal status suggests a trend for interaction with a reduction in the risk of contralateral breast cancer in the postmenopausal women and a marginal increase in the risk of contralateral breast cancer in premenopausal women. Plausible mechanisms exist to explain this difference in outcome and these data need to be confirmed or refuted by other large trials of adjuvant tamoxifen especially at this time when the chemoprophylaxis of breast cancer in high risk premenopausal women by tamoxifen is being considered.

Perioperative Kurzzeitprophylaxe in der Kopf-Hals-Chirurgie

A prospective perioperative trial with cefotiam and metronidazol was carried out in 114 patients undergoing head and neck surgery. The patients were stratified in one group receiving a single-dose prophylaxis and a second group receiving a 24-hour prophylaxis. The postoperative complication rates were analysed depending on various risk factors and the size and duration of surgery. For operations of similar size the long term prophylaxis had no advantage over the one-dose prophylaxis. It is concluded that a one-dose prophylaxis appears sufficient in major head and neck cases.

Methodological and statistical aspects in perioperative chemotherapy trials.

Cancer clinical trials designed to test the value of perioperative chemotherapy present special statistical problems for the investigator. Because chemotherapy must begin within hours of surgery, aspects of the design, conduct, and analysis of such trials are more complex than for many other types of clinical investigations. Special attention must be given to the logistics of patient entry. In some situations, patients may receive a treatment assignment prior to the determination of eligibility or even prior to histological diagnosis of cancer. Design problems may arise when important prognostic factors are not known at the time of randomization. A comparison of perioperative chemotherapy to other, conventionally timed adjuvant chemotherapy requires that adjuvant treatment be purposely delayed for some patients. Because patients enter a perioperative chemotherapy trial before or soon after surgery, the patient population is not the same as that treated in standard adjuvant trials. Thus it is not possible to compare results directly between perioperative and standard adjuvant trials. Analyses of toxicity will include surgical morbidity which would not be seen in conventional adjuvant trials. The analysis of perioperative chemotherapy trials requires care, as many case exclusion factors may make it difficult to determine the true effectiveness of the perioperative treatment plan. Analysis by intent to treat is recommended. These and other statistical and logistic aspects are discussed with reference to the current trial being conducted by the Ludwig Breast Cancer Study Group.