Historically, the preoperative and postoperative care of patients with gastrointestinal cancer was provided by surgeons. Contemporary perioperative care is a truly multidisciplinary endeavour with implications for cancer-specific outcomes.
A literature review was performed querying PubMed and the Cochrane Library for articles published between 1966 to 2012 on specific perioperative interventions with the potential to improve the outcomes of surgical oncology patients. Keywords used were: fast-track, enhanced recovery, accelerated rehabilitation, multimodal and perioperative care. Specific interventions included normothermia, hyperoxygenation, surgical-site infection, skin preparation, transfusion, non-steroidal anti-inflammatory drugs, thromboembolism and antibiotic prophylaxis, laparoscopy, radiotherapy, perioperative steroids and monoclonal antibodies. Included articles had to be randomized controlled trials, prospective or nationwide series, or systematic reviews/meta-analyses, published in English, French or German.
Important elements of modern perioperative care that improve recovery of patients and outcomes in surgical oncology include accelerated recovery pathways, thromboembolism and antibiotic prophylaxis, hyperoxygenation, maintenance of normothermia, avoidance of blood transfusion and cautious use of non-steroidal anti-inflammatory drugs, promotion of laparoscopic surgery, chlorhexidine–alcohol skin preparation and multidisciplinary meetings to determine multimodal therapy.
Significant efforts to improve the outcomes of patients with gastrointestinal cancer have produced impressive results with higher survival statistics now than ever1, 2. Contemporary treatment strategies rely on multidisciplinary care teams, channelling individual expertise through a unified healthcare process. Similarly, perioperative care has evolved from a surgical and nursing team to a broad interdisciplinary cooperative endeavour. Prompt recovery is in the interest of patients with cancer, whether they require completion of adjuvant therapy, are returning to work, or have a short life expectancy. In this context, surgical leadership has proven invaluable in establishing perioperative care standards.
The purpose of this review is to report on current advances in perioperative care, to assess whether they translate into improved outcomes, and to discuss their relative contribution. This is particularly important in an era of enhanced scrutiny of healthcare practice, constrained resources and rising medical needs. This article has a focus on gastrointestinal cancer, as this is by far the most studied disease entity in the field.
The literature search for this narrative review was based on a synthesis of the many specific perioperative interventions and care strategies retrieved by using systematic reviews where appropriate, rather than multiple references of original works. In addition, the Cochrane Library and MEDLINE/PubMed were searched (January 1966 to March 2012) using the following keywords: fast-track, enhanced recovery, accelerated rehabilitation, multimodal and perioperative care. Specific interventions were queried, including normothermia, hyperoxygenation, surgical-site infection (SSI), skin preparation, transfusion, non-steroidal anti-inflammatory drugs (NSAIDs), thromboembolism and antibiotic prophylaxis, laparoscopy, radiotherapy, perioperative steroids and monoclonal antibodies.
Priority was given to pragmatic perioperative interventions that have the potential to improve the outcomes of oncology patients under the care of surgeons, as opposed to unproven trends. Furthermore, a selection of topics was made owing to length limitations. Major themes, such as perioperative nutrition, that may warrant a dedicated review were not included.
Inclusion criteria were randomized controlled trials (RCTs), prospective or nationwide series, and systematic reviews/meta-analyses. Exclusion criteria were retrospective series, papers published in languages other than English, French or German, and papers excluding cancer.
Accelerated recovery protocols
A recent meta-analysis3, including six RCTs, found that enhanced recovery pathways halved 30-day morbidity and reduced length of hospital stay by 2 days. These results were demonstrated across different healthcare systems, including Switzerland4, the UK5–7, the Czech Republic8, the Netherlands9 and the USA10. Colorectal resection was the commonest procedure studied because it is associated with a quarter of all complications11, 12. Encouraging results were observed for other surgical procedures, together with improved patient satisfaction and effectiveness of care3, 13. Nonetheless, the uptake of standardized care has been low, with less than one-third of institutions implementing such programmes in Europe and North America14–16. Meanwhile, there is increasing pressure on healthcare providers and institutions owing to a shortage of qualified personnel and resources, compounded by rising costs and demand. In this context, specific protocols may provide some relief by optimizing resources3. The implementation of diagnosis-related group compensation schemes and withholding of payments for excessive complications may encourage standardized perioperative care in some countries17–19.
Information about the care process
Continuous information about the care process is paramount, starting in the preoperative clinic and extending to postdischarge management20–23. Written information about the planned procedure, the care process and the related expectations should be provided in plain language, including preset discharge criteria and postdischarge contact/follow-up arrangements. Appropriate discharge planning starts at the preoperative clinic where patient-specific needs that may delay discharge are identified and accounted for (for example, preoperative stoma education). Typical standardized discharge criteria include: the ability to tolerate three meals in a row, satisfactory oral analgesia (pain score of less than 4 on a visual analogue scale), passage of flatus or stool, and a patient agreeable to discharge with adequate social support. Ultimately, the patient, relatives and all healthcare providers involved in an episode of care should share a common understanding of the expected care pathway.
Preservation of gastrointestinal function
Preservation of gastrointestinal function is crucial to early recovery. Liquids are safe up to 2 h before surgery, including tea or coffee with milk, but solid food should be avoided for 6 h before elective surgery. These European guidelines also apply to obese or diabetic patients, and to pregnant women not in labour24, 25. Administration of a carbohydrate solution the evening before surgery and for up to 2 h before surgery may reduce postoperative insulin resistance and catabolism26–28, although the specific type (or constituents) may not matter. Prevention of postoperative nausea and vomiting can be achieved effectively by a multimodal strategy, including propofol-based total intravenous anaesthesia and a combination of antiemetic drugs acting at different receptor sites (dexamethasone, antidopaminergic drugs and serotonin receptor antagonists)29, 30. Hence, liquids can be offered immediately after surgery without restriction on progression to diet. Early enteral feeding has been shown in meta-analysis to be effective in hastening recovery of gastrointestinal function and in reducing catabolism and morbidity31–33.
Postoperative ileus is a physiological response to major surgery resulting in discomfort, morbidity and protracted hospital stay. It was estimated that in 2000 ileus in the USA was responsible for direct healthcare costs exceeding US $ 1 billion34, 35. Several randomized trials have shown that the following techniques reduce the duration of ileus: avoidance of routine nasogastric intubation, prevention of fluid excess, laparoscopy instead of open surgery, thoracic epidural analgesia, intravenous and incisional local anaesthetics, peripheral opioid antagonists, laxatives and chewing gum36. Adherence to these techniques reduced the duration of ileus following colorectal resection to 24–48 h in over 90 per cent of patients, compared with 96–120 h in traditional care7, 22, 37. Of the many drugs tried (metoclopramide, erythromycin, neostigmine, propanolol, cisapride, methylnaltrexone), a peripheral opioid antagonist (alvimopan) was found to be cost-effective in the presence of an intestinal anastomosis38–41.
Fluids and electrolytes
Minimization of fluid and electrolyte imbalance maintains homeostasis and promotes recovery. Unnecessary fluid and electrolyte shifts may be prevented by avoiding bowel preparation. A number of RCTs and meta-analyses including up to 5805 patients concluded that orally delivered mechanical bowel preparation (MBP) had no influence on the rate of wound infection (9·6 per cent versus 8·5 per cent with no MBP; odds ratio (OR) 1·16, 95 per cent confidence interval (c.i.) 0·95 to 1·42), leak of colonic anastomosis (3·0 per cent versus 3·5 per cent with no MBP; OR 0·85, 0·58 to 1·26) and leak of low rectal anastomosis (8·8 per cent versus 10·3 per cent with no MBP; OR 0·88, 0·55 to 1·40)42. Similar results were reported when MBP was compared with enema. Moreover, replacement of fluid and electrolyte losses suffered during MBP contributes to intraoperative fluid overload. Preoperative tattooing of small intraluminal lesions may minimize the need for intraoperative colonoscopy, whereas the ease of bowel handling desired by many laparoscopic surgeons may be obtained with an enema.
Meta-analysis demonstrated that prevention of fluid excess reduced the morbidity of major abdominal surgery by up to two-thirds and consequently hospital length of stay43–46. Current UK and US recommendations for intraoperative goal-directed administration of fluid boluses using transoesophageal monitoring of the cardiac stroke volume may be outdated47, 48. Recently, RCTs have found that maximization of stroke volume (as opposed to optimization) added no additional benefits49, whereas goal-directed fluid therapy using crystalloid instead of colloid boluses necessitated reduced total intravenous fluid and was associated with less morbidity50. For practical purposes, restriction of perioperative fluids with or without monitored or goal-directed administration aiming at zero weight gain reduces postoperative morbidity4, 51.
Active pain control and sound collaboration with the anaesthetist are key to postoperative care. Options include thoracic epidurals52–55, wound catheters, local anaesthetics, total intravenous anaesthesia, short-acting volatile anaesthetics, opioids and muscle relaxants. For laparoscopic cases, patient-controlled analgesia is as effective as an epidural, with no additional side-effects when replaced by oral analgesia within 72 h56–59. Although there appears to be some physiological benefit to a transverse abdominal incision compared with a midline incision, meta-analyses and large randomized trials have provided no clear support in favour of a particular incision60, 61. Conversely, meta-analyses of RCTs have established consistent benefits for a laparoscopic approach compared with laparotomy: earlier resumption of a normal diet, reduced blood loss62, 63, halved short- and long-term morbidity36, 64–69, and decreased postoperative pain and opioid use. Those benefits translated into a reduction of hospital stay of about 2 days, 30 per cent less skilled nursing facility utilization70, and improved quality of life and recovery62, 71–74. Oncological outcomes for gastric, colonic and rectal cancer surgery did not differ68, 75–80.
Pre-emptive multimodal non-opioid analgesia may be initiated with paracetamol/acetaminophen52 and gabapentin81; the latter may reduce opioid consumption and related adverse effects (nausea/vomiting, urinary retention) at the cost of increased sedation and dizziness.
NSAIDs should be used with caution, owing to a possible association with an increased risk of anastomotic leak82. Perioperative administration of intravenous lidocaine, dexamethasone or ketamine reduces pain scores and opioid consumption, time to return of bowel function and nausea/vomiting29, 30, 83, 84. Recently, transversus abdominis plane/rectus sheath local anaesthetic blocks have been proposed as a further component to multimodal analgesia: a meta-analysis85 and subsequent randomized trials86–91 showed a consistent improvement in postoperative pain scores and a reduction in opioid requirements at 24 and 48 h, translating into less postoperative sedation88, 91. A further randomized trial90 suggested equivalent pain control when an epidural infusion was compared with transversus abdominis plane block bolusing. Finally, two randomized trials showed transversus abdominis plane blocks to be superior to patient-controlled analgesia in terms of pain control for open surgery87, 88.
Patient mobility and independence
Efforts to promote the patient's autonomy are crucial, including avoidance or early removal of intravenous lines, drains and urinary catheter. Enforced mobilization, breathing exercises and preservation of the sleep pattern with night-time sedation as needed are important.
Routine use of abdominal drainage92, 93 and nasogastric tubes94 increases gastrointestinal and infectious morbidity, with no benefit for the patient. Abdominal drains are used in the presence of an abscess or gross intra-abdominal contamination, or selectively for low colorectal anastomosis if needed. Importantly, the presence of an epidural does not prevent removal of a urinary catheter on the first postoperative day after abdominal or thoracic procedures. Recatheterization rates of 10 per cent were found consistently in randomized trials investigating early removal of bladder catheters, whereas urinary tract infections and length of stay were significantly reduced95, 96. Suprapubic bladder drainage is an often forgotten means of reducing infectious morbidity97.
Example of a standardized protocol
Starting on the first postoperative day, meals are taken with free access to non-carbonated drinks, and five walks outside the patient's room are requested. Promotion of autonomy saved a mean of 83 min per day of nursing time over a typical 5-day stay after open colectomy for cancer (Fig.1). Others have reported similar findings22, 98, with early restoration of organ function translating into improved autonomy, quicker recovery and faster discharge without a major impact on readmissions99–103, the burden on relatives, or referrals to a skilled nursing facility104. Interestingly, patients discharged earlier seem to have fewer readmissions than those who stay longer105–107, whereas non-adherence to standardized protocols may be associated with increased readmissions99. Overall, however, complications requiring readmission had similar outcomes and duration as those identified in hospital99, 106.
Laparoscopic excision of colorectal cancer has comparable oncological outcomes, with improved perioperative recovery, quality of life, adhesion and incisional hernia risk, whereas societal costs are equal or improved, in comparison with open resection. This was demonstrated in the context of conventional care by multicentre randomized trials, nationwide cohort series and meta-analysis3, 68–70, 76, 77, 80, 108–115. The combination of laparoscopy and standardized perioperative protocols has been investigated in three randomized and three controlled trials3. The larger trials, in particular a multicentre randomized Dutch trial, showed a 2-day reduction in hospital stay with accelerated programmes whether the procedure was open or laparoscopic. On multivariable analysis, laparoscopy was the single independent factor to reduce both morbidity and hospital stay9. Physiological studies showed faster recovery of colonic transit time with optimized care and/or laparoscopy, whereas gastric emptying time remained unchanged116. Lastly, a detailed investigation of which protocol elements were independently associated with early recovery found that female sex, laparoscopy, a normal diet and enforced mobilization on postoperative days 1–3 determined earlier recovery32.
Venous thromboembolism (VTE) represents one of the most common preventable causes of death in patients with cancer undergoing surgery117. The incidence of VTE increases to nearly 10 per cent within 2 years of a cancer diagnosis, with recent surgery, advanced malignancy, chemotherapy and hospital admission being additional risk factors. The risk of recurrent VTE and readmission is also threefold higher than in the absence of malignancy118. Most institutions support in-hospital VTE prophylaxis based on updated evidence-based guidelines118–120. These guidelines also address perioperative bridging for patients receiving vitamin K antagonist or antiplatelet therapy, taking into account renal function and refining risk stratification. An important point emerging in a 2009 Cochrane review117, and included in the current guidelines of the European Society for Medical Oncology118, proposes extended VTE prophylaxis with low molecular weight heparin for 30 days, that is beyond hospital discharge. Adherence to this recommendation may decrease the 3-month rate of VTE (14·3 versus 6·1 per cent; OR 0·41, 95 per cent c.i. 0·26 to 0·63), with no increase in the risk of bleeding at a comparatively low number needed to treat of 12. The evidence in favour of outpatient VTE prophylaxis beyond 30 days is weaker. A marginal survival benefit at 2 years (risk reduction 0·92, 95 per cent c.i. 0·88 to 0·97) was found. The risk of VTE remained halved, and no increase in minor or major bleeding was found in meta-analysis121.
Antibiotic prophylaxis and skin preparation
SSIs are the second most common cause of nosocomial infections, as about 20 per cent of patients undergoing abdominal operations develop a SSI122. Adherence to recommended antibiotic prophylaxis reduces the rate of SSI by more than two-thirds in clean-contaminated surgery (relative risk 0·3, 95 per cent c.i. 0·22 to 0·41)123. For bowel surgery, cephalosporins and metronidazole are used widely against commensal aerobes and anaerobes, ciprofloxacin being a common alternative to cephalosporin if a history of severe allergy to penicillin is present. Antibiotics should be administered 30–60 min before incision for a bactericidal concentration to be reached when the skin barrier is breached. Just missing the appropriate antibiotic administration window may double the rate of SSI124. As distractions are common during this opportunity window, inclusion of timely antibiotic administration has been added to surgical checklists. Redosing of antibiotic prophylaxis in procedures longer than 4 h to reflect pharmacological half-life or when major blood loss occurs is recommended. Conversely, multiple doses of prophylactic antibiotics following procedure completion may not be useful and may risk pseudomembranous colitis123. In the context of colorectal surgery, the combination of oral and intravenous antibiotic prophylaxis may be more effective than intravenous antibiotics alone (risk reduction 0·55, 95 per cent c.i. 0·41 to 0·74)123.
Use of hair clippers instead of shavers to remove body hair shortly before skin incision125, as well as a preference for alcohol rubs rather than aqueous scrubbing, are further established means to reduce SSI126. A multicentre randomized trial demonstrated the superiority of chlorhexidine–alcohol over skin cleansing with povidone–iodine by halving the rate of superficial and deep incisional infections127. If this is true, the cost-effectiveness would be substantial128. Alcohol-based skin preparations, however, carry a risk of fire when used in conjunction with electrodissection close to a source of high oxygen concentration.
Perioperative oxygen supplementation
Preclinical studies have shown that high oxygen tension in subcutaneous tissue enhances the oxidative killing of pathogens by neutrophils129 and promotes wound healing in animals130. Although antibiotic prophylaxis, perioperative normothermia, normoxia and normoglycaemia have proved to be effective strategies in reducing SSIs, the role of perioperative hyperoxygenation (defined as a perioperative oxygen concentration of 80 per cent) remains controversial in human studies131–134. Several randomized trials of hyperoxygenation have shown a significant reduction in the incidence of SSI in colorectal surgery135–137, but these results have not been confirmed in other studies, mostly including the whole range of surgical procedures138–141. A recent meta-analysis of five randomized trials including a total of 3001 patients undergoing abdominal procedures showed a relative risk reduction of 25·3 (95 per cent c.i. 8·1 to 40·1) per cent and an absolute risk reduction of 3 (1·1 to 5·3) per cent for a number needed to treat of 33142. No adverse effects of perioperative oxygen supplementation were reported. The beneficial effect of hyperoxygenation was maximized in patients with colorectal cancer, and was confirmed in a second meta-analysis which showed a halving of SSI in these patients (OR 0·48, 95 per cent c.i. 0·32 to 0·71)143. Therefore, perioperative supplemental oxygen therapy should be used routinely as a non-invasive and inexpensive intervention, particularly in clean-contaminated and colorectal surgery, where intraoperative exposure to a significant bacterial load is the rule.
Hypothermia in surgical patients remains a common problem despite recognition of its deleterious physiological effects and the availability of straightforward techniques to reduce its occurrence. Both general and epidural/neuraxial anaesthesia impair thermoregulation in patients exposed to cold air and who are unable to counterbalance core heat loss144. Mild hypothermia (34–36°) occurs in about 30–70 per cent of surgical patients145, 146, accounting for increased morbidity, hospital length of stay and costs147. Coagulopathy induced by hypothermia leads to impairment of thrombocyte activity148 and inactivation of coagulation factors149, all of which increase blood loss and thus the requirement for allogeneic blood transfusion (ABT)150. Of note, most routine coagulation tests obtained during surgery are performed at 37 °C, irrespective of the patient's actual core temperature; their results may thus not reflect the ongoing coagulopathy. A meta-analysis including 24 randomized trials concluded that mild hypothermia significantly increased blood loss by an estimated 16 (95 per cent c.i. 4 to 26) per cent and the relative risk for transfusion by 22 (3 to 37) per cent. This detrimental effect was observed at a median core temperature of 35·6 °C, about a single degree less than that of normothermic patients; hypothermia in this meta-analysis was thus of a magnitude typical for unwarmed surgical patients150.
Beyond blood loss, hypothermia promotes the development of SSI132, 151. Hypothermia-induced vasoconstriction occurs during operation in more than 75 per cent of patients. Vasoconstriction, in turn, reduces oxygen tension and impairs the oxidative activity of neutrophils. In addition, collagen deposition in the surgical wound is decreased and cell proliferation is impaired, compromising wound healing. Many randomized trials reported a significantly higher rate of SSI in hypothermic patients131, 132, 152, 153. For instance, a randomized trial conducted in 200 colorectal patients showed a threefold increase in the rate of SSI in the hypothermic group (19 per cent SSI, 34·7 ± 0·6 °C) in comparison with normothermic patients (6 per cent SSI, 36·6 ± 0·5 °C)128.
By simply maintaining intraoperative normothermia with inexpensive methods such as a warm blanket, warm intravenous fluids and a high room temperature, the rate of SSI can be decreased greatly. In this context, maintenance of perioperative normothermia has recently been linked to hospital reimbursement for the institutions participating to the US Surgical Care Improvement Project.
Are blood transfusions bad?
Anaemia is a common finding in patients undergoing surgery for cancer. Gantt154 first suggested that immunomodulation induced by ABT may be implicated in tumour recurrence after curative surgery. Multiple trials have since been conducted to confirm this hypothesis and to improve our understanding of the impact of transfusion-related immunomodulation (TRIM) on the immune system. Despite a large number of experimental publications, the mechanism of TRIM remains poorly understood, with multiple mediators and mechanisms acting in combination to downregulate the immune system of recipients155–159. Many trials suggested a role for leucoreduction in minimizing transfusion-related lung injury160, including a reduction in short-term mortality after cardiac surgery using extracorporeal bypass circulation161. However, a systematic review of more than 100 studies on cancer recurrence and SSI found no support for routine leucoreduction162. Nevertheless, patients undergoing surgery for cancer and receiving ABT remain prone to worse outcomes in terms of tumour growth and recurrence, with decreased long-term survival163–173. Hence, a Cochrane review focusing on colorectal cancer demonstrated a dose-dependent increase in tumour recurrence in patients receiving perioperative ABT174. Finally, the negative impact of TRIM in terms of SSI was confirmed in two large prospective observational studies published recently175, 176.
Meticulous and gentle technique, including electrosurgical dissection and laparoscopy, and acute haemodilution are effective in reducing the need for ABT177. Conversely, intraoperative blood salvage remained controversial, owing to a possible infusion of cancer cells shed during tumour resection. However, a recent meta-analysis suggested that cancer outcomes were not inferior to ABT when blood cells lost during surgery were transfused back178. The authors recommended cell salvage in all cases where estimated blood loss was above 1000 ml, including use of leucodepletion. Indeed, a National Institute for Health and Clinical Excellence guideline now recommends intraoperative cell salvage with leucodepletion for radical prostatectomy and cystectomy. Of note, the use of cell salvage during liver transplantation for hepatocellular carcinoma was found to be both safe and cost-effective179, 180, in spite of the requirement for postoperative lifelong immunosuppression.
In the case of anaemia requiring treatment, autologous transfusion and recombinant erythropoietin were proposed to reduce the need for ABT. Although autologous transfusion may not entirely prevent TRIM, adverse reactions including negative cancer outcomes may be minimized181, 182. Trials investigating the use of recombinant erythropoietin to stimulate erythropoiesis before surgery demonstrated a significant reduction in the number of units transfused in cardiac183, orthopaedic184, and head and neck cancer surgery185. Conversely, a Cochrane review including four randomized trials in colorectal cancer did not demonstrate any difference in transfusion requirements or morbidity in favour of perioperative administration of erythropoietin186. A further Cochrane review investigating the use of erythropoietin in medical oncology suggested a marginally decreased overall survival187, whereas a 2012 systematic review published in the British Journal of Cancer concluded that current clinical data do not support a significant effect of erythropoietin on disease progression188. Overall, recombinant erythropoietin may have a marginal role in the perioperative context, owing to its delayed effect, contrasting with the acute need of surgical patients when unplanned major blood loss occurs.
Perioperative stress-dose steroids are administered routinely to patients presenting with adrenal insufficiency, most frequently as a consequence of long-course steroid therapy for autoimmune diseases or transplant, or less commonly from metastatic disease to both adrenal glands. Adrenal insufficiency is postulated in patients taking prednisone at a dose greater than 20 mg/day for 3 weeks or more. Perioperative dexamethasone has also gained wide clinical acceptance for the prevention of nausea and vomiting29. A meta-analysis of 24 RCTs including 2571 patients suggested further benefits: a single administration of dexamethasone at doses between 0·11 and 0·2 mg/kg reduced postoperative pain, opioid consumption and length of stay, particularly when administered before surgery. Wound healing was unaffected, as were rates of SSI30. Hence, dexamethasone may be propagated as an useful adjunct to perioperative care.
In a different setting, two meta-analyses of up to 21 RCTs suggested that prompt initiation of low-dose intravenous corticosteroid therapy in patients with severe septic shock (defined as a persisting systolic blood pressure of less than 90 mmHg despite adequate volume resuscitation and vasopressor support) decreased the mortality rate (absolute risk reduction of 6 per cent). The benefit of steroids was correlated to the severity of illness, with a detrimental effect in less severely ill patients189, 190.
Non-steroidal anti-inflammatory drugs and anastomotic leak
NSAIDs provide effective pain relief, thereby reducing perioperative opioid requirements. They exert anti-inflammatory and analgesic effects by inhibition of cyclo-oxygenase (COX)-dependent prostaglandin synthesis. Unfortunately, production of proinflammatory mediators involved in anastomotic healing is also affected191, 192. Anastomotic leakage has significant implications, being associated with increased morbidity, mortality, length of stay and costs, and worse oncological outcomes193, 194. If the theoretical risk of impaired anastomotic healing were to translate into clinically apparent leaks, this would severely limit the utility of NSAIDs in surgery. Several animal studies showed a negative impact of NSAIDs on anastomotic healing195–197, whereas other preclinical studies were inconclusive198, 199. To date, there have been no randomized trials investigating this relationship in patients. A small number of retrospective studies suggested a negative effect of NSAIDs on leak rates. Holte and colleagues200 studied the rate of leakage before and after introduction of celecoxib for pain management (28 patients), and found a significantly higher incidence of anastomotic leakage in patients using this selective COX-2 inhibitor. Klein and co-workers201 obtained similar results in a retrospective case–control study based on 75 consecutive patients undergoing laparoscopic colorectal resection. The largest published study is a retrospective analysis of 795 colorectal patients in which NSAIDs were associated with a nearly twofold increased anastomotic leak rate (13·2 versus 7·6 per cent; OR 1·84, 95 per cent c.i. 1·13 to 2·98). This effect was due mainly to the non-selective NSAID diclofenac (OR 2·13, 1·24 to 3·65), as the association with the selective COX-2 inhibitor celecoxib or meloxicam was not significant (OR 1·16, 0·49 to 2·75). Interestingly, a dose-dependent risk was apparent with each additional day on NSAIDs, increasing the risk of leakage by 24 (1·08 to 1·43) per cent82. Thus, increasing evidence may indicate a higher anastomotic leak rate when NSAIDs are used in colorectal surgery. A large multicentre randomized trial is needed urgently to answer definitively whether NSAIDs increase the risk of anastomotic leak in abdominal surgery (in contrast to current recommendations202).
Multidisciplinary team meetings
An increasing number of national guidelines make regular multidisciplinary team (MDT) meetings a prerequisite to certification as a cancer centre or simply to the practice of oncological surgery. Indeed, a prospective Dutch series of nearly 300 patients at an academic medical centre found that management plans were altered in over a third of patients with upper gastrointestinal malignancy discussed at the MDT meeting. A similar effect was observed in North American studies of pancreatic and urological cancers203, 204, and an interventional cohort study of 13 722 Scottish women suggested improved breast cancer survival and reduced regional variation in cancer outcomes when MDT meetings were attended205.
Rectal cancer is a prime example of the benefits that MDT meetings may provide by reviewing complex multimodal therapy options and tailoring those to the needs of an individual patient. Neoadjuvant radiochemotherapy is recommended for some stage II/III rectal cancers, followed by surgery within 10 days (short course) or after 6–8 weeks (long course). Neoadjuvant therapy has a higher completion rate than its postoperative counterpart, owing to surgical morbidity and delayed recovery after surgery206. Tumour downstaging, some complete pathological responses, better local control and a better disease-free survival (but not overall survival) are further advantages of neoadjuvant chemoradiotherapy in comparison with adjuvant radiochemotherapy207–209. The addition of sensitizing chemotherapy to neoadjuvant radiotherapy nearly doubles the acute toxicity of neoadjuvant therapy to nearly 14 per cent210, 211. The benefit of multimodal therapy in terms of tumour response (threatened circumferential or distal margins) and local recurrence rates may, however, justify its side-effects, whereas postoperative complications, including anastomotic leak, are unchanged209.
The absence of a significant difference in perioperative morbidity between three radiotherapy regimens (short-course radiotherapy followed by immediate surgery, short-course radiotherapy followed by surgery after 4–8 weeks, or long-course radiotherapy) was confirmed recently by the Stockholm III trial212. On the other hand, radiation toxicity is responsible for most of the lasting morbidity of rectal cancer treatment, including damage to bowel, sexual and urinary functions209. Growing evidence suggests that waiting a longer interval between neoadjuvant radiotherapy and total mesorectal excision increases clinical responses, including complete pathological responses213–217. Sphincter preservation, when in doubt, is best achieved by external-beam neoadjuvant radiation with dose escalation and endocavity contact radiotherapy218, 219—neoadjuvant radiochemotherapy is less effective in this respect.
Impact of monoclonal antibodies
Monoclonal antibodies are playing an increasingly important role in oncology. Therefore, surgeons should be familiar with complications associated with their use. Side-effects of the angiogenesis inhibitors bevacizumab and pazopanib include delayed wound and anastomotic healing, bowel ischaemia and perforation, bleeding, thromboembolism, hypertension and proteinuria. Previous radiotherapy and anastomotic leak increase the likelihood of antibody-related complications220, 221. Waiting at least a month before undertaking major surgery is recommended following administration of angiogenesis inhibitors. To date in colorectal surgery, no survival benefit has been found by adding monoclonal antibodies to adjuvant therapy222, 223, in contrast to their use in the neoadjuvant setting (as in synchronous colorectal liver metastasis) where there is proven benefit.
The present review has addressed important factors in the care of surgical oncology patients (Table1). Although they are not all directly effective against cancer per se, they do make a difference in clinical outcomes when applied. Perioperative care strategies include elements as diverse as adherence to perioperative protocols, thromboembolism and antibiotic prophylaxis, normothermia and hyperoxygenation, use of laparoscopic surgery, minimal blood transfusion, postoperative pain control, perioperative steroids, and whether to advocate in favour of or against radiotherapy. Many of these elements belong to clinical routine and may be influenced by tradition as much as by the current evidence available.
Table 1. Perioperative care strategies in patients with gastrointestinal cancer
Venous thromboembolism prophylaxis
Timely perioperative antibiotic prophylaxis
Appropriate antisepsis and asepsis standards
Perioperative oxygen supplementation
Perioperative normothermia maintenance
Minimization of perioperative blood loss and transfusion requirements
Standardized recovery protocols
Multidisciplinary team meetings for cancer care
Uptake of innovations and compliance to recommendations may lag many years behind published evidence, sometimes requiring a nationwide initiative to get rid of a trusted but deleterious companion, like the routine use of a nasogastric tube3, 224. Indeed, dissemination of innovation in healthcare can be a daunting task. Failure to use available science is harmful and costly. Interventions as simple as administering antibiotic prophylaxis in the correct time window may halve the rate of SSI120. Maintaining core body temperature above 36 °C with warmed air and fluids has the same magnitude of effect128. Yet, these simple, inexpensive and effective targets may remain elusive. Although many clinicians are aware of an association between SSI and worse oncological outcomes, or between hypothermia and blood loss, fluid overload and perioperative recovery, surgical morbidity and delayed chemotherapy, compromises in the care delivered are frequently made that may not serve well the quality one strives to achieve. Indeed, in order to implement even small changes in clinical routine, many members of the care team have to be convinced and motivated.
Incentives and authority may differ when addressing nursing staff, residents or hospital staff. Surgical leadership is crucial to change management, with efforts ultimately paying off. The implementation of standardized perioperative protocols3 or the adoption of laparoscopic resection outside of expert centres225 or in training programmes226 follows a learning curve. Surgeons are familiar with this concept and know what it takes to overcome initial clumsiness, although institutions have a much slower learning pace than does an individual. At the heart of disseminating new approaches lies first the perception of innovation before contextual factors involving communication, incentives and management skills227. Surgeons are seasoned leaders by their everyday accomplishments in the duty of care to patients. The present review should help to reinforce the perception of the little changes in daily practice that collectively do make a difference to patients with gastrointestinal cancer.
The authors thank Thomas Clerici, Andreas Lüthi and Maggie Khan for providing the data about nursing time utilization in the context of the enhanced recovery programme at the Kantonsspital St Gallen. They also thank Ulrich Beutner for his assistance in reference retrieval and editing.
Disclosure: The authors declare no conflicts of interest.