Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d1491 (Published 29 March 2011) Cite this as: BMJ 2011;342:d1491
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We read with interest your article regarding the relationship between epidural analgesia and survival rates in patients undergoing major abdominal surgery for cancer. All surgeons are keen to explore any avenue which may improve outcomes, and your research is especially pertinent with regards to the recent introduction of “enhanced recovery after surgery” (ERAS) protocols. These are multi faceted interventions which have dramatically decreased the length of stay in post operative patients by reducing the physiological stress of surgery, and have been widely implemented, especially within the field of colorectal surgery. One of the key principles of ERAS is the minimisation of opiate usage, combined with the use of epidurals, to provide appropriate analgesia, whilst reducing the risk of post operative ileus. 1, 2. Therefore it would be beneficial if an intervention used to improve short term morbidity could also improve long term survival.
Unfortunately your article did not find a significant link between the use of epidural analgesia and survival rates, however the study group was very heterogeneous with regards to the operations performed, and the underlying primary cancer; it would be difficult to apply these results specifically, say to the field of colorectal surgery. There was also some vagueness with regards to the opiate usage post operatively; despite it being a multicentre study, the data regarding this has come from a single site, and therefore is questionable as to its validity. The hypothesis formed is based on the concept that morphine has an immunosuppressive affect, and therefore may promote tumour spread. It therefore seems critical to precisely know how much opiate was used in each group.
We therefore feel that this study raises some useful questions which merit further investigation, especially within the area of ERAS and colorectal cancer. Has the implementation of ERAS protocols which attempt to maintain a normal physiological state and therefore reduce the immunosuppressive effect of surgery improved disease free survival? As surgeons, it is critical to know the long term effects of our apparently short term decisions.
References
1. Abraham N, Albayati S. Enhanced recovery after surgery programs hasten recovery after colorectal resections. World Journal of Gastrointestinal Surgery. 2011; 3(1): 1-6
2. Fearon KCH, Ljungqqvist O, Von Meyenfeldt M, Revhaug A, Dejong CHC, Lassen K, Nygren J, Hausel J, Soop M, Anderson J, Kehlet H. Enhanced recovery after surgery: A consensus review of clinical care for patients undergoing colonic resection. Clinical Nutrition. 2005; 24: 466-477
Competing interests: No competing interests
To the Editor:
We read the paper published in the Journal with great interest on the
effect of perioperative epidural analgesia on long-term cancer-free
survival.1 This multicentral follow-up study compared the cancer
recurrence-associated mortality in patients undergone epidural
postoperative analgesia with those without epidural analgesia, and found
epidural analgesia early after the cancer surgeries will not increase the
long-term mortality. This was an intriguing trial and added information
for the understanding upon the safety of early epidural analgesia after
cancer excision, whereas imprecise data were reported.
The authors described the background information of the study through
underlining the impact of analgesia with or without opioids on immune
functions that may be associated with the tumor matastasis. From the study
protocol appeared in the present and previously published reports,1-3 the
patients were randomised into one of the two groups: group epidural,
intraoperative general anaesthesia plus intraoperative epidural
anaesthesia and postoperative epidural analgesia; group control,
intraoperative general anaesthesia plus postoperative intravenous opioids
based analgesia. Such a design would undoubtedly result in a big
difference in the consumption of anaesthetics and analgesics because of
the role of combined epidural and general anaesthesia in reducing
intraoperative drugs usage compared with general anaesthesia alone,4, 5
and these changed drugs might produce undetected role in affecting immune
cells function.6 Therefore, as the data presented in the study did not
include the intraoperative drugs consumption, which consequently makes us
want to know whether or not a difference in drugs usage exists, and if
yes, was there any positive or negative influence of this difference on
the study outcome?
Second, pain, specifically the postoperative pain itself is an immune
suppressor,7 and even a tumor-promoting mediator.8 Although the authors
presented pain intensity measured with visual analogue scale (VAS), they
did not performed in-depth analyses of the effect of pain changes on the
cancer survival. The pain intensity in the present study was at the mild-
to-moderate level, though, the study found a significant difference in
pain at day 1 after surgeries (both at rest and with coughing) and at days
1 to 3 with coughing, thus it was still possible that the pain affected
the function of immune cells which finally influences the recurrence of
the cancer. So it would be better to do a subgroup analysis of the
potential effect of postoperative pain on the long term cancerous
survival.
Third, the authors reported their observations of pain with mean and
standard deviation (SD). This may be an issue needs to be corrected.
Theoretically and practically, pain scorings are skewed data that need to
be converted to logarithmic values if presented with means and SDs.9, 10
If without such a conversion, the median and interquartile range (IQR) of
the pain scorings would be far more precise in predicting the overall
effect of analgesia. Given the difference of statistical methods used in
analysing normally and non-normally distributed data, it might be lead to
different statistical results (Table 1). Therefore, the pain intensity
scores in this study should be corrected to median and corresponding IQR
or converted to logarithmic values.
References:
1 Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI, et al.
Perioperative epidural analgesia for major abdominal surgery for cancer
and recurrence-free survival: randomised trial. BMJ 2011;342:d1491.
2 Peyton PJ, Myles PS, Silbert BS, Rigg JA, Jamrozik K, Parsons R.
Perioperative epidural analgesia and outcome after major abdominal surgery
in high-risk patients. Anesth Analg 2003;96:548-54.
3 Rigg JR, Jamrozik K, Myles PS, Silbert B, Peyton P, Parsons RW, et
al. Design of the multicenter Australian study of epidural anesthesia and
analgesia in major surgery: the MASTER trial. Control Clin Trials
2000;21:244-56.
4 Lu CH, Borel CO, Wu CT, Yeh CC, Jao SW, Chao PC, et al. Combined
general-epidural anesthesia decreases the desflurane requirement for
equivalent A-line ARX index in colorectal surgery. Acta Anaesthesiol Scand
2005;49:1063-7.
5 Li Y, Zhu S, Yan M. Combined general/epidural anesthesia
(ropivacaine 0.375%) versus general anesthesia for upper abdominal
surgery. Anesth Analg 2008;106:1562-5.
6 Welden B, Gates G, Mallari R, Garrett N. Effects of anesthetics and
analgesics on natural killer cell activity. AANA J 2009;77:287-92.
7 Page GG, Ben-Eliyahu S. The immune-suppressive nature of pain.
Semin Oncol Nurs 1997;13:10-5.
8 Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative
pain is a mediator of the tumor-promoting effects of surgery in rats. Pain
2001;90:191-9.
9 Bowalekar SK. Statistics in medical research-II. Measures of
central tendency. J Postgrad Med 1993;39:166-73.
10 McCluskey A, Lalkhen AG. Statistics II: Central tendency and
spread of data. Continuing Education in Anaesthesia, Critical Care &
Pain. Brit J Anaesth 2007;7:127-30.
Table 1. Example of skewed pain data with same mean but different median.
Competing interests: This work is supported in part by the Natural Scientific Foundation of China (NSFC, 30901397), Nanjing Medical University Grant for Science & Technology Development (08NMUZ033), and Nanjing Municipal Foundation of Medical Science (ZKX10018). It does not reflect the view of the National Natural Science Foundation of China, Nanjing Medical University and Nanjing Municipal Bureau of Health, and in no way anticipates their future policies in this area. No additional conflict of interests exists.
Finding The Independent Variable Under Anesthesia during a Surgical
or Medical Procedure, which
would destroy a mitochondrial toxin that inhibits Immune Function, would
possibly improve Patient Survival
Congratulations to the Authors for such a detailed Study.
The Anesthesiologist's concern has always been to have minimal impact
on the vicissitudes of disease, as a particular Anesthetic is chosen for
each Surgical or Medical case, except, of course, as a positive
intervention to curing disease.
Since there are some nowadays who are of the opinion that
mitochondrial toxins cause many
chronic illnesses, perhaps an Anesthetic which ameliorates their action
would be of benefit to Patients experiencing cancer surgery.
That is to say, since a particular mitochondrial toxin, valinomycin,
synthesized by the ubiquitous fifth column bacteria, Steptomyces griseus,
disrupts
mitochondria, destroys NK cells, and inhibits portions of the Thiamine
Metabolic Pathway (1)(4), an Anesthetic which inhibits or neutralizes such
a toxic agent would be of value. That work has yet to be done.
Perhaps something as simple as breaking the valinomycin circle
structure, or altering the ion fluxes of the inner membrane of the
mitochondria would be of benefit.(2)
If such mitochondrial toxin neutralizing compounds could be used
during a Surgical or
Medical procedure in a Patient with cancer, then perhaps the NK cells
would be more likely to destroy potentially metastatic cells immediately,
since processing through a lymph node etc wouldn't be necessary.
valinomycin, known since the 1950's,(3) has been shown to cause NK and
mitochondrial damage at dosages 1/100 of what had been thought pathogenic
The Anesthesiologist objective is to minimize any adverse effect of
an Anesthetic, and optimize its beneficial effects.
As Dr Mattox once said, "Explore to the center of the matter, for
there you will find safety." Unfortunately all parameters of Immune System
dysfunction aren't known, but attempts to neutralize mitochondrial toxins,
whether with Anesthetics or
conventional Medical Agents would be a step in the right direction.
There are several mitochondrial toxins which cause severe disease, or
worse. Apparently there are variable numbers of mitochondria per cell. And
all
mitochondrial don't seem to be created equally
Another example would be cereulide and Diabetes Mellitus.
The purpose of Anesthetic is to provide analgesia, General or
Regional &c, have the patient
relaxed, and PRN amnesia for the procedure. If en route to doing that, a
therapeutic Anesthetic which inhibits mitochondrial toxins and improves
Immune
System Function should be utilized, if indeed it exists.
Keep up the good work
Cordially,
Joseph W Arabasz MD
Past Division Chairman, Anesthesiology, Cook County Hospital,
Chicago, Illinois
Past Chairman, Respiratory Therapy, Cook County Hospital, Chicago
Diplomate ABA
Mensa
Sigma Xi, The Professional Science Research Society
< http://www.SigmaXi.org >
PO Box 6939,
Denver, CO 80206
USA
References
(1) Inhibition of Human NK Cell Function by Valinomycin, a Toxin from
Streptomyces griseus in Indoor Air
Auli Paananen,1,* Raimo Mikkola,2 Timo Sareneva,3 Sampsa Matikainen,3
Maria Andersson,2 Ilkka Julkunen,3 Mirja S. Salkinoja-Salonen,2 and Tuomo
Timonen1
Infection and Immunity, January 2000, p. 165-169, Vol. 68, No. 1
http://iai.asm.org/cgi/content/full/68/1/165
(2) Unpublished Letter of Finland Researcher on valinomycin.
(3) Chem. Ber. 1955, 88, 57-61
http://www3.interscience.wiley.com/journal/112297012/issue
Valinomycin I, XXVII. Mitteil. ?ber Antibiotica aus Actinomyceten (p
57-61)
Hans Brockmann, Gunter Schmidt-Kastner
Published Online: Jan 21 2006 2:17PM
DOI: 10.1002/cber.19550880111
http://en.wikipedia.org/wiki/Chemische_Berichte
Archives
All issues from 1868 to 2008 can be found at
http://www3.interscience.wiley.com/journal/117930400/tocgroup
Chemische Berichte
(4)http://www.jbc.org/content/early/2009/11/11/jbc.M109.054379.full.pdf+html
Thiamine triphosphate synthesis in rat brain occurs in mitochondria and is
coupled to the respiratory chain
Marjorie Gangolf1, Pierre Wins1, Marc Thiry2, Benaissa El Moualij1 and
Lucien Bettendorff1,* ThTP synthesis is strongly inhibited by respiratory chain inhibitors
such as myxothiazol and inhibitors of the H+ channel of F0F1-ATPase. It is
also impaired by disruption of the mitochondria or by depolarization of
the inner membrane (by protonophores or valinomycin), indicating that a
proton-motive force is required.
Competing interests: No competing interests
Gottschalk and colleagues point out that there is considerable basic
science suggesting that regional analgesia may reduce the risk of cancer
recurrence. We agree and this work was the basis for our general
theory.[1] And consistent with our theory, we and others have published
small retrospective studies suggesting that regional analgesia reduces
recurrence risk.[2,3] But we and others have also published negative
retrospective studies. Among them was a study by Gottschalk et al.[4]
Small retrospective studies are important hypothesis generators but
are obviously insufficient to guide clinical practice. This is
particularly the case since retrospective analyses have varying and
unquantifiable amounts of selection bias and confounding -- thus the
importance of randomisation.
A randomised controlled trial is not, as Scott asserts, determined by
the outcome being investigated but by the groups being compared. Large
randomised trials are rightly considered the best form of evidence for
very good reasons.[5,6] Random assignment to treatment groups not only
avoids selection/allocation bias but, with sufficient size, balances both
known and unknown confounders that may of themselves affect outcome. This
includes oncological data, use of chemotherapy or radiotherapy, surgeon
seniority, and genetic predisposition. We reported many demographic,
perioperative and tumour characteristics in our paper,[7] and demonstrated
good balance. This is in marked contradistinction to non-randomised
observational datasets.
The assertion by Gottschalk and others that the MASTER trial had a
high rate of protocol violations is simply wrong. As reported in our
study, the insertion failure rate was 4.6% and the average duration of
epidural analgesia was 74 hours. For the cancer cohort, 66% had their
epidural infusion continued for at least 72 hours. The duration of
regional block exceeds other regional block studies on this subject,[2,3]
and other large case series of epidural block for major surgery.[8-10] We
would like to remind readers that in routine practice around 10-20% of
epidural catheters are removed prematurely because of technical problems
or poor pain control.[8,9] Our pain score data clearly show an analgesic
benefit equal to most studies on this subject. We went to great lengths to
show that the epidural block was appropriate and effective. It is true we
did not measure the stress response or immunological response, but the
purported beneficial effects of local anaesthetic block on both of these
should be manifest by reduced opioid requirement during and after surgery.
Scott's assertion that "no benefit is going to accrue to any individual
patient unless the block is effective from before the skin incision" is
curious. There is no reason to assume that regional analgesia cannot be
effective when started somewhat later -- although we in fact demonstrated
analgesic efficacy in the epidural group. Furthermore, we demonstrated a
marked reduction in opioid use with regional analgesia. The effects of
epidural analgesia on the stress response to surgery are well known. The
unknown issue is whether epidural analgesia has any clinical effect on
cancer recurrence -- and that was the important question we addressed.
There is a sound rationale for using intention-to-treat analysis.[11]
A per-protocol analysis would bias our analysis because major
complications after surgery often lead to protracted stay in intensive
care for which maintenance of epidural block is unnecessary and dangerous,
as well as introducing survivor bias into the analysis.
Gottschalk and colleagues criticize our sample size estimate because
the recurrence rate turned out to be slightly less than we anticipated.
But of course sample size was fixed by our design. The issue thus is not
whether the sample size estimate was correct, but whether we have
reasonable power to support our conclusions. Clearly we do: specifically,
our upper 95% confidence limit shows that an effect greater than 14% is
highly unlikely. Furthermore, the point estimate leans towards a negative
effect of epidural block.
We caution against surgical oncology specialties disregarding either
the MASTER trial or the other negative studies in their assessment of
effectiveness of epidural block.[4,7,12,13] That said, additional
randomised trials are necessary and are, in fact, already in progress. But
until such data are forthcoming, there is no good reason to recommend
regional block for this purpose.
References
1. Sessler DI: Does regional analgesia reduce the risk of cancer
recurrence? A hypothesis. Eur J Cancer Prev 2008; 17: 269-72
2. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI: Can
anesthetic technique for primary breast cancer surgery affect recurrence
or metastasis? Anesthesiology 2006; 4: 660-4
3. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ:
Anesthetic technique for radical prostatectomy surgery affects cancer
recurrence: a retrospective analysis. Anesthesiology 2008; 109: 180-7
4. Gottschalk A, Ford JG, Regelin CC, You J, Mascha EJ, Sessler DI, et al:
Association between epidural analgesia and cancer recurrence after
colorectal cancer surgery. Anesthesiology 2010; 113: 27-34
5. Collins R, MacMahon S: Reliable assessment of the effects of treatment
on mortality and major morbidity, I: clinical trials. Lancet 2001; 357:
373-80
6. Hennekens CG, DeMets D: The need for large-scale randomized evidence
without undue emphasis on small trials, meta-analysis, or subgroup
analysis. JAMA 2009; 302: 2361-2
7. Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI:
Perioperative epidural analgesia for major abdominal surgery for cancer
and recurrence-free survival: randomised trial. BMJ 2011; 342: d1491
8. Scott DA, Beilby DS, McClymont C: Postoperative analgesia using
epidural infusions of fentanyl with bupivacaine. A prospective analysis of
1,014 patients. Anesthesiology 1995; 83:727-37
9. Liu S, Allen H, Olsson G: Patient-controlled epidural analgesia with
bupivacaine and fentanyl on hospital wards. Prospective experience with
1030 surgical patients. Anesthesiology 1998; 88; 688-95
10. Liu SS, Bieltz M, Wukovits B, John RS: Prospective survey of patient-
controlled epidural analgesia with bupivacaine and hydromorphone in 3736
postoperative orthopedic patients. Reg Anesth Pain Med 2010; 35:351-4
11. Hollis S, Campbell F: What is meant by intention to treat analysis?
Survey of published randomised controlled trials. BMJ 1999; 319: 670-4
12. Tsui BC, Rashiq S, Schopflocher D, Murtha A, Broemling S, Pillay J, et
al: Epidural anaesthesia and cancer recurrence rates after radical
prostatectomy. Can J Anaesth 2010; 57: 107-12
13. Ismail H, Ho KM, Narayan K, Kondalsamy-Chennakesavan S: Effect of
neuraxial anaesthesia on tumour progression in cervical cancer patients
treated with brachytherapy: a retrospective cohort study. Br J Anaesth
2010; 105: 145-9
Competing interests: No competing interests
Editor,
I fully concur with the observations of Drs Gottschalk, Schug, Van Aken
and Brodner concerning the 'controlled clinical trial' by Myles et al on
the association between epidural anaesthesia and tumour recurrence. BMJ
2011;342:doi:10.1136/bmj.d1491. This follow-up subgroup analysis of the
MASTER study from 2002, together with an accompanying BMJ editorial and a
BMJ editor's choice purported to provide a definitive answer to this
topic, namely that there is no evidence to support the existing
retrospective data suggesting a benefit in cancer recurrence.
The MASTER study, published in the Lancet in 2002, was NOT a
controlled clinical trial. In particular it was uncontrolled for
oncological outcomes, since the authors did not document adjuvant
chemotherapeutic agents, or control, inter alia, psychological stress,
perioperative physiological stress, the choice of anaesthetic agents or
opioid analgesia, all of which - as they state in this subsequent
manuscript - affect outcomes. Regrettably, too, neither the seniority,
competence and experience of the surgeons, transfusion requirements nor
the epidural regimens were made known.
Perhaps most importantly, the MASTER study did not define what an
effective block for abdominal cancer surgery is, which would be a
prerequisite for the successful interpretation of this therapy on tumour
recurrence at follow-up. They suggest a thoracic epidural is the best
option and imply the 'anti-cancer' effect is assured with a working block
but did not ensure such efficacy before general anaesthesia commenced.
Clearly, no benefit is going to accrue to any individual patient unless
the block is effective from before the skin incision and Myles et al are
completely wrong to suggest '... ..minimum and maximum heart rates and
systolic blood pressures during surgery ... (are) indicators of the
clinical efficacy of intraoperative epidural block' At best these are weak
markers that vary with the type of general anaesthetic agents used and
concomitant medical therapy especially preoperative beta-blockers which
would not have been stopped.
Crucially, Myles et al did not measure the stress response or
immunological response as proof of an 'anti-cancer' effect although they
concede these are extremely important (more than heart rate or blood
pressure) in preventing tumour recurrence. Primary failure as a result of
misplacement of an epidural prior to surgery commencing would result in
failure to obtund these responses resulting in increased general
anaesthetic requirements and opioid usage, both of which Myles et al
rightly state have immunosuppressive effects. The epidural failure rate in
the MASTER study, as defined by their working hypothesis, was a remarkable
49% (indeed 'some patients received a lumbar block') . At worst therefore,
having assumed that heart rate and blood pressure accurately predicted a
working block many of the patients in the study were not only 'unblocked'
but would have received only light general anaesthesia for a major
abdominal procedure which would have maximized the stress response-
leaving patients stressed and not analgesed regardless of the amount of
intraoperative opioid.
Furthermore, the MASTER study kept the patients in the two arms of
the study on an intention-to-treat basis. When an epidural was noted at
any point postoperatively to have failed, the patient then received the
control (opioid) therapy leading to at least 75% of all MASTER study
patients receiving opioid analgesia. Regrettably, they were therefore
comparing 'like with like', namely a general anaesthetic with a general
anaesthetic plus ineffective block, both supplemented by opioid analgesia
and therefore no differences would ever be established for tumour
recurrence, as they have shown.
In summary, the design and clinical conduct of this uncontrolled
MASTER study was unintentionally biased and skewed in favour of showing no
difference on the original outcomes and negates any subsequent (subgroup)
analysis.
Caution should most certainly be urged in the interpretation of all
the existing data on this, potentially, very important subject. Surgical
oncology specialties should disregard both the MASTER study and this
follow-up study and sit down with their anaesthetic colleagues to
investigate the influence of effective central neuraxial blockade on
cancer recurrence after surgery properly in a prospective, randomised and
controlled procedure-specific manner. Crucially, although labour
intensive, an effective working block needs to be established
preoperatively and continued throughout the study period. If there is any
substance to the retrospective data, we may be doing a great disservice to
the patients we treat and the public at large if we do not investigate
this topic seriously.
Competing interests: No competing interests
We read with great interest the article by Myles and colleagues on
the relationship between type of anaesthesia and cancer recurrence in
patients undergoing major abdominal surgery.[1] Annually millions of
people require tumour surgery; therefore it is important to question some
of the results and conclusions. A wealth of basic science data supports
the hypothesis that the surgical stress response increases the likelihood
of cancer dissemination and formation of metastases in patients undergoing
cancer surgery.[2] Anaesthetic management of the cancer patient,
therefore, could potentially influence long-term outcome. However, the
results by Myles et al do not support this hypothesis, as the use of
epidural block in abdominal cancer surgery was not associated with
improved cancer-free survival in their published trial. In our opinion the
study suffers from several problems we will discuss below:
The study population is a secondary analysis of subjects enrolled in
the MASTER trial.[3] The major criticism of the MASTER trial was the high
rate of protocol violations. Only 50% of patients randomized to the
epidural group actually received epidural analgesia throughout the entire
study period; as this secondary analysis is based on intention to treat
principle, this might have relevant implications for the outcome.[1,4]
Additionally, the authors state that their study is likely to be the only
randomized data on this subject for years to come. However, this is not a
randomized prospective study for the outcome of cancer survival; it is a
retrospective follow-up study of a previous RCT for an outcome not
intended at point of randomization. The use of the terminology 'This
randomized trial' in the conclusion of the paper is therefore incorrect.
Certainly, a lot of information about the perioperative anaesthetic
course is given to the reader; unfortunately important oncological data
are missing. For example, a lot of patients in both groups were not graded
either to the Duke or TNM system (Group "epidural" n=230: Dukes
characteristics reported for n=58 patients, TNM characteristics reported
for n=125 patients; Group "no epidural" n=216: Dukes characteristics
reported for n=54 patients, TNM characteristics reported for n=106.) Does
this missing data imply that patients without information provided were
patients potentially with metastatic diseases at time of surgery?
Additionally, there is no information given to the reader about the
quality of oncological resection to obtain R0 results (no evidence of
microscopic cancer in the margins). How many patients got a chemotherapy
or radiotherapy after cancer surgery and how many patients refused this?
No information is given about stringent postoperative follow-up, which has
been shown to help the early identification of potentially radically
treatable oligometastatic disease. Those resections of lung or liver
metastases after colorectal cancer substantially improve 5-year and 10-
year survival rate.[5] In the Result section the reader cannot find any
information about treatment with adjuvant chemotherapeutics that further
improves survival in colon and rectal cancers.[5]
The power analysis is questionable for three reasons:
1.The authors have performed a power analysis on a dichotomous outcome:
percentage of five-year survival. However, they defined cancer-free
survival as the main outcome measure in the abstract and reported and
discussed survival times in the manuscript that were analysed by the log
rank test. This would need a power analysis, in which the alternative
hypothesis is expressed as a hazard ratio. This power-analysis, using a
realistic hazard ratio might result in a significant bigger sample size as
compared to the power analysis for a one third treatment effect in the chi
-square test.
2.The authors assume a five-year survival of approximately 50%. They
report survival rates of 42 % and 44 % respectively. Thus, the study may
lack external validity and the authors cannot be sure that the conclusions
drawn about cause-effect-relationships observed in this study can be
generalized and do apply to patients undergoing abdominal surgery for
cancer.
3. In their power analyses Myles et al state that most of these patients
had primary colorectal cancer, for which five year survival is
approximately 50% and 12 year survival is less than 20%. If epidural block
reduced recurrence-free survival by 25%, then 250 patients per group would
provide 89% power with a two sided alpha of 0.05.[1] Why would epidural
block reduce, not increase survival rate? According to results of basic
science studies the cancer free survival rate or time should be increased
with the use of epidural block. [2] On the other hand, if the author meant
increase then the hypothesis seems too optimistic. For example in the
QUASAR study of 3239 patients with mostly stage II colorectal cancer, who
were randomly assigned to fluorouracil and folinic acid or to observation,
there was a significant improvement in overall survival (risk reduction of
18% and 3.6% overall survival gain).[6] If this hypothesis of Myles et al
would be confirmed, than the use of epidural block is more effective than
chemotherapy.
In summary, in the Introduction the authors present important
arguments in favour of an effect of epidural analgesia on the long-term
prognosis after cancer surgery. These arguments gave reason to carry out
the follow-up of the MASTER-trial, which due to its retrospective nature
presents a variety of shortcomings. The authors have therefore to observe
caution in the evaluation of their study and the discussion of their
findings. It is difficult to qualify the study as a randomized trial and
dangerous to conclude that "use of epidural block in abdominal surgery for
cancer is not associated with improved cancer-free survival." In view of
the good arguments to conduct this study and its many methodological
problems such a conclusion might put cancer patients at harm if the
alternative hypothesis is still true and epidural anaesthesia improves
cancer-free survival. It would have been more appropriate to conclude that
better designed studies are needed to evaluate the use of epidural block
in abdominal cancer surgery. Even though their study does not support the
hypothesis that epidural anaesthesia improves recurrence-free survival, it
has too many flaws to refute this hypothesis.
In our opinion this paper has too many "Questions marks". Therefore,
we still have to wait for the results of the randomized prospective
studies, which are focused primarily on the cancer outcome for patients
undergoing tumour surgery with different types of anaesthesia.
Sincerely,
Antje Gottschalk, Clinical Research Fellow, Department of
Anaesthesiology and Intensive Care Medicine, University Hospital Muenster,
Muenster, Germany
Stephan A Schug, Professor of Anaesthesiology and Chair of
Anaesthesiology, Pharmacology and Anaesthesiology Unit, School of Medicine
and Pharmacology, Director of Pain Medicine, Royal Perth Hospital, Perth,
Australia
Hugo K Van Aken, Professor of Anaesthesiology and Head of the
Department of Anesthesiology and Intensive Care Medicine, Department of
Anaesthesiology and Intensive Care Medicine, University Hospital Muenster,
Muenster, Germany
Gerhard Brodner, Professor of Anaesthesiology and Head of the
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy,
Fachklinik Hornheide, Muenster, Germany
References
1. Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI:
Perioperative epidural analgesia for major abdominal surgery for cancer
and recurrence-free survival: randomised trial. BMJ 2011; 342: d1491
2. Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M: Review
article: the role of the perioperative period in recurrence after cancer
surgery. Anesth Analg 2010; 110: 1636-43
3. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW,
Collins KS: Epidural anaesthesia and analgesia and outcome of major
surgery: a randomised trial. Lancet 2002; 359: 1276-82
4. Van Aken H, Gogarten W, Brussel T, Brodner G: Epidural anaesthesia
and analgesia in mayor surgery. Lancet 2002; 360: 568; author reply 569
5. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B,
Starling N: Colorectal cancer. Lancet 2010; 375: 1030-47
6. Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ:
Adjuvant chemotherapy versus observation in patients with colorectal
cancer: a randomised study. Lancet 2007; 370: 2020-9
Corresponding Author:
Antje Gottschalk, MD
Department of Anaesthesiology and Intensive Care Medicine, University of
Muenster
Albert-Schweitzer-Strasse 33
48149 Muenster, Germany
Email: antjegottschalk@gmx.net
Competing interests: No competing interests
Volatile and intravenous anaesthesia in patients with cancer
A systematic review with meta-analysis of clinical trials involving patients with cancer who were operated on under total intravenous versus volatile anesthesia concluded that intravenous propofol-TIVA may be associated with improved recurrence-free survival and overall survival in those patients having cancer surgery.
Reference
https://link.springer.com/article/10.1007/s12630-019-01330-x
Competing interests: No competing interests