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.
Rapid Response:
Re:Too many "Question marks"
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