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We enjoyed reading Baum & Houghton's lucid and
provocative interpretation of the current results of randomised controlled
trials in the management of early breast cancer. The editorial decision
to sandwich this discourse between two other accounts of the specific
application of the science of randomised controlled trials suggests that
one should not take the whole content of this paper too seriously.
Therefore, rather than deal with specific issues, such as errors of
omission (e.g. the positive randomised controlled trial demonstrating a
survival advantage for high-dose chemotherapy in early breast cancer1), or
referencing (reference 27 does not confirm a substantial benefit for
adjuvant tamoxifen in ER-negative tumours), we will address this article
from the philosophical standpoint taken by its authors.
The thesis that the failure of radical surgery parallels the supposed
failure of adjuvant high-dose chemotherapy is flawed by the juxtaposition
of two dissimilar hypotheses. Radical surgery was predicated on a linear
approach to the spread of cancer, not on a linear approach to the "dose"
of therapy. High-dose chemotherapy on the other hand assumes, if not a
linear dose-response effect, at the very least a continuously increasing
relationship. The key therefore is whether or not there is a linear
relationship between the treatment and its outcome, and parenthetically,
whether there is an additive effect for different therapies.
The data
quoted in the paper clearly argue for the latter : the addition of
systemic therapy and/or radiotherapy to surgery has been shown in many
randomised trials to improve patient survival. What remains unclear
however is the optimum quality of each therapy : how much of the axillary
nodal mass does a surgeon need to remove, how and when should
radiotherapy should be given to patients, for how long should adjuvant
tamoxifen be given. For chemotherapy there remain several unanswered
questions :
how much, when, what schedule, what drugs and possibly what dose of drug
gives the best outcome. It is worth bearing in mind that even the
considerable beneficial effects of adjuvant chemotherapy (30% reduction in
relapse as quoted by Baum & Haughton) were not evident in the earlier
overview reports of randomised trials. For node-negative patients it
required 10 years of follow-up before the benefits emerged, and for
anthracyclines, it is only with 15 years follow-up data that an advantage
over non-anthracycline regimens is becoming apparent.
What is needed in the treatment of early breast cancer is a refinement of
the quality and targeting of our current treatments, and, almost
certainly, the discovery of yet another therapeutic strategy, such as anti
-angiogenic, pro-immunosurveillance etc. In the process of determing the
optimum use of each modality, randomised controlled trials are necessary.
Many questions remain unanswered, and we should all ensure that
appropriate rigour and time are given to answering them before shifting
the paradigms we use to treat breast cancer. A solid hypothesis is a safer
launch-pad than the shifting sands of unsupported speculation, especially
when this arises from the gold-standard research tool of clinical
medicine, a randomised, controlled, clinical trial.
DA Cameron
Senior Lecturer in Medical Oncology
RCF Leonard
Consultant Medical Oncologist
Dr. R.H. MacDougall
Consultant Clinical
Oncologist
Department of Oncology,
Western General Hospital
Crewe Road South,
EDINBURGH EH4 2XU
Reference List
1. Bezwoda WR. Randomised Controlled Trial of High Dose Chemotherapy
(HD-CNVp) Versus Standard Dose (CAF) Chemotherapy for High Risk,
Surgically Treated, Primary Breast Cancer. Proc ASCO 1999;18:2a (abstract
4)
Management of breast cancer
Dear Sir,
We enjoyed reading Baum & Houghton's lucid and
provocative interpretation of the current results of randomised controlled
trials in the management of early breast cancer. The editorial decision
to sandwich this discourse between two other accounts of the specific
application of the science of randomised controlled trials suggests that
one should not take the whole content of this paper too seriously.
Therefore, rather than deal with specific issues, such as errors of
omission (e.g. the positive randomised controlled trial demonstrating a
survival advantage for high-dose chemotherapy in early breast cancer1), or
referencing (reference 27 does not confirm a substantial benefit for
adjuvant tamoxifen in ER-negative tumours), we will address this article
from the philosophical standpoint taken by its authors.
The thesis that the failure of radical surgery parallels the supposed
failure of adjuvant high-dose chemotherapy is flawed by the juxtaposition
of two dissimilar hypotheses. Radical surgery was predicated on a linear
approach to the spread of cancer, not on a linear approach to the "dose"
of therapy. High-dose chemotherapy on the other hand assumes, if not a
linear dose-response effect, at the very least a continuously increasing
relationship. The key therefore is whether or not there is a linear
relationship between the treatment and its outcome, and parenthetically,
whether there is an additive effect for different therapies.
The data
quoted in the paper clearly argue for the latter : the addition of
systemic therapy and/or radiotherapy to surgery has been shown in many
randomised trials to improve patient survival. What remains unclear
however is the optimum quality of each therapy : how much of the axillary
nodal mass does a surgeon need to remove, how and when should
radiotherapy should be given to patients, for how long should adjuvant
tamoxifen be given. For chemotherapy there remain several unanswered
questions :
how much, when, what schedule, what drugs and possibly what dose of drug
gives the best outcome. It is worth bearing in mind that even the
considerable beneficial effects of adjuvant chemotherapy (30% reduction in
relapse as quoted by Baum & Haughton) were not evident in the earlier
overview reports of randomised trials. For node-negative patients it
required 10 years of follow-up before the benefits emerged, and for
anthracyclines, it is only with 15 years follow-up data that an advantage
over non-anthracycline regimens is becoming apparent.
What is needed in the treatment of early breast cancer is a refinement of
the quality and targeting of our current treatments, and, almost
certainly, the discovery of yet another therapeutic strategy, such as anti
-angiogenic, pro-immunosurveillance etc. In the process of determing the
optimum use of each modality, randomised controlled trials are necessary.
Many questions remain unanswered, and we should all ensure that
appropriate rigour and time are given to answering them before shifting
the paradigms we use to treat breast cancer. A solid hypothesis is a safer
launch-pad than the shifting sands of unsupported speculation, especially
when this arises from the gold-standard research tool of clinical
medicine, a randomised, controlled, clinical trial.
DA Cameron
Senior Lecturer in Medical Oncology
RCF Leonard
Consultant Medical Oncologist
Dr. R.H. MacDougall
Consultant Clinical
Oncologist
Department of Oncology,
Western General Hospital
Crewe Road South,
EDINBURGH EH4 2XU
Reference List
1. Bezwoda WR. Randomised Controlled Trial of High Dose Chemotherapy
(HD-CNVp) Versus Standard Dose (CAF) Chemotherapy for High Risk,
Surgically Treated, Primary Breast Cancer. Proc ASCO 1999;18:2a (abstract
4)
Competing interests: No competing interests