920 135 MATCHED PAIRS: (A) ALL (PROVEN AND HEARSAY) AND (B) CONFIRMED
TABLE I-FAMILY HISTORIES IN
Letters
to
the Editor
HISTORIES
HISTORIES ONLY
TRIALS OF
ADJUVANT CHEMOTHERAPY IN BREAST CANCER
SIR,-Two recent letters (Feb. 10, p. 324) exhort us to put patients with breast cancer into clinical trials of adjuvant chemotherapy. Indeed Dr Edelstyn and Dr MacRae go further : "Whatever our own personal prejudices and doubts, it is only in supporting trials that facts can be substituted for opinion. Non-participation in clinical trials is a decision not to contribute to medical progress and this, surely, is morally, if not professionally indefensible." At Nottingham we have at present no intention of subjecting patients to adjuvant chemotherapy, and we would like to explain why we take this "indefensible" stand. In the first instance all is not based on blind personal prejudice. Two well-known trials have been, or are being, undertaken. The overall results of these trials have so far failed to show a significant prolongation of life of patients with breast cancer. For the defenders of the Bonadonna trial’ we will observe that prolongation of the free interval does not necessarily mean longer survival. Also before the survival figures are considered in these trials it should be borne in mind that the comparison required is of adjuvant therapy against later therapy : the only acceptable controls therefore are those who subsequently received chemotherapy for the treatment of their metastases; those who received no chemotherapy at all in the course of their disease are invalid. To put it another way, the total life dose of chemotherapy should be the same in adjuvant and control groups. Secondly, what about the personal prejudices of the patient? Women--often attractive and in their 40s-are to be asked not only to lose their breast but to follow this by having a good chance of losing their hair. For what? For no guarantee of even a short prolongation of life. What does Dr Edelstyn tell his patients? Turning to Dr Senanayake and Mr Baum we fear that there is further objection to trials of adjuvant therapy: this is the extreme likelihood that such trials will fail to demonstrate an effect even if one is present. The difficulty in using adjuvant therapy is that there are no firm guides as to which tumours are, and which are not, responding. Therefore even if there is response in a subgroup it may be swamped by the fact that the great majority of the patients in the overall test group will behave in exactly the same way as the great majority in the overall control group. If 90 patients out of 100 in both test and control groups behave in exactly the same way, and 10 in both behave differently, then only in a perfect system could there be a significant difference; in clinical work the systems are not perfect and response is not absolute. However if all these 10 constitute an identifiable subgroup that have, for example, endocrine receptors, then clearly they have done a great deal better than the 10 untreated controls which lack receptors. Until tumour biology can be characterised in the individual patient we are unable to compare like-with-like. The sacred cow of randomisation on a temporal basis is not enough. City Hospital, Nottingham NG5
R. W. BLAMEY 1PB
C. W. ELSTON
TABLE II-FAMILY HISTORY AND AGE AT ONSET OF ULCER SYMPTOMS
*Unknown for 29 patients.
study with a matched-pairs design I interviewed 135 peptic-ulcer patients and their families, together with an equal In
a
number of controls and their families. The questionnaire used was the one validated by Doll and Kellock.3 Of the 135 ulcer patients 63 had a family history of peptic ulcer (26 confirmed + 37 unconfirmed) while only 33 (7+26) of the controls had such a history. When family histories (restricted this time to blood relatives) were compared in each of the 135 matched pairs individually 75 pairs were concordant. If family history played no part in the occurrence of duodenal ulcer there would be an even chance that the duodenal ulcer families, confirmed and unconfirmed, would turn up equally in the controls. However, they were much more common in the ulcer patients than in the controls (p
TABLE I-FAMILY HISTORIES IN
Letters
to
the Editor
HISTORIES
HISTORIES ONLY
TRIALS OF
ADJUVANT CHEMOTHERAPY IN BREAST CANCER
SIR,-Two recent letters (Feb. 10, p. 324) exhort us to put patients with breast cancer into clinical trials of adjuvant chemotherapy. Indeed Dr Edelstyn and Dr MacRae go further : "Whatever our own personal prejudices and doubts, it is only in supporting trials that facts can be substituted for opinion. Non-participation in clinical trials is a decision not to contribute to medical progress and this, surely, is morally, if not professionally indefensible." At Nottingham we have at present no intention of subjecting patients to adjuvant chemotherapy, and we would like to explain why we take this "indefensible" stand. In the first instance all is not based on blind personal prejudice. Two well-known trials have been, or are being, undertaken. The overall results of these trials have so far failed to show a significant prolongation of life of patients with breast cancer. For the defenders of the Bonadonna trial’ we will observe that prolongation of the free interval does not necessarily mean longer survival. Also before the survival figures are considered in these trials it should be borne in mind that the comparison required is of adjuvant therapy against later therapy : the only acceptable controls therefore are those who subsequently received chemotherapy for the treatment of their metastases; those who received no chemotherapy at all in the course of their disease are invalid. To put it another way, the total life dose of chemotherapy should be the same in adjuvant and control groups. Secondly, what about the personal prejudices of the patient? Women--often attractive and in their 40s-are to be asked not only to lose their breast but to follow this by having a good chance of losing their hair. For what? For no guarantee of even a short prolongation of life. What does Dr Edelstyn tell his patients? Turning to Dr Senanayake and Mr Baum we fear that there is further objection to trials of adjuvant therapy: this is the extreme likelihood that such trials will fail to demonstrate an effect even if one is present. The difficulty in using adjuvant therapy is that there are no firm guides as to which tumours are, and which are not, responding. Therefore even if there is response in a subgroup it may be swamped by the fact that the great majority of the patients in the overall test group will behave in exactly the same way as the great majority in the overall control group. If 90 patients out of 100 in both test and control groups behave in exactly the same way, and 10 in both behave differently, then only in a perfect system could there be a significant difference; in clinical work the systems are not perfect and response is not absolute. However if all these 10 constitute an identifiable subgroup that have, for example, endocrine receptors, then clearly they have done a great deal better than the 10 untreated controls which lack receptors. Until tumour biology can be characterised in the individual patient we are unable to compare like-with-like. The sacred cow of randomisation on a temporal basis is not enough. City Hospital, Nottingham NG5
R. W. BLAMEY 1PB
C. W. ELSTON
TABLE II-FAMILY HISTORY AND AGE AT ONSET OF ULCER SYMPTOMS
*Unknown for 29 patients.
study with a matched-pairs design I interviewed 135 peptic-ulcer patients and their families, together with an equal In
a
number of controls and their families. The questionnaire used was the one validated by Doll and Kellock.3 Of the 135 ulcer patients 63 had a family history of peptic ulcer (26 confirmed + 37 unconfirmed) while only 33 (7+26) of the controls had such a history. When family histories (restricted this time to blood relatives) were compared in each of the 135 matched pairs individually 75 pairs were concordant. If family history played no part in the occurrence of duodenal ulcer there would be an even chance that the duodenal ulcer families, confirmed and unconfirmed, would turn up equally in the controls. However, they were much more common in the ulcer patients than in the controls (p
