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7. If a separate program for laboratory or other investigations is indicated : (a) Investigator is selected. (b) Available basic information is given to investigator.

(c) Experiment as designed should be mutually agreeable to the investigator and the committee (and in selected instances to the proponent.)

(d) Financial arrangements for the study are made. C. Formulation of study plan

1. Proponent and committee agree on criteria and study plan.

2. Investigators are selected, are given available basic information (as in III D) and are invited to make suggestions.

3. Plan of study, including criteria, must receive the mutual agreement of investigators, the proponent, and the committee.

4. Financial and other arrangements for effectuation of plan are made. 5. Records of supplies of agents, etc. are kept in committee office.

6. Reports from investigators are sent to committee office. D. Evaluation of reports

1. Reports are reviewed and data compiled.

2. Records of the study are evaluated by the committee. E. Formulation of report or opinion

1. Opinion, if it is deemed that data provide sufficient evidence.

2. Report, if an impasse has been reached and further progress of the inquiry, appears improbable.

3. Plans for further action, if data are considered deficient and additional investigation is desired.

4. The report or opinion will be submitted to the legal counsel of the National Academy of Sciences for approval. If major changes are advised, it will be recirculated to the committee. All changes should receive the approval of the chairmen of the committee and of the division as well as legal counsel.

VI. TRANSMISSION OF REPORTS AND OPINIONS

A. To the sponsors

After full approval has been given, the opinion or report will be presented to the sponsors. B. Notification of proponent

The proponent will be informed by the committee office when a report or opinion has been presented to the sponsors. C. Responsibility for utilization of report or opinion

1. The sponsors (preferably the sponsor who made the request or has been most interested in the study) will assume the responsibility for presenting the report or opinion to the proponent.

2. The sponsors will assume the responsibility for securing further legal advice whenever necessary and will decide questions involving utilization and publication of the report or opinion.

TENTATIVE CRITERIA FOR CANCER DIAGNOSIS AND THERAPY

Committee on cancer diagnosis and therapy, division of medical sciences,

National Research Council, Washington, D. C.

1. CRITERIA FOR DIAGNOSIS

A. Microscopic diagnosis

Microscopic diagnosis of a lesion is essential for the diagnosis of cancer. This microscopic material, including the slide on which the diagnosis was based, should be available for examination. A board of review, composed of competent pathologists, should be set up to study the microscopic slides of any particular case. B. Presumptive criteria

X-ray studies, Papanicolaou smears, gross appearance of lesions, etc., are regarded as presumptive criteria. These are acceptable for the diagnosis of certain lesions which are consistent with the spread of a previously biopsied

tumor.. Presumptive criteria are not acceptable when used alone in cases where a single cure for cancer is claimed, but may be permitted as a portion (up to 10 or 25 percent) of a series of cases. For a number of cases, autopsies will provide additional or confirmatory data. C. Extent of the lesion

The diagnosis of a cancer should include not only the diagnosis of the disease, but information regarding the extent of the disease. Furthermore, once the type of diagnosis is established, the extent of the lesion or the severity of the process may be estimated by different criteria depending on the specific type of

Staging of disease, such as the League of Nations stages for cancer of the cervix, should be employed whenever possible. D. Ancillary studies

Ancillary studies may provide additional information. Thus, the bonemarrow picture in acute leukemia is of considerable diagnostic importance in indicating the extent and spread of the disease, whereas the acid phosphatase in prostatic cancer is useful in indicating the presence and activity of the disease but is of no value in determining the extent of the disease or prognosis.

cancer.

II. CRITERIA FOR RESPONSE TO THERAPY

A. Criteria for measuring individual response to therapy ! 1. Subjective improvement.

2. Objective improvement.

3. Performance status—PS. (This criterion is not unanimously considered to be an essential one, since some members of the committee feel it might be included in subjective improvement.)

4. Duration of improvement.

5. Consistency of response to a specific form of treatment in a given clinical situation.

6. Cure, a complete absence of disease, is the most satisfactory and acceptable criterion. B. Quantitative response :: Anything less than complete freedom from disease is a quantitative improvement, and for this group details of objective and subjective response are important. Improvement in an isolated or individual case, without reference to any series of patients treated, is misleading and meaningless for the purpose of evaluating a method of therapy. Cancer is so variable in its course and spontaneous improvement has been noted before, so that any form of treatment might be able to present remarkable isolated instances of improvement. The value of an indiridual case is provocative in that it may lead an investigator to duplicate this result in similar types of patients. C. Qualitative response

The important criteria of qualitative response to therapy are also dependent on the treatment of a number of patients. D. Criteria for measuring group response to therapy

1. Percentage of apparent cure rate, if it can be shown that there is no clinical, laboratory, necropsy, or other evidence of disease,

2. Five-year survival rate, or any other arbitrary number of years which may be considered most appropriate for the particular type of disease.

3. The criteria of improvement in individual signs and symptoms and the consistency and duration of this improvement.

The measurement of these effects will vary almost entirely with the site and the type of cancer treated. A chart has been prepared which lists the major types of cancer and some of the objective and subjective manifestations of these diseases which may be suitable for clinical study in the evaluation of a therapeutic response.

III. CRITERIA ON TYPES OF TUMORS TO BE CONSIDERED Certain tumors are of particular value in the therapeutic evaluation of a treatment because of specific effects on the body and the precise objective criteria which may indicate improvement. Such conditions are noted in chart I. Ex

1 If possible, these rates should be given on an absolute as well as a relative basis.

ternal or easily accessible tumors are not necessarily the most satisfactory for clinical study, since regression and changes in their histological appearance often furnish unreliable criteria. However, serial biopsies are easier to obtain and do provide some evidence. In general, each type of tumor is a separate entity and requires different criteria ; therefore, the tumors to be studied and the criteria to be employed will vary according to the purpose of the study and the agent under investigation.

IV. CRITERIA IN RELATION TO OTHER FORMS OF THERAPY

A. Combination therapy

Studies involving a primarily curative procedure in combination with a questionably effective agent are usually unsatisfactory since long-term statistical studies on large numbers of patients are required to prove that the added procedure appreciably increases the cure rate. Similarly, combination therapy involving two variable and slightly effective agents is also extremely difficult to carry out. This does not imply that combination therapy studies are of no value, since very useful results may stem from such investigations; however, the pitfalls and dangers of premature conclusions must be kept in mind, unless remarkable synergistic effects are obtained. B. Relation to previous therapy

Since many patients with cancer have had previous therapy, it is necessary that the patient's condition be carefully evaluated. The time interval before initiation of another form of treatment will vary—for instance, after X-ray an interval month, or every 6 months, would be desirable. O. Relation to other factors

In essence, therefore, it is extremely difficult to prescribe a procedure for evaluating a proposed method of therapy. This depends on the nature of the proposed treatment, the type of effects that may be expected from its use and the type and natural course of the tumor treated. Similar variable factors apply to the evaluation of combined forms of therapy. The experience, clinical judgment, integrity and objectivity of the clinical investigator are far more important than the following of set, prescribed procedures which can never be precisely applicable to a given patient for a given type of study.

V. CONTROL DATA

A. Natural course of the disease

There already exists a large body of knowledge on the natural course of cancer, and the results obtained with inadequate forms of therapy, and this information will serve as a control series for the evaluation of most new agents. This is based on the fact that most forms of chemotherapy do not cure or produce prolonged remissions in cancer and any agent which will consistently alter the course of the disease would immediately be a conspicious improvement over the control data, B. Alternate case control

In evaluating curative forms of therapy or in comparing the activity of one chemotherapeutic agent with another, it would be obviously desirable to have alternate control cases. In view of the marked variations in the natural course of cancer, however, we require a large series to draw any important conclusions unless a really outstanding difference exists between the two forms of therapy. C. Time of onset

In determining the survival of a patient, it is suggested that the time when the definitive diagnosis is made be taken as the time of onset of the disease. D. Reporting of results

In reporting the results of any experimental series, it is essential that all the patients presenting themselves for treatment be reported. This is necessary because one can obtain remarkable results by eliminating the patients who do not survive longer than a certain period after the onset of therapy or by selecting patients who appear to be favorable cases.

You have before you after 2 years of deliberations, because this is a new idea in many ways, a statement of policy which has evolved as a result of the deliberations of the committee over the period since

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its inception in February 1951. This statement of policy is before you and I think that it is self-explanatory.

Briefly the committee is interested in any type of proposal which may show merit for the control of the disease, whether it be control on a permanent basis or whether it is temporary control.

You have heard from the various sources around the table that the sex hormones might significantly alter the course of an established cancer of breast origin or protastic origin. These agents are made in our own bodies. These are some of the agents which are being directed against cancer, and this, to us, is exceedingly exciting and points up to the fact that it has offered us a tool for the study of cancer. Also, we have the other techniques and mechanisms which involve the hormones of the adrenal, such as cortisone. These compounds have led us into a whole new area of research.

With that idea in mind this committee has been approaching these various proposals from the standpoint of effectiveness of the procedure. Are the proposals sound and legitimate on the basis of the evidence presented! Do we need more evidence to accept a proposal or should we dismiss it and pay no attention to it?

I can say for the committee, since I am speaking for them, that this committee has been one of the hardest working committees I know. Our heart and soul have been in it. They recognized full well that scientific merits are only part of the situation as to the sponsoring agency. We recognize our moral and social responsibility to this Nation and other nations.

I feel that what I have to say now is a summary of what we have done and are trying to do today.

I have before me a summary of what we have done and we can make it available to you if you so desire. This information is in much more detail.

The way we approach a problem is this: Proposals may be divided into two groups; one group comes through the usual channel of scientific publications such as the journals mentioned by Dr. Wermer today and such journals as sponsored by the American Cancer Society, the National Cancer Institute, and many other organizations. Full information on these is usually published and they will be evaluated by investigation. In other words, there is a desire to go ahead with this work. This is what I allude to when I talk about the hormone situation. There are just a few of us working in this and it was not until this was recognized and that it could be done, that other investigators begged to come into the study.

There are other proposals, however, which are not given to scientific journals and which may be advocated by either laymen or physicians. The information which is available is sometimes incomplete. There are many factors involved in the proposals. These proposals may have merit and they may not have merit. We do not know at the time they are made and it is our concept that we will evaluate as best we can for the sponsoring agency the possibilities of any proposal. During this last year from September 15, 1952, to September 15, 1953, the committee files have accepted information on 200 different forms of therapy proposed as classified above: One, scientific investigators and publications and other proposals which' I just stated. Out of these, 75 came from scientific investigators and publications and 125 from other proposals.

39087-53-pt. 14--22

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