Cancer of the breast - still an enigma Cancer of the breast, despite years of investigation and thousands of articles, remains an unsolved clinical problem. It affects 1 woman in 15 and has an estimated annual attack rate of 90000 cases in the United States and Canada. Its cause remains unknown, its treatment is uncertain and its outcome seems to be death in most of the women in whom it develops.1 In this issue of the Journal four papers dealing with facets of the breast cancer problem are concerned with clues to the identification of high-risk groups, improvement in diagnostic accuracy and discovery of etiologic factors that might relate to the development of breast cancer and its outcome. Fabia, Barnard and Hill (page 1135) note changes in the death rate of breast cancer in Quebec during the past 10 years. They reconfirm that the incidence of cancer in older women is greater than that in younger women and postulate that changes in treatment seem unlikely sources of explanation for the changes in death rate that they have noted. Although statistical signifance is reached, the real significance of these data is uncertain. In another paper (page 1127) Devitt reviews the office records of a consultant surgeon. searching for factors of importance in determining the likelihood of a woman with a breast mass having carcinoma. He discovered 133 carcinomas in 1059 presenting patients and again emphasized age as a determinant by showing that the likelihood of malignant disease in the older woman is greater than that in the younger: 80% of his patients over the age of 70 had cancer of the breast, compared with 5% of those under 40. Candidly he acknowledges the inadequacy of the patient's history relative to menstrual status, nulliparity, current hormone use or duration of symptoms in establishing a diagnosis of cancer. The two other papers are by Mahoney and colleagues (page 1129) and by Burns and associates (page 1131). Mahoney and his group, in a breast
cancer clinic at a major Toronto hospital, reported on 126 cases of cancer in 2800 women referred for assessment by thermography, mammography and clinical examination. Their report deals with the usefulness of these three diagnostic modalities. They resorted to a unique staging system by dividing their cases into groups on the basis of the clinical phase and results of examination, as follows: (a) very early (occult) carcinoma, with normal clinical findings but radiographic findings that were suspicious; (b) early disease, when suspicion was aroused by results of the clinical examination but not by the radiographic results; and (c) late disease, when results of both the clinical and radiographic examination gave rise to suspicion. This constitutes a modification of usual anatomic staging systems and reflects the thesis that size of the primary carcinoma is the determinant of "lateness". The "later" tumours will be larger and more likely to be both clinically and radiographically suspicious. Burns and colleagues, who discuss the northern Alberta registry, approach the breast cancer problem by having all women with breast cancer enrolled at the time of diagnosis and by having features recorded such as menopausal status. nulliparity and other variables currently thought to bear on the etiology and epidemiology of breast cancer. A comprehensive registry will ultimately enrol all cases, for patients who are missed initially will be enrolled subsequently as a later stage of the disease makes the tumour obvious. This seems more likely to provide answers to the epidemiologic questions than other methods, but will do so only if important data are collected and recorded. The collection of data at the time of diagnosis is an attempt to relate input (prognostic) information to the final outcome (death or survival). In the past most reports have dealt with single variables of prognostic significance in the hope that some of them might subsequently be modified or ameliorated
so that future women subject to a carcinogenic force would be prevented from having cancer of the breast. With newer computerized statistical techniques (for example, multivariate analysis) it is now possible to identify the influences of several variables simultaneously. It remains to be seen whether this approach can provide useful epidemiologic information about breast cancer that may explain observations like those of Fabia and colleagues or identify characteristics that can be modified. Patient characteristics at the time of diagnosis, such as age, sex, menopausal and menstrual history, fertility and family history are currently being analysed in the hope of identifying highrisk groups, possibly tailoring the treatment to the disease, and identifying one or more features that could lead to successful preventive measures. This approach has been disappointing. The few high-risk factors that have been identified are visible only in large groups and have been of little help in treating the individual patient. It is well known that disseminated breast cancer at the time of diagnosis prognosticates early death, and 5-year survival figures are consistently better in groups of women whose disease is localized at diagnosis than in those with disseminated cancer. This has led to strenuous efforts to find smaller and smaller lesions in the expectation that as 5- and 10-year survival is improved the ultimate mortality associated with breast cancer might diminish. As yet this point has not been confirmed with certainty. The classic treatment of primary breast cancer limited to the breast or axilla is excision of varying amounts of tumour, breast and axilla, and to this has been added radiation therapy, hormone deprivation and, more recently, anticancer drugs. The evidence suggests that patients with either stage I or stage II disease have an equal chance of survival regardless of which
CMA JOURNAL/MAY 21, 1977/VOL. 116 1101
of several techniques is used to ablate the local tumour.2 Outcome is defined in several ways and measured by many techniques. Time and cause of death require a 15to 30-year experience with a comprehensive registry and a reasonably stable population in order to assess the impact of the disease and the possible effect of treatment. Registries such as the northern Alberta registry will ultimately give information about longterm outcome, but much information is already available from other registries. Information garnered at the time of diagnosis of necessity must be e.panded in the hope that it will contain those items that, years later, will prove important. At the time of diagnosis the histologic type and the degree of dissemination are fixed and therapeutic maneuvers are socially ordained, so that the ultimate outcome, lethal or otherwise, may well be determined at diagnosis. Owing to the chronicity of this disease, many studies have relied on outcome measurements of shorter term than time of death; currently the most popular is that of the interval between treatment and the first recurrence or metastasis in women whose primary disease was amenable to local therapy. Evidence suggests that delay in the first appearance of a metastasis is reflected in somewhat longer survival but does not change the cause of death. As experience accumulates, longterm results associated with each or any method of treatment of the local lesion are disappointing.3'4 Unable to produce notable overall cure rates, some authors are led to believe that breast cancer is a systemic disease almost from its inception - a belief that increases interest in the possibilities of chemotherapy, the concepts of which are derived from successes in the treatment of microbiologic diseases. Other authors, believing that the treatment failures are due to late diagnosis and that the disease is incurable because the patients present with metastases, have aggressively advocated earlier and earlier diagnosis, which has led to the current interest in thermography, mammography, xerography and extensive self-examination campaigns by cancer societies. At present no method of acceptable treatment of the local lesion - that is, in breast and axilla - has been proved greatly superior to any other treatment; conversely, no treatment is any less effective than the rest. Differences in survival among various series may be explained by differences in patient selection, difficulties in clinical staging, or changing criteria for diagnosis as much as by therapy. Large-
scale cooperative studies may finally identify the best of the several currently acceptable modes of treatment, but these studies will be successful only if treatment has an effect upon the outcome that is sufficiently great to overwhelm other features of the disease. Disease limited to the breast, the target of the major therapeutic effort and of most reports, is not the major problem. Distant metastases are the ominous factors in the background at all times. Microscopic or macroscopic deposits beyond the bounds of extirpation or irradiation produce the disease that kills. These influence the management of the local lesion when they are known to be present; survival figures suggest that they are frequently present and account for the ultimate outcome. The control of metastases beyond the reach of local modalities of surgery or radiation therapy now belongs to the oncologist, who must be a chemotherapist, endocrinologist and immunologist. The known relation of breast cancer to the patient's hormonal milieu has led to procedures for estrogen deprivation or addition in the hope of modifying metastatic growth. After two large studies, adjuvant prophylactic oophorectomy has been discarded as initial treatment in premenopausal women; it is now used only for treatment of known metastases. Estrogen deprivation or testosterone administration has been empiric in the past but interest has been rekindled with the demonstration of estrogen receptors in breast cancer cells. Mastectomy tissue specimens may now be tested to determine whether breast cancer cells possess estrogen receptor activity and thus assist in planning endocrine therapy at the time of appearance of metastases.5 Women who currently respond to treatment with hormone therapy are unlikely to gain increased benefit from these studies, but those who do not respond may be spared personal clinical trials of hormones or operations that are of no value. The current role of chemotherapy and the use of the newer chemotherapeutic agents have been stimulated by studies in cell kinetics that suggest that the effectiveness of these agents is a first-order type of reaction producing destruction of a fixed proportion of accessible cancer cells. Surgical removal of large tumour masses is thus adjuvant to chemotherapy. As new agents are developed they must be tested in clinical trials that deal with a disease whose chronicity is measured in years, and the effectiveness of any drug therapy must necessarily await several years of trials before significant results occur. Early conclusions are always suspect.
1102 CMA JOURNAL/MAY 21, 1977/VOL. 116
Locasalen® (flumethasone pivalate/salicylic acid)
topical corticosteroid! squamolytic Indications LOCASALEN is intended for the treatment of subacute to hyperchronic inflammatory and/or dysplastic skin diseases, as well as hyperkeratotic conditions in particular. The indications for LOCASALEN thus include chronic constitutional eczema or neurodermatitis; chronic exogenous eczema irrespective of origin. (e.g.: skin disorders due to attrition, occupational eczema); chronic eczema of microbial or mycotic origin; tylotic eczema; hyperkeratosis as encountered in ichthyosis or chronic dyshidrosis; pustulosis of the palms and soles; lichen planus; chronic cutaneous lupus erythematosus; psoriasis.
Contraindications Tuberculosis of the skin, syphilitic skin affections, viral and acute fungal infections of the skin. Systemic fungal infections. This preparation is not for ophthalmic use. LOCASALEN is contraindicated in individuals with a history of hypersensitivity to its components.
Adverse Reactions
The local tolerability of LOCASALEN proved to be very good. cases in which local irritation made it advisable to discontinue the medication accounted for less than 2% of the total number of patients treated. Adverse reactions consist mainly of local reddening of the skin, desquamation, pruntis and smarting. LOCASALEN contains no preservatives, odour correcting agents, emulsifiers, stabilizers or antibiotic supplements which have been recognized as potential sensitizers. Hypersensitivity to salicylic acid can occur; however, the incidence in the population as a whole is approximately 0.2%. Systemic side effects attributable to the transcutaneous absorption of salicylic acid or flumethasone pivalate have not been reported. Absorption of salicylic acid does occur; however, investigations have shown that irrespective of the amount of LOCASALEN employed, and even applied under occlusive dressings, plasma concentrations of salicylic acid did not exceed ordinary therapeutic levels as a result of transcutaneous absorption. Investigations have shown that under extreme conditions-where 40 to 60 grams of ointment were applied daly to 80-90% of the body surtace under occlusive dressings-plasma cortisol and urinary steroids have been observed to decrease below normal levels. This decrease proved transitory and was not accompanied by any clinical symptoms.
Precautions If sensitivity or idiosyncratic reactions occur, LOCASALEN should be discontinued and appropriate measures taken. The safety of the use of topical corticosteroids in pregnant females has.not been established. Therefore they should not be used extensively on pregnant patients in large amounts or for prolonged periods of time. Patients should be advised to inform subsequent physicians of the prior use of corticosteroids. In the presence of an infection, the use of an appropriate antifungal or antibecterial agent should be instituted. If a favourable response does not occur promptly, LOCASALEN should be discontinued until the infection has been adequately controlled.
Warnings
LOCASALEN is not indicated in acute weeping or subacute exudative stages. As transcutaneous absorption of the salicylic acid component may give rise to systemic effects, LOCASALEN should not be applied to extensive areas of the skin in smell children or pregnant women. Likewise corticosteroids are known to be absorbed percutaneously, therefore in patients requiring applications of LOCASALEN to extensive areas or for prolonged periods, adrenal function should be carefully monitored. All confect of the drug with the eyes, mouth, mucous membranes should be avoided.
Dosage and Administration
As a rule LOCASALEN should be applied once or twice daily when dressings are not used and once daily when empioyed under occlusive dressing. It is not usually necessary to cover the treated area. The thickness of the layer should vary depending on the nature and severity of the skin disorder, since in this way, it is possible to regulate moisture retention. In cases in which transitory exudative must be anticipated, LOCASALEN should be applied in a very thin layer, thereby allowing larger quantities of moisture to be released through the film of ointment. LOCASALEN can also exert an occlusive effect but only it applied in a thick layer. it penetrates well into the skin and when rubbed in thoroughly, leaves on the skin a transparent, oily film that can be removed with soap and weter or a skin cleanser. Excess film can be removed relatively well with paper tissue, scarcely leaving any perceptible sheen.
Supplied
Flumethasone Pivalate 0.02% and salicylic acid 3.0% ointmentintubesof 15gm and 50 gin.
Reference: 1. Jenny, 0., Schuppli, R.: Progress in the Treatment of Eczema, Praxix 59: 589, 1970.
CIBA DORVAL, QUEBEC H95 181
C-6035
A recently reported study of L-phenylalanine mustard6 dealt with a diseasefree interval of only 18 months following treatment - probably too short a time for any valid conclusion to be drawn. All such trials require 3 to 8 years to organize, administer, complete and report.7'8 Immunotherapy, either stimulative or suppressive, has barely touched the field of breast cancer although it has been actively studied in the treatment of melanoma and lung cancer. No investigations have demonstrated immune properties in breast cancer that are sufficient to stimulate large-scale studies of this treatment modality. Survival rates for women with breast cancer are not accurately known. It appears that nearly 5000 years after the first recorded mention of breast cancer it is not possible to claim a significant overall cure rate despite the modest accomplishments that can be claimed with early clinical stage I disease, which has a 5-year tumour-free survival of approximately 75%. At present, survival is known to be a function of the clinical stage, the cell type, the age at diagnosis and the treatment, as well as some unknown and undefined characteristic constituting the host-tumour relation. It is almost certain that a better understanding of this hosttumour relation will be the clue that leads to better results. Cure of breast cancer seems unlikely in the near future. And, in the future, methods designed to identify, understand and treat patients with this disease will probably not be defined in terms of our currently accepted staging characteristics - for example, tumour size and type, and menopausal status - but in terms of some as yet undiscovered relation between the patient and her cancer. C. BARBER MUELLER, MD, FRCs[C1 Professor of surgery MeMaster University Hamilton, Ont.
References 1. MUELLER CB, JEFI'RIEs W: Cancer of the breast: its outcome as measured by the rate of dying and causes of death. Ann Surg 182: 334, 1975 2. MANSFIELD M: Early Breast Cancer: Its History and Results of Treatment, Basel, Karger, 1976 3. DUNCAN W, KERR GR: The curability of breast cancer. Br Med J 2: 781, 1976 4. PARK WW, LEES JC: The absolute curability of cancer of the breast. Surg Gynecol Obstet 93: 129, 1951 5. McGunut WY: Current status of estrogen receptors in human breast cancer. Cancer 36 (suppl): 638, 1975 6. FISHER B, CAREONE P, ECONOMOU 5G. et al: 1-phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N Engl I Med 292: 117, 1975 7. FISHER B: Status of adjuvant therapy: results of the national surgical adjuvant breast project studies on oophorectomy, postoperative radiation therapy, and chemotherapy. Other comments concerning clinical trials. Cancer 28: 1654, 1971 8. TORMEY DC: Combined chemotherapy and surgery in breast cancer - review. Cancer 36: 881. 1975
Pollution in the operating room Long before the establishment of universal national health insurance schemes, the right of workers to good health was recognized implicitly in the enactment of legislation regulating safety standards and working conditions, including atmospheric pollution within the working environment. Of recent concern has been pollution of operating rooms. Recent epidemiologic evidence1 suggests that long-term exposure to trace concentrations of waste gases and vapours from anesthetics is detrimental to the health of operating-room personnel and their offspring. Although a cause-and-effect relation has not been established, the data suggest a more than casual connection. The paper by Oulton in this issue of the Journal (page 1148) is timely and deserves to be widely read. It has always been apparent to those working in an operating room that waste anesthetic gases permeate the air. Where no attempt has been made to scavenge waste gases, average concentrations are 300 to 400 parts per million (ppm) and 10 ppm for nitrous oxide and halogenated agents, respectively. Permissible concentrations are unknown at present; however, acceptable values will probably approximate to 30 ppm of nitrous oxide and 0.5 ppm of halogenated agents. These concentrations may be achieved with proper scavenging systems, but future studies may lead to recommendations for lower concentrations. It is known from shortand long-term studies that intellectual function becomes impaired at 500 ppm of nitrous oxide and 10 ppm of halothane.1 The three main sources of gas contamination are faults in anesthetic technique, excess gas "pop-off" and leakage from high- and low-pressure circuits; one must now add malfunctioning scavenging systems. Between 1967 and 1970, preliminary studies in Russia,3 Denmark,4 the United Kingdom5 and the United States6 suggested that spontaneous abortion occurred at an increased rate in women exposed to waste anesthetic gases over a long period. In 1972 a 2-year study was initiated by the American Society of Anesthesiologists under the auspices of the National Institute for Occupational Safety and Health (NIOSH).1 In the NIOSH study, questionnaires were sent to 49 585 exposed operating-room personnel in four professional societies and to 23 911 unexposed individuals in two professional societies who served as a comparison (control) group; one of the
1104 CMA JOURNAL/MAY 21, 1977/VOL. 116
control groups was the membership of the American Academy of Pediatrics. In 1974 detailed analysis of the results of the survey led the investigators "to strongly suggest that working in the operating rooms (and presumably exposure to trace concentrations of anesthetic agents) entails a variety of health hazards for operating-room personnel and their offspring". Briefly, the findings of the NIOSH study were as follows: 1. The risk of spontaneous abortion is increased for women who are exposed to the operating-room environment during the 1st trimester of pregnancy and who have been exposed during the year preceding pregnancy; the risk is estimated to be 1.3 to 2 times that of unexposed personnel. 2. There is evidence of an increased risk of congenital abnormalities among the liveborn babies of exposed women, including the wives of exposed male anesthetists (P = 0.04); the latter was unexpected and "a matter for serious concern". 3. The risk of cancer was increased (approximately 1.3 to 2 times) in exposed female respondents but not in exposed male respondents. 4. Hepatic disease (even excluding hepatitis) was more frequent in exposed male anesthetists than in male pediatricians (P < 0.01) and in exposed female respondents compared with unexposed controls (P = 0.04, < 0.01, and 0.08 for three comparisons). 5. Higher rates of renal disease were found in exposed female groups than in other groups. The investigators cautioned that, because of several factors, "the increased rates for the exposed groups may be due to some undetected bias" and that "there may be an unknown hazard in these locations which is unrelated to anesthetics". In this connection, it is unfortunate that radiologists and radiographers were not also chosen as a control group; portable x-ray equipment is used increasingly in the operating room and one wonders about the precautions taken to shield those who have to remain there. No provision was made in the questionnaire for a history of exposure to x-rays, though it is realized that this might have introduced too many variables. Walts, Forsythe and Moore7 criticized aspects of the study and particularly the decision of the NIOSH investigators to consider P = 0.05 as significant; WaIts and associates would have preferred a significance level of 0.01. The problems of a retrospective study are well known; one must be cautious in interpreting
cancer clinic at a major Toronto hospital, reported on 126 cases of cancer in 2800 women referred for assessment by thermography, mammography and clinical examination. Their report deals with the usefulness of these three diagnostic modalities. They resorted to a unique staging system by dividing their cases into groups on the basis of the clinical phase and results of examination, as follows: (a) very early (occult) carcinoma, with normal clinical findings but radiographic findings that were suspicious; (b) early disease, when suspicion was aroused by results of the clinical examination but not by the radiographic results; and (c) late disease, when results of both the clinical and radiographic examination gave rise to suspicion. This constitutes a modification of usual anatomic staging systems and reflects the thesis that size of the primary carcinoma is the determinant of "lateness". The "later" tumours will be larger and more likely to be both clinically and radiographically suspicious. Burns and colleagues, who discuss the northern Alberta registry, approach the breast cancer problem by having all women with breast cancer enrolled at the time of diagnosis and by having features recorded such as menopausal status. nulliparity and other variables currently thought to bear on the etiology and epidemiology of breast cancer. A comprehensive registry will ultimately enrol all cases, for patients who are missed initially will be enrolled subsequently as a later stage of the disease makes the tumour obvious. This seems more likely to provide answers to the epidemiologic questions than other methods, but will do so only if important data are collected and recorded. The collection of data at the time of diagnosis is an attempt to relate input (prognostic) information to the final outcome (death or survival). In the past most reports have dealt with single variables of prognostic significance in the hope that some of them might subsequently be modified or ameliorated
so that future women subject to a carcinogenic force would be prevented from having cancer of the breast. With newer computerized statistical techniques (for example, multivariate analysis) it is now possible to identify the influences of several variables simultaneously. It remains to be seen whether this approach can provide useful epidemiologic information about breast cancer that may explain observations like those of Fabia and colleagues or identify characteristics that can be modified. Patient characteristics at the time of diagnosis, such as age, sex, menopausal and menstrual history, fertility and family history are currently being analysed in the hope of identifying highrisk groups, possibly tailoring the treatment to the disease, and identifying one or more features that could lead to successful preventive measures. This approach has been disappointing. The few high-risk factors that have been identified are visible only in large groups and have been of little help in treating the individual patient. It is well known that disseminated breast cancer at the time of diagnosis prognosticates early death, and 5-year survival figures are consistently better in groups of women whose disease is localized at diagnosis than in those with disseminated cancer. This has led to strenuous efforts to find smaller and smaller lesions in the expectation that as 5- and 10-year survival is improved the ultimate mortality associated with breast cancer might diminish. As yet this point has not been confirmed with certainty. The classic treatment of primary breast cancer limited to the breast or axilla is excision of varying amounts of tumour, breast and axilla, and to this has been added radiation therapy, hormone deprivation and, more recently, anticancer drugs. The evidence suggests that patients with either stage I or stage II disease have an equal chance of survival regardless of which
CMA JOURNAL/MAY 21, 1977/VOL. 116 1101
of several techniques is used to ablate the local tumour.2 Outcome is defined in several ways and measured by many techniques. Time and cause of death require a 15to 30-year experience with a comprehensive registry and a reasonably stable population in order to assess the impact of the disease and the possible effect of treatment. Registries such as the northern Alberta registry will ultimately give information about longterm outcome, but much information is already available from other registries. Information garnered at the time of diagnosis of necessity must be e.panded in the hope that it will contain those items that, years later, will prove important. At the time of diagnosis the histologic type and the degree of dissemination are fixed and therapeutic maneuvers are socially ordained, so that the ultimate outcome, lethal or otherwise, may well be determined at diagnosis. Owing to the chronicity of this disease, many studies have relied on outcome measurements of shorter term than time of death; currently the most popular is that of the interval between treatment and the first recurrence or metastasis in women whose primary disease was amenable to local therapy. Evidence suggests that delay in the first appearance of a metastasis is reflected in somewhat longer survival but does not change the cause of death. As experience accumulates, longterm results associated with each or any method of treatment of the local lesion are disappointing.3'4 Unable to produce notable overall cure rates, some authors are led to believe that breast cancer is a systemic disease almost from its inception - a belief that increases interest in the possibilities of chemotherapy, the concepts of which are derived from successes in the treatment of microbiologic diseases. Other authors, believing that the treatment failures are due to late diagnosis and that the disease is incurable because the patients present with metastases, have aggressively advocated earlier and earlier diagnosis, which has led to the current interest in thermography, mammography, xerography and extensive self-examination campaigns by cancer societies. At present no method of acceptable treatment of the local lesion - that is, in breast and axilla - has been proved greatly superior to any other treatment; conversely, no treatment is any less effective than the rest. Differences in survival among various series may be explained by differences in patient selection, difficulties in clinical staging, or changing criteria for diagnosis as much as by therapy. Large-
scale cooperative studies may finally identify the best of the several currently acceptable modes of treatment, but these studies will be successful only if treatment has an effect upon the outcome that is sufficiently great to overwhelm other features of the disease. Disease limited to the breast, the target of the major therapeutic effort and of most reports, is not the major problem. Distant metastases are the ominous factors in the background at all times. Microscopic or macroscopic deposits beyond the bounds of extirpation or irradiation produce the disease that kills. These influence the management of the local lesion when they are known to be present; survival figures suggest that they are frequently present and account for the ultimate outcome. The control of metastases beyond the reach of local modalities of surgery or radiation therapy now belongs to the oncologist, who must be a chemotherapist, endocrinologist and immunologist. The known relation of breast cancer to the patient's hormonal milieu has led to procedures for estrogen deprivation or addition in the hope of modifying metastatic growth. After two large studies, adjuvant prophylactic oophorectomy has been discarded as initial treatment in premenopausal women; it is now used only for treatment of known metastases. Estrogen deprivation or testosterone administration has been empiric in the past but interest has been rekindled with the demonstration of estrogen receptors in breast cancer cells. Mastectomy tissue specimens may now be tested to determine whether breast cancer cells possess estrogen receptor activity and thus assist in planning endocrine therapy at the time of appearance of metastases.5 Women who currently respond to treatment with hormone therapy are unlikely to gain increased benefit from these studies, but those who do not respond may be spared personal clinical trials of hormones or operations that are of no value. The current role of chemotherapy and the use of the newer chemotherapeutic agents have been stimulated by studies in cell kinetics that suggest that the effectiveness of these agents is a first-order type of reaction producing destruction of a fixed proportion of accessible cancer cells. Surgical removal of large tumour masses is thus adjuvant to chemotherapy. As new agents are developed they must be tested in clinical trials that deal with a disease whose chronicity is measured in years, and the effectiveness of any drug therapy must necessarily await several years of trials before significant results occur. Early conclusions are always suspect.
1102 CMA JOURNAL/MAY 21, 1977/VOL. 116
Locasalen® (flumethasone pivalate/salicylic acid)
topical corticosteroid! squamolytic Indications LOCASALEN is intended for the treatment of subacute to hyperchronic inflammatory and/or dysplastic skin diseases, as well as hyperkeratotic conditions in particular. The indications for LOCASALEN thus include chronic constitutional eczema or neurodermatitis; chronic exogenous eczema irrespective of origin. (e.g.: skin disorders due to attrition, occupational eczema); chronic eczema of microbial or mycotic origin; tylotic eczema; hyperkeratosis as encountered in ichthyosis or chronic dyshidrosis; pustulosis of the palms and soles; lichen planus; chronic cutaneous lupus erythematosus; psoriasis.
Contraindications Tuberculosis of the skin, syphilitic skin affections, viral and acute fungal infections of the skin. Systemic fungal infections. This preparation is not for ophthalmic use. LOCASALEN is contraindicated in individuals with a history of hypersensitivity to its components.
Adverse Reactions
The local tolerability of LOCASALEN proved to be very good. cases in which local irritation made it advisable to discontinue the medication accounted for less than 2% of the total number of patients treated. Adverse reactions consist mainly of local reddening of the skin, desquamation, pruntis and smarting. LOCASALEN contains no preservatives, odour correcting agents, emulsifiers, stabilizers or antibiotic supplements which have been recognized as potential sensitizers. Hypersensitivity to salicylic acid can occur; however, the incidence in the population as a whole is approximately 0.2%. Systemic side effects attributable to the transcutaneous absorption of salicylic acid or flumethasone pivalate have not been reported. Absorption of salicylic acid does occur; however, investigations have shown that irrespective of the amount of LOCASALEN employed, and even applied under occlusive dressings, plasma concentrations of salicylic acid did not exceed ordinary therapeutic levels as a result of transcutaneous absorption. Investigations have shown that under extreme conditions-where 40 to 60 grams of ointment were applied daly to 80-90% of the body surtace under occlusive dressings-plasma cortisol and urinary steroids have been observed to decrease below normal levels. This decrease proved transitory and was not accompanied by any clinical symptoms.
Precautions If sensitivity or idiosyncratic reactions occur, LOCASALEN should be discontinued and appropriate measures taken. The safety of the use of topical corticosteroids in pregnant females has.not been established. Therefore they should not be used extensively on pregnant patients in large amounts or for prolonged periods of time. Patients should be advised to inform subsequent physicians of the prior use of corticosteroids. In the presence of an infection, the use of an appropriate antifungal or antibecterial agent should be instituted. If a favourable response does not occur promptly, LOCASALEN should be discontinued until the infection has been adequately controlled.
Warnings
LOCASALEN is not indicated in acute weeping or subacute exudative stages. As transcutaneous absorption of the salicylic acid component may give rise to systemic effects, LOCASALEN should not be applied to extensive areas of the skin in smell children or pregnant women. Likewise corticosteroids are known to be absorbed percutaneously, therefore in patients requiring applications of LOCASALEN to extensive areas or for prolonged periods, adrenal function should be carefully monitored. All confect of the drug with the eyes, mouth, mucous membranes should be avoided.
Dosage and Administration
As a rule LOCASALEN should be applied once or twice daily when dressings are not used and once daily when empioyed under occlusive dressing. It is not usually necessary to cover the treated area. The thickness of the layer should vary depending on the nature and severity of the skin disorder, since in this way, it is possible to regulate moisture retention. In cases in which transitory exudative must be anticipated, LOCASALEN should be applied in a very thin layer, thereby allowing larger quantities of moisture to be released through the film of ointment. LOCASALEN can also exert an occlusive effect but only it applied in a thick layer. it penetrates well into the skin and when rubbed in thoroughly, leaves on the skin a transparent, oily film that can be removed with soap and weter or a skin cleanser. Excess film can be removed relatively well with paper tissue, scarcely leaving any perceptible sheen.
Supplied
Flumethasone Pivalate 0.02% and salicylic acid 3.0% ointmentintubesof 15gm and 50 gin.
Reference: 1. Jenny, 0., Schuppli, R.: Progress in the Treatment of Eczema, Praxix 59: 589, 1970.
CIBA DORVAL, QUEBEC H95 181
C-6035
A recently reported study of L-phenylalanine mustard6 dealt with a diseasefree interval of only 18 months following treatment - probably too short a time for any valid conclusion to be drawn. All such trials require 3 to 8 years to organize, administer, complete and report.7'8 Immunotherapy, either stimulative or suppressive, has barely touched the field of breast cancer although it has been actively studied in the treatment of melanoma and lung cancer. No investigations have demonstrated immune properties in breast cancer that are sufficient to stimulate large-scale studies of this treatment modality. Survival rates for women with breast cancer are not accurately known. It appears that nearly 5000 years after the first recorded mention of breast cancer it is not possible to claim a significant overall cure rate despite the modest accomplishments that can be claimed with early clinical stage I disease, which has a 5-year tumour-free survival of approximately 75%. At present, survival is known to be a function of the clinical stage, the cell type, the age at diagnosis and the treatment, as well as some unknown and undefined characteristic constituting the host-tumour relation. It is almost certain that a better understanding of this hosttumour relation will be the clue that leads to better results. Cure of breast cancer seems unlikely in the near future. And, in the future, methods designed to identify, understand and treat patients with this disease will probably not be defined in terms of our currently accepted staging characteristics - for example, tumour size and type, and menopausal status - but in terms of some as yet undiscovered relation between the patient and her cancer. C. BARBER MUELLER, MD, FRCs[C1 Professor of surgery MeMaster University Hamilton, Ont.
References 1. MUELLER CB, JEFI'RIEs W: Cancer of the breast: its outcome as measured by the rate of dying and causes of death. Ann Surg 182: 334, 1975 2. MANSFIELD M: Early Breast Cancer: Its History and Results of Treatment, Basel, Karger, 1976 3. DUNCAN W, KERR GR: The curability of breast cancer. Br Med J 2: 781, 1976 4. PARK WW, LEES JC: The absolute curability of cancer of the breast. Surg Gynecol Obstet 93: 129, 1951 5. McGunut WY: Current status of estrogen receptors in human breast cancer. Cancer 36 (suppl): 638, 1975 6. FISHER B, CAREONE P, ECONOMOU 5G. et al: 1-phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N Engl I Med 292: 117, 1975 7. FISHER B: Status of adjuvant therapy: results of the national surgical adjuvant breast project studies on oophorectomy, postoperative radiation therapy, and chemotherapy. Other comments concerning clinical trials. Cancer 28: 1654, 1971 8. TORMEY DC: Combined chemotherapy and surgery in breast cancer - review. Cancer 36: 881. 1975
Pollution in the operating room Long before the establishment of universal national health insurance schemes, the right of workers to good health was recognized implicitly in the enactment of legislation regulating safety standards and working conditions, including atmospheric pollution within the working environment. Of recent concern has been pollution of operating rooms. Recent epidemiologic evidence1 suggests that long-term exposure to trace concentrations of waste gases and vapours from anesthetics is detrimental to the health of operating-room personnel and their offspring. Although a cause-and-effect relation has not been established, the data suggest a more than casual connection. The paper by Oulton in this issue of the Journal (page 1148) is timely and deserves to be widely read. It has always been apparent to those working in an operating room that waste anesthetic gases permeate the air. Where no attempt has been made to scavenge waste gases, average concentrations are 300 to 400 parts per million (ppm) and 10 ppm for nitrous oxide and halogenated agents, respectively. Permissible concentrations are unknown at present; however, acceptable values will probably approximate to 30 ppm of nitrous oxide and 0.5 ppm of halogenated agents. These concentrations may be achieved with proper scavenging systems, but future studies may lead to recommendations for lower concentrations. It is known from shortand long-term studies that intellectual function becomes impaired at 500 ppm of nitrous oxide and 10 ppm of halothane.1 The three main sources of gas contamination are faults in anesthetic technique, excess gas "pop-off" and leakage from high- and low-pressure circuits; one must now add malfunctioning scavenging systems. Between 1967 and 1970, preliminary studies in Russia,3 Denmark,4 the United Kingdom5 and the United States6 suggested that spontaneous abortion occurred at an increased rate in women exposed to waste anesthetic gases over a long period. In 1972 a 2-year study was initiated by the American Society of Anesthesiologists under the auspices of the National Institute for Occupational Safety and Health (NIOSH).1 In the NIOSH study, questionnaires were sent to 49 585 exposed operating-room personnel in four professional societies and to 23 911 unexposed individuals in two professional societies who served as a comparison (control) group; one of the
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control groups was the membership of the American Academy of Pediatrics. In 1974 detailed analysis of the results of the survey led the investigators "to strongly suggest that working in the operating rooms (and presumably exposure to trace concentrations of anesthetic agents) entails a variety of health hazards for operating-room personnel and their offspring". Briefly, the findings of the NIOSH study were as follows: 1. The risk of spontaneous abortion is increased for women who are exposed to the operating-room environment during the 1st trimester of pregnancy and who have been exposed during the year preceding pregnancy; the risk is estimated to be 1.3 to 2 times that of unexposed personnel. 2. There is evidence of an increased risk of congenital abnormalities among the liveborn babies of exposed women, including the wives of exposed male anesthetists (P = 0.04); the latter was unexpected and "a matter for serious concern". 3. The risk of cancer was increased (approximately 1.3 to 2 times) in exposed female respondents but not in exposed male respondents. 4. Hepatic disease (even excluding hepatitis) was more frequent in exposed male anesthetists than in male pediatricians (P < 0.01) and in exposed female respondents compared with unexposed controls (P = 0.04, < 0.01, and 0.08 for three comparisons). 5. Higher rates of renal disease were found in exposed female groups than in other groups. The investigators cautioned that, because of several factors, "the increased rates for the exposed groups may be due to some undetected bias" and that "there may be an unknown hazard in these locations which is unrelated to anesthetics". In this connection, it is unfortunate that radiologists and radiographers were not also chosen as a control group; portable x-ray equipment is used increasingly in the operating room and one wonders about the precautions taken to shield those who have to remain there. No provision was made in the questionnaire for a history of exposure to x-rays, though it is realized that this might have introduced too many variables. Walts, Forsythe and Moore7 criticized aspects of the study and particularly the decision of the NIOSH investigators to consider P = 0.05 as significant; WaIts and associates would have preferred a significance level of 0.01. The problems of a retrospective study are well known; one must be cautious in interpreting
