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The influence of steroid hormone receptors on response rate to cytotoxic chemotherapy in 70 patients with metastatic breast cancer was determined in a retrospective study. We have previously reported that 34 of 45 patients with tumors containing low or absent estrogen-receptor values had objective responses to chemotherapy while three of 25 patients with positive estrogen-receptor tumors responded. In the present study, 22 of 34 patients with low or absent progesterone-receptor tumors had an objective response to cytotoxic chemotherapy, while none of eight patients with a positive progesterone-receptor tumor responded (P less than 0.05). Patients having tumors with a negative estrogen receptor and a negative progesterone receptor had a response rate of 88% (21 of 24 patients). There were three patients whose tumors were estrogen-receptor negative but progesterone-receptor positive; none had a response to chemotherapy. Chemotherapy response was not associated with the presence or absence of either androgen or glucocorticoid receptor. We conclude that progesterone-receptor values in addition to estrogen-receptor status may prove to be important correlates of response to cytotoxic chemotherapy in metastatic breast cancer. Androgen- and glucocorticoid-receptor analyses are not helpful in predicting response to chemotherapy.

We carried out a phase I trial with chlorambucil. Thirty patients with advanced cancer were entered in six dose levels: 36, 48, 60, 84, 108, and 144 mg/m2. The drug was given in six divided oral doses every 6 hours and the regimen was repeated every 3 weeks. The median age was 62 years (31-84), median Karnofsky performance status (KPS) 60 (40-90). All patients but one had received prior radiation therapy, chemotherapy, or both. Central nervous system toxicity was dose limiting, occurring in 5 of 6 patients at 144 mg/m2. It was characterized by transient seizures, hallucinations, lethargy, stupor, and coma. Metoclopramide was successful in controlling nausea and vomiting, which was severe if the antiemetic was not used. Leukopenia (3 patients) and thrombocytopenia (2 patients) were mild. One patient with colorectal carcinoma had a minor response, and two patients with non-small cell lung cancer had stable disease. A safe dose for phase II trials is 108 mg/m2 in six 6-hourly oral doses.

Twenty-three patients with recurrent unresectable carcinoma of the cervix or distant metastasis at initial presentation were treated with methyl-CCNU (175 mg/m2) and doxorubicin (45 mg/m2) on day 1 and cis- diamminedichloroplatinum II (90 mg/m2) on day 22 of a 42-day treatment cycle. Twenty-two patients had squamous carcinoma and 1 had adenosquamous carcinoma. There were two complete responses (CR), five partial responses (PR) (greater than 50% tumor reduction, greater than 3-month duration), four patients with stable disease (less than 50% reduction, greater than 3-month duration), and 12 patients who had tumor progression. One CR has been maintained greater than 28 months, and the other greater than 8 months. Total CR and PR was 7 of 23 (30.4%). Three 23 responses occurred among 15 patients (20%) who had cancer primarily confined to the pelvis, while 4 of 8 patients (50%) with distant metastasis responded. During the initial 2 cycles of chemotherapy, 12 patients had myelosuppression, defined as a leukocytes less than 3000/mm3, granulocytes less than 1,000/mm3, or platelets less than 100,000/mm3. There were no treatment-related deaths.

In order to enhance subtle changes not apparent in resting ECGs by conventional criteria, a computerized signal processing technique, biopotential coordinate transformation (BCT), has been developed to increase the physician's perceptibility of CAD in seemingly "normal" resting ECGs. ECGs initially read as normal then can be tested with this process to predict the presence or absence of CAD. A blinded, retrospective study of 93 Caucasian patients with normal ECGs was performed using coronary angiography as the test standard. The BCT process identified the presence or absence of CAD with an 84.3% sensitivity and 81.8% specificity in 62 men. Similarly, a 76.2% sensitivity and 80% specificity was obtained for 31 women. These results suggest that the BCT process may provide the emergency physician with a noninvasive screening test for the detection of CAD in patients with apparently normal resting ECGs. Further studies are necessary for process refinement and verification.

The usefulness of estrogen receptor (ER) analyses was assessed in a variety of clinical situations. The predictive accuracy of the test is substantially increased by quantification. ER analyses accurately predict objective responses to endocrine therapy independently of other clinical prognostic criteria. In addition, ER positivity is associated with a decreased response rate to cytotoxic chemotherapy in patients with metastatic breast cancer. Finally, the presence of ER is positively associated with a prolonged disease-free interval independent of menopausal status, tumor size, and axillary lymph node involvement.

After a hundred years of using hormonal therapy for the treatment of breast cancer, and developments since 1942 in chemotherapy, combining the two modalities seemed a logical next step. However, trials using tamoxifen plus cyclophosphamide, methotrexate, and 5-FU, or dibromodulcitol and doxorubicin with tamoxifen showed no improvement in survival, and considerable toxicity. But it was learned from these trials that breast cancers exhibit cellular heterogeneity with regard to estrogen-receptor status and that hormonal therapy and chemotherapy have different actions and toxicity. Also, cell cycle specific agents are most effective against rapidly dividing cells. Further trials utilizing these concepts are warranted, although routine use of combined chemohormonal therapy is not yet recommended.

A clinical protocol outline of a study randomizing prednimustine v doxorubicin in patients with metastatic breast cancer is presented. The study has just been initiated, and no results are available at the present time. Unique features of this clinical trial are discussed, including the correlation of objective parameters of tumor response with symptomatic improvement as measured by quality of life, performance status, and pain indices as well as alterations in body weight.

An in vitro tissue culture system utilizing human breast cancer cells in long-term culture was employed to examine mechanisms of action of progestational agents such as progesterone and megestrol acetate. Growth experiments were performed under various defined media conditions. Concentrations of both progesterone and megestrol acetate (10(-5) mol/L), which are attainable in patients, led to direct cytotoxicity of hormone-dependent cells and also to a modification of the known estrogen stimulation of growth in these cells.

Bronchospasm can be induced in asthmatics when exercised according to a multistage branching treadmill protocol that allows them to achieve 80 per cent of maximal age-predicted heart rate. This degree of exercise is usually achievable and allows inducible bronchospasm to occur. This present study was undertaken to investigate the effect of terbutaline sulfate aerosol in exercise-induced broncho-spasm. Asthmatics were exercised to 80 per cent of their maximal heart rate, and FEV1.0 and MMEFR were assessed while standing using a Jones Pulmonar II waterless spirometer at 5, 15, and 30 minutes after exercise. After a standard rest period defined by a return to baseline of FEV1.0, MMEFR, and heart rate for 30 minutes, the subjects were administered either 0.50 mg aerosolized terbutaline sulfate or placebo and then exercised again. The pulmonary function parameters were again recorded after this exercise. Preterbutaline and postplacebo exercise resulted in a significant reduction in FEV1.0 and MMEFR, while after treatment with terbutaline not only did bronchospasm not occur but bronchodilation occurred (P less than 0.01). Inhaled terbutaline appeared to normalize the exercise tolerance of the asthmatics and restore physiologic pulmonary airway conductance according to the parameters of FEV1.0 and MMEFR.

Complete remissions in patients with advanced breast cancer using either endocrine therapy or chemotherapy are infrequent. Breast tumors are known to be heterogeneous with respect to estrogen receptor (ER) status, and the low complete remission rate may be secondary to this biochemical heterogeneity. Laboratory experiments using breast cancer cells in long-term tissue culture revealed that tamoxifen is cytotoxic, estrogen stimulates the growth of ER-positive cells and can rescue cells from tamoxifen's effect, and sequential MTX/5-FU is synergistic in rapidly growing breast cancer cells. Based on this, a phase II protocol was designed using tamoxifen, 10 mg p.o. b.i.d. for days 1 to 10. This was followed by Premarin, 0.625 mg p.o. b.i.d., on days 11 to 14. On day 14 the patients were given MTX, 200 mg/m2 i.v., followed in 1 hr by 5-FU, 600 mg/m2 i.v. The patients were rescued with leucovorin, 10 mg/m2 24 hr later. This dose of leucovorin was repeated every 6 hr for six doses. The cycle is repeated every 18 days. Thus far, 35 patients have been entered and 32 are currently evaluable for response. The median age is 57 years. The median Karnofsky performance status was 90. Of the 35 patients, 63% were ER-positive, and 23% had received prior endocrine therapy or chemotherapy; 71% were postmenopausal. One third of the patients had visceral-dominant disease. The overall response rate was 69%; 15 of 32 (47%) attained a complete remission, and 7 of 32 (22%) had a partial remission. Toxicity was minimal. Median nadir white blood cell counts were 5600/cu mm, and median nadir platelet counts were 252,000/cu mm. Nausea and vomiting occurred in 25% of patients, but there was no hair loss, rash, or diarrhea. Mucositis was rare. In summary, this combination hormonal-chemotherapy regimen is highly effective with a high complete remission rate and minimal toxicity.

Ambulatory patients frequently ingest liquids or smoke just before temperature measurement. The change in body temperature measurements over time following ingestion of ice water, hot water, and smoking were investigated. Twenty-two healthy, afebrile study subjects sequentially ingested temperature-controlled water and smoked a cigarette. Simultaneous oral and auditory canal temperatures were measured over 15 minutes following ingestion. Auditory canal temperatures were obtained with an infrared detection probe; we designated this process a tympanic membrane-derived (TMD) temperature. To determine the correlation between rectal and TMD temperatures, 100 patients had simultaneous measurements at both sites. Mean initial temperatures were rectal, 37.1 +/- 0.5 degrees C (mean +/- S.D.); oral, 36.4 +/- 0.4 degrees C; and TMD, 37.4 +/- 0.4 degrees C. Maximal mean oral temperature change was greatest at 1.5 minutes after hot, +0.9 +/- 0.1 degrees C, and cold, -1.2 +/- 0.2 degrees C, water. This change was statistically significant for seven minutes at the 95% confidence level (analysis of variance test with Dunnett's multiple range test for significance). There was no significant change in the TMD temperature with any ingestion. The Pearson correlation coefficient for 107 pairs of rectal and TMD temperatures, r = 0.90 (P less than .001), was excellent. It was concluded that hot and cold liquids significantly influence oral temperature measurement for seven to nine minutes following ingestion. TMD temperature is unaffected by liquid ingestion and may allow accurate measurement of body temperature. Further studies are needed to determine the accuracy of TMD temperature over a wide range of body temperature in diverse clinical settings.

Hormonal therapy is very effective in the treatment of patients with metastatic breast cancer. Response to various therapies leads to improved quality of life and prolonged survival. This clinical trial compared two commonly utilized additive hormonal agents, tamoxifen citrate and megestrol acetate (Megace). Preliminary data indicate equal efficacy and equal toxicity of these two hormones and suggests that both are suitable for first-line hormonal treatment of stage IV breast cancer.

Bronchospasm can be induced in asthmatics when exercised according to a multistage branching treadmill protocol that allows them to achieve 80 per cent of their age-predicted maximal heart rate. This present study was undertaken to investigate the effect of oral terbutaline sulfate in ameliorating exercise-induced bronchospasm. Ten asthmatics were exercised, and FEV1.0 and MMEFR were assessed while standing, using a Jones Pulmonar II waterless spirometer at 5, 15, and 30 minutes after exercise. Three hours before exercise, the subjects received no medication, oral placebo, or 5 mg terbutaline sulfate orally. At all time intervals after exercise, the pulmonary function of the group pretreated with oral terbutaline was superior when compared to the no-medication group (P less than 0.01) and to the placebo-treated group (P less than 0.05). Oral terbutaline appeared to normalize the exercise tolerance of the asthmatics and restore physiologic pulmonary airway conductance by the parameters of FEV1.0 and MMEFR.

Complete remissions in patients with metastatic breast cancer using endocrine therapy or chemotherapy are infrequent. Breast tumors are known to be heterogeneous with respect to estrogen receptor status, and the low complete remission rate may be related to this biochemical heterogeneity. Based on laboratory experiments using human breast cancer cells in tissue culture, a phase II protocol was designed using tamoxifen, premarin, methotrexate, and 5-fluorouracil. Thus far, twenty-nine (29) patients have been entered into this study and twenty-five (25) are currently evaluable for response. Overall response rate was 72%, and 14 of 25 (56%) attained a complete remission. Toxicity was minimal. Median nadir white blood cell count was 5,800 and median nadir platelet count was 252,000. In summary, this combination chemo-hormonal therapy regimen is effective with a more than 50% complete remission rate and minimal toxicity.

It has been suggested that the atopic population has decreased risk of cancer. This investigation examined the cumulative prevalence of atopy in a population with neoplastic disease and compared this with the prevalence of atopy in an age-matched control group and with published estimates of atopy in the general peopulation. Seventy-four patients with neoplastic disease and 86 patients without cancer were evaluated. The subjects were given a standard allergic questionnaire which evaluated them with regard to a history of allergic symptoms, hives, eczema, frequent colds, frequent unexplained rashes, hay fever, and asthma. All were skin tested with a representative group of regionally significant allergens. There was a 15-fold decrease in prevalence of atopy in the cancer population, compared with the control group and compared with published estimates of atopy in the general population.

Aerosolized terbutaline sulfate at a dose of 0.50 mg has been shown to produce significant bronchodilation in patients with reversible airway disease. The purpose of this study was to evaluate the safety and efficacy of 0.50 mg terbutaline aerosol used on a regular dosage schedule over a six-week period. Sixteen ambulant patients with chronic obstructive pulmonary disease with a component of reversible airway disease were evaluated. The patients were tested at two-week intervals during a six-week period. The patients abstained from all bronchodilatory medications for at least 10 hours prior to the time of evaluation. The evaluation consisted of baseline pulmonary function tests, ECG, CBC, urinalysis, and renal and liver function tests. After the terbutaline was administered, a rhythm strip and pulmonary function tests were repeated at 5, 15, 30, 60, 120, and 180 minutes. Throughout the six-week study, there was a statistically significant increase in FEV1.0 and MMEFR (P less than 0.001): deltaFEV1.0 (ml) 740 (63%) 550 (45%) 340 (25%) 320 (25%) deltaMMEFR (liters/min) 42 (74%) 29 (46%) 28 (43%) 36 (42%). No abnormal laboratory results or paradoxical bronchospasm were noted during the study period; however, sympathomimetic side effects were observed. Aerosolized terbutaline sulfate (0.50 mg) when used on a regular schedule over a six-week period is effective in the treatment of reversible airway disease.

The possibility of an association between steroid hormone receptor status and disease-free interval was examined in 292 patients with breast cancer. Estrogen receptor positivity was associated with a prolonged disease-free interval. This association was independent of age, menopausal status, tumor size, or nodal status. There was no association between the presence or absence of progesterone, androgen, or glucocorticoid receptor and disease-free interval.

The distribution and frequency of steroid hormone receptors are described 329 patients with breast cancer. The distribution of each of the steroid hormone receptors is unimodal with a progressive increase in the proportion of patients positive at lower receptor values. Receptor values expressed as fmol/mg cytoplasmic protein are well correlated with values expressed as fmol/mg breast tumor. Estrogen receptor was positive in 53% of the patients; progesterone receptor was positive in 38% of the patients; glucocorticoid receptor was positive in 52% of the patients; and androgen receptor was positive in 31% of the patients. The type of tissue assayed did not affect steroid hormone receptor positivity. For primary tumors, there was no correlation between steroid hormone receptor positivity and location of the tumor in the breast, size of the tumor, or extent of the disease. Each of the steroid hormone receptors was positively associated with each of the other steroid hormone receptors. Estrogen receptor was correlated with menopausal status and axillary nodal status, but these correlations did not exist for the other steroid hormone receptors. Estrogen receptor was not correlated with age after adjustment for menopausal status. The other steroid hormone receptors were not correlated with age.

Paradoxic bronchospasm induced by adrenergic aerosols, especially isoproterenol, is a well-known clinical entity. It normally occurs in patients who abuse the use of isoproterenol, but has also been reported in a small group of other patients. This study attempted to identify patients who exhibit paradoxic bronchospasm after administration of aerosolized isoproterenol. Forty-one stable, ambulant asthmatics, whose FEV 1.0 was less than 70 percent of predicted normal were studied. None of the asthmatics had taken isoproterenol for one year prior to evaluation. Baseline pulmonary function tests (FVC,FEV 1.09 MMEFR), blood pressure and ECG rhythm strips were recorded, and repeated at 15, 30, 60 and 120 min after administration of isoproterenol. Twenty-nine of the asthmatic patients had the expected normal response ( delta FEV 1.09 15 min: + 579; 30 min: + 464; 60 min: + 372; 120 min: + 307 ml: + 44, + 36, + 23 and + 24 percent) (delta MMEFR, 15 min: + 37; 60 min: + 29; 120 min: + 18L/Min: + 75, + 69, + 47 and + 37 percent). Twelve asthmatic patients (29 percent) had paradoxic bronchospasm (delta FEV 1.09 15 min: - 38; 30 min: - 60; 60 min: - 175; 120 min: - 27 ml; -1, -4, - 10 and - 4 percent) (delta MMEFR - 15 min: - .5; 30 min: - 3; 60 min: - 9; 120 min: - 2L/min; + 4, - 3, - 6 and - 5 percent, P less than 0.001).

Prostaglandins, unsaturated fatty acid derivatives with diversified pharmacologic activity, have been implicated in the pathophysiology of many diseases. Prostaglandin E (PGE) levels were measured by radioimmunoassay in the plasma of 41 normocalcemic patients with various stages of malignancies. Delayed hypersensitivity was assessed by a battery of six recall skin test antigens (ST) and by Dinitrochlorobenzene (DNCB) sensitization and challenge. Twenty-five patients with one or more positive skin tests had a mean PGE level of 87+/-8 pg/ml, whereas 16 patients with negative ST had a mean PGE level of 96+/-12 pg/ml. Twenty-one DNCB negative patients had a mean PGE level of 98+/-12 pg/ml and eight totally anergic patients had a mean PGE of 96+/-12 pg/ml. All PGE values were within the normal range and there was no statistical difference between the four groups. (p less than 0.1). We concluded that circulating PGE does not correlate with the non-specific immunosuppression seen in cancer patients.

In an attempt to diminish the severity of the acute and late effects of irradiation to the rectum of dogs, oral prednisone was administered to 10 dogs for 1 week prior to, during, and for 1 month following a 3-week fractionated course of 60Co exposures to the pelvis. A control group of 10 dogs received irradiation alone. The dogs were observed clinically, serial rectal biopsies were done during and following the acute reaction, and the rectum was studied following sacrifice. Observations suggest that prednisone has no beneficial effect on the acute inflammatory reaction, and increases the severity of the late tissue damage.

The purpose of this study was to evaluate the safety and efficacy of a new lowdose terbutaline sulfate aerosol (375 micrograms) over a six-week period. The question of drug tolerance was also evaluated. Twenty-four ambulant patients with chronic obstructive pulmonary disease with a component of reversible airway disease was evaluated. The patients were tested at two-week intervals during a six-week period. The patients abstained from all bronchodilatory medications for at least 10 hours prior to the time of evaluation. The evaluation consisted of baseline FEV1 and MMEFR determinations, ECG, CBC, urinalysis, and renal and liver function tests. After the terbutaline was administered, a rhythm strip and pulmonary function tests were repeated at 5, 15, 30, 60, 120, and 180 minutes. Throughout the six-week study there was a statistically significant increase in FEV1 and MMEFR, (P less than 0.001). No change was noted in the systolic blood pressures; however, heart rate and diastolic blood pressure decreased significantly. No drug tolerance, paradoxical bronchospasm, subjective side effects, no abnormal laboratory results were noted during the study period.

The regulation of progesterone receptor by 17 beta estradiol and tamoxifen in the ZR-75-1 human breast cancer cell line in defined medium is described. ZR-75-1 cells maintained in serum free hormone supplemented medium minus estradiol lack progesterone receptor activity. Readdition of estradiol to these cells leads to a marked stimulation of progesterone receptor activity (0 to greater than 100 fmols of specifically bound progesterone per million cells). Tamoxifen (10(-6)M-10(-8)M) does not stimulate progesterone receptor activity in this cell line. The presence of progesterone receptor activity is not directly related to growth. Withdrawal of insulin in the continued presence of estradiol has no effect on progesterone receptor concentration although net cell growth ceases. Conversely, withdrawal of estradiol in the continued presence of insulin induces a cessation of net cell growth accompanied by a loss of all progesterone receptor activity within 3-5 days.

A Phase II trial of high-dose chlorambucil at 108 mg/m2 was undertaken in non-small cell lung cancer. No complete or partial objective responses were observed, and significant toxicity, including nausea, vomiting, and seizures, was noted. Chlorambucil at this dose and schedule of administration is not recommended for the treatment of non-small cell lung cancer.

Mitoxantrone (Novantrone; dihydroxyanthracenedione) is an anthraquinone previously shown to be active in human breast cancer. It appears to have less toxicity than doxorubicin. Results of this phase II-III randomized cross-over trial to determine the relative efficacy and toxicity of mitoxantrone in comparison to doxorubicin, are presented. Patients with measurable, recurrent breast cancer with limited prior chemotherapy with or without radiotherapy for metastatic disease, and who had not been exposed to prior doxorubicin, were randomized to receive either mitoxantrone or doxorubicin every three weeks with cross-over on progression. Response rates, duration of remission, time to treatment failure, and drug toxicity, including cardiac toxicity evaluated with serial radionuclide angiocardiography, were evaluated. Differences in the response rates for the two groups were not statistically significant. Neither time to treatment failure nor duration of response are significantly different (p greater than 0.05). With respect to toxicity, mitoxantrone treated patients consistently exhibited a lower incidence and less severe drug toxicity as compared to their doxorubicin-treated counterparts. Cardiac toxicity was carefully monitored and thus four patients on doxorubicin have had drug related congestive heart failure, as compared to none on mitoxantrone. In summary, mitoxantrone appears to be as active as doxorubicin in patients with stage IV breast cancer previously treated with chemotherapy; however, mitoxantrone causes significantly less nausea, vomiting, stomatitis and alopecia at doses which induce equal or greater myelosuppression than doxorubicin, and appears to be less cardiotoxic.

Chemotherapy employed in the treatment of metastatic breast cancer effectively palliates the disease. Response rates to combination chemotherapy are high (greater than 50%); response durations, however, are still very short (less than 1 year). Future investigations must focus on the development of alternate maintenance regimens to improve response duration. Other areas for future study include the use of immunotherapy in conjunction with chemotherapy and the combination of chemotherapy and endocrine manipulation.

ZR-75-1, a human breast cancer cell line, has been grown in hormone-supplemented medium without serum. The factors required for optimal growth include 17beta-estradiol, insulin, transferrin, dexamethasone, and L-triiodothyronine. If estradiol, insulin, or L-triiodothyronine is omitted, cells cease division within 7 days, but viability is retained for at least 14 days. Omission of transferrin leads to cell death within 7 days. The cells have been continuously maintained in this environment without morphological alteration or cessation of growth for more than 5 months. Addition of the anti-estrogen, Tamoxifen (10(-6) M), inhibited cells below the growth rate seen when estradiol was omitted from the medium, even when Tamoxifen was added 4 days and two medium changes after the removal of estradiol from the medium, thus suggesting an action of Tamoxifen which may be independent of competition with estradiol. The availability of a human breast cancer cell line that can be propagated in hormone-supplemented medium without serum should aid in the study of the mechanisms by which hormones effect cell growth.

Estrogen receptors and progesterone receptors were measured in tumors from patients with previously untreated endometrial carcinoma before and after a 5-day course of tamoxifen citrate. On initial biopsy, 13 of 25 tumors (52%) were progesterone receptor-positive, whereas 21 of 25 tumors (84%) were progesterone receptor-positive after tamoxifen. Grades 1 and 2 tumors were more likely to demonstrate this increased incidence of measurable progesterone receptors. Considering these results, and the work of others who have shown that progesterone receptor-positive metastatic endometrial cancer is more responsive to progestin therapy than are progesterone receptor-negative tumors, we instituted a phase II clinical trial of tamoxifen plus progestin for patients with recurrent endometrial carcinoma. Thus far, however, the 33% total response rate achieved with the combination therapy has not been superior to standard progestin therapy.

To date, the therapeutic challenge of improving the poor prognosis of malignant melanoma has not been met by adjuvant therapy for disseminated disease. But the tedious determination of ineffective therapy has closed some lines of research and opened others. Disseminated melanoma is a fertile field for application of new drugs and phase II studies. An effective drug for advanced disease is the key to defining adjuvant therapy. In the next years, clinical application of antimelanoma monoclonal antibodies will be feasible to determine efficacy. Viral oncolysate, a new and promising agent, will also be studied in prospective randomized trials. Continuing research to define an effective systemic therapy for malignant melanoma is warranted.

Clinical observations have shown that approximately one third of breast malignancies respond to hormonal manipulation, resulting in palliation of disease and increased survival. The need to increase the benefits of such therapy and minimize morbidity has encouraged a search for a better means of patient selection. Clinical and biologic characteristics have not been sufficiently reliable in differentiating hormone-dependent and hormone-independent tumors. The presence of estrogen receptors is the best indicator of hormone dependency. The role of progesterone receptors is still under investigation, but the response rate in patients with both types of receptors appears to be increased. Therapy for the patient with an estrogen-receptor-positive tumor is a function of her menopausal status. For the premenopausal woman, oophorectomy is the treatment of choice; in the postmenopausal patient, tamoxifen is currently most frequently used. Selection of a specific therapy, however, must be based on consideration of relative efficacy and toxicity. Response rates with antiestrogens, progestational agents, and aromatase inhibitors are similar but toxicities differ. All are preferable to ablative procedures, which are irreversible and require replacement therapy for the duration of life.

Breast cancer is either hormone independent or hormone dependent. Hormone-dependent tumors are responsive to hormonal manipulation about 80% of the time, because their cells contain specific steroid hormone receptors that bind to the hormone. Tumors lacking these receptors demonstrate response rates of less than 10%, and patients with such tumors are not candidates for hormonal therapy. Additive hormonal therapy, which lacks the morbidity and mortality of ablative procedures, is reversible, and does not require life-long replacement therapy, has replaced many of the ablative procedures. A recent, randomized, prospective, controlled clinical trial compared megestrol acetate and tamoxifen in 197 postmenopausal women with metastatic breast cancer. Efficacy, as measured by response rate and duration of remission, was equal in both groups. Moreover, each agent was associated with little toxicity. As women with stages I and II operable breast cancer have recurrences of their tumors after exposure to antiestrogen therapy, it is practical to consider treatment with megestrol acetate, whose mechanism of action of killing tumor cells may be different from that of tamoxifen.

A mathematical model for prediction of response to endocrine therapy of breast cancer has been developed based on a clonal concept of metastatic spread. The model includes an expression of the likelihood of response of an estrogen receptor-positive site and an expression of the concordance of receptor assays when multiple sites are assayed. Both of these are raised to a power function based on the number of sites of metastases to yield a predicted response rate. An excellent fit of the predictions of this mathematical model and response data from a series of patients receiving endocrine therapy was observed. This model provides a worthwhile insight into the biology of response to endocrine therapy. The model may be extended and refined through additional analyses.

Serum magnesium determinations were obtained on 10 dogs and 11 patients undergoing fractionated irradiation to the pelvis and lower abdomen. Five of dogs received oral prednisone during irradiation. There was no significant change in magnesium concentration in either the control dogs or the patients, but there was a significant increase in stool frequency in both the dogs and patients. A significant increase in magnesium concentration was noted in the dogs receiving prednisone. It is concluded that radiation-induced diarrhea is not caused by reduced serum magnesium concentration.