Dutzu Rosner

Chemotherapy induces regression of brain metastases in breast carcinoma

This study improves treatment options and ultimately survival by using systemic chemotherapy in brain metastases from breast carcinoma, since most of these patients have disseminated disease and a dismal prognosis when treated by conventional brain irradiation alone. One hundred consecutive patients with symptomatic brain metastases documented by radionuclide and/or computerized tomography scan were treated with systemic chemotherapy. Fifty of 100 patients demonstrated an objective response of brain metastases which was similar for extracranial metastases. There were 10 complete responders (CR), 40 partial responders (PR), 9 stable, and 41 nonresponders. Median duration of remission was 10+ months for CR and 7 months for PR (range, 2–72 months). Primary chemotherapy of brain metastases yielded responses in 27 pf 52 patients (52%) treated with Cytoxan (cyclophosphamide) (C), 5‐fluorouracil (F) and prednisone (P); 19 of 35 (54%) receiving CFP‐methotrexate (M) and vincristine (V); 3 of 7 (43%) treated with MVP, and 1 of 6 (17%) receiving Cytoxan plus Adriamycin (doxorubicin) (CA). Thirteen of 35 patients (37%) who subsequently had relapse of brain metastases were retreated successfully with secondary chemotherapy. The median survival for CR and PR was 39.5 months and 10.5 months, respectively, in contrast with nonresponder patients who had a median survival of 1.5 months. Thirty‐one percent of all treated patients survived more than 12 months. These findings suggest that the chemotherapeutic agents used penetrate the blood‐brain barrier inducing regression of brain metastases. This approach offers a significant benefit by simultaneously controlling extracranial disease, improving the response and prolonging survival.

Predicting recurrence in axillary-node negative breast cancer patients.

SummaryThis study attempted to identify the risk groups in axillary node negative breast cancer patients using validated first-generation prognostic clinical and pathologic factors. An updated 10-year follow-up in 407 such patients treated by surgery alone at Roswell Park between 1976–1987 showed a 10-year recurrence rate (RR) of 19% (95% confidence interval ±5%). Predictors of outcome were, in order of strength: (1) Tumor size (p= 0.0006); RR at 10 years was 2% ± 4 for tumors ≤ 0.5cm, 6% ± 7 for tumors 0.6-1.0cm, 16% ± 9 for 1.1–2cm, 29% ± 12 for 2.1–5cm, and 40% ± 31 over 5cm; (2) Histologic differentiation (p = 0.017); poorly differentiated/anaplastic (P/A) tumors had a greater RR (24% ± 8) than well or moderately differentiated (W/M) tumors (13% ± 8); (3) Age (p = 0.046); patients < 35 showed a RR of 28% ± 20, pts 35–50, 22% ± 10, and pts > 50, 17% ± 7 (p = 0.046). Cox Model analysis showed tumor size (4 groups) significant at < 0.0001, histologic differentiation (2 groups) significant at < 0.0005 after allowing for size, and age (±50) significant at <0.05 after allowing for size and differentiation.Combining these variables into subgroups enables selecting groups at various risks of recurrence. Groups with low risk are: (1) patients with tumor≤1cm, W/M (0% RR), (2) patients with ductal carcinomain situ with microinvasion (0% RR), and (3) patients with tumors ≤1cm, P/A (8% RR). In a suggestive finding in this last group, those over age 50 achieved a RR of 3% ± 6, while those age 50 or less had RR 14% ± 15. With the exception of this last group, all should be considered highly curable using loco-regional therapy alone, and might be spared the risks and costs of routine systemic adjuvant therapy. Groups with high risk are: (1) patients with tumors > 2cm (RR 32% ± 12), and (2) patients with tumors 1.1–2cm, P/A (RR 21% ± 14). These should receive adjuvant therapy. Groups with intermediate risk are patients with tumor 1.1-2cm, W/M (RR 12% ± 12). In a suggestive finding, those in this group over age 50 had a RR of 11% ± 12, while those up to 50 had a RR of 17% ± 30. These patients should be considered to be prime candidates for clinical trials.Adding second generation factors such as DNA ploidy or S-phase fraction to first generation factors should provide additional information on which to base therapy decisions, particularly in the gray area of intermediate risk. Our study indicates that node-negative breast cancer patients represent a heterogeneous population in terms of risk and prognosis, and that an individualized approach to adjuvant therapy should be taken.

Should all patients with node‐negative breast cancer receive adjuvant therapy? Identifying additional subsets of low‐risk patients who are highly curable by surgery alone

This study, which used combined first‐generation prognostic factors (tumor size, histologic differentiation, and age) on 408 patients with axillary node‐negative (ANN) breast cancer treated by surgery alone without systemic adjuvant therapy between 1976 and 1987 at the Roswell Park Cancer Institute, discerned four subsets of low‐risk patients with a 7‐year relapse rate of 6% or better. The first subset consisted of 48 patients (12% of the population) with tumors 1 cm or less in diameter that were well or moderately differentiated. These patients had a disease‐free rate (DFR) of 100% (95% confidence interval [CI], 94% to 100%). The second subset consisted of 35 patients (9% of the population) with tumors less than or equal to 1 cm that were poorly differentiated or anaplastic. These patients older than 50 years of age had a DFR of 97% (95% CI, 91% to 100%). The third subset consisted of 36 patients (9% of the population) with tumors 1.1 to 2 cm that were well or moderately differentiated. These patients were older than 50 years of age and had a DFR of 94% (95% CI, 85% to 100%). The fourth subset consisted of 36 patients with ductal carcinoma in situ with microscopic invasion. These patients had a DFR of 100% (95% CI, 87% to 100%). Twenty‐two of these patients, not in the other subsets mentioned, comprised 5% of the total population. These patients at low risk of recurrence, who comprise one third of the entire node‐negative population, are highly curable by local therapy alone and may be spared the risks and costs of routine adjuvant systemic therapy (AST). Patients with tumors larger than 2 cm (152 patients; 37% of the population) are at high risk of recurrence (26% with a DFR of 74% [95% CI, 64% to 84%]) and should routinely receive systemic adjuvant therapy. Patients with tumors up to 2 cm who are not in the low‐risk groups fall in a gray area (recurrence, 15% to 21%; DFR, 79% to 85%). For these groups, combining second‐generation prognostic factors such as DNA ploidy, S‐phase fraction, or cathepsin D should give the physician additional information to aid in making decisions regarding adjuvant therapy.

Oral contraceptive use has no adverse effect on the prognosis of breast cancer

This study evaluates the possible effect of OC use on the prognosis of established breast cancer. Three hundred forty‐seven patients with primary invasive breast carcinoma age 50 and under treated from 1971 to 1981 are included in this study. There were 112 OC Users (U) and 235 Non‐Users (NU). Separate retrospective analysis were done for a group of 154 patients (59 U and 95 NU) under age 35 (Group A) and for 193 patients (53 U and 140 NU) age 35 to 50 (Group B), in order to pay particular attention to relationship of duration, recency and latency of OC usage. Both subsets of U and NU presented similar clinical characteristics regarding menstrual, reproductive, family history, histology, receptor status. Users presented with a similar extent of disease as Non‐Users. No significant differences were found between U and NU in disease‐free interval (Gr A p = .41; Gr B p = .81), metastatic period (Gr A p = .66; Gr B p = .41) or survival (Gr A p = .54; Gr B p = .79), either alone or when adjusted for extent of node involvement. Users of less than two years (78 patients) had a similar survival (Gr A = .54; Gr B p = .36) as those of longer duration (33 patients). Recent OC users within a year of diagnosis had a similar survival as other users who stopped the pills more than one year (Gr A p = .86; Gr B p = .14). No significant differences were noticed in survival between the patients who began the use 10 years or more before diagnosis from those beginning more recently (Gr A p = .82; Gr B p = .69). Our data suggests no adverse effect of OC on the outcome of breast cancer, regardless the duration of use, latency or recency period.

Management of brain metastases from breast cancer by combination chemotherapy

SummarySince most patients with brain metastases from breast cancer have disseminated disease elsewhere and a dismal prognosis when treated by whole brain irradiation alone, we investigated the use of systemic chemotherapy in 66 such patients. Fifty-two percent (34 of 66 patients) demonstrated an objective response to this therapy which was similar to the results obtained in patients treated for extracranial metastases. Eighteen patients who subsequently had recurrence of brain metastases were successfully retreated with secondary chemotherapy. The median duration of remission in 34 responders was ten months. The median survival, from the time of chemotherapy for brain metastases, was 13.1 months in 34 responders (range 5–74+) vs. 3.0 months in 32 non-responders (P < 0.001).These findings suggest that systemic chemotherapy is effective in the treatment of patients with brain metastases from breast cancer by inducing remission and prolonging survival.

Preliminary observations on tumor regressions induced by local administration of a lymphoid cell culture supernatant fraction in patients with cutaneous metastatic lesions

Abstract A fraction with lymphokine properties was isolated from supernatant medium of the continuous cultured human lymphoblast cell line, 1788. Culture medium containing 2% human serum was used for cell growth in order to minimize antigenicity of isolated supernatant fractions. The culture medium was passed through an Amicon XM-100 membrane, concentrated over a PM-10 membrane, lyophilized and reconstituted to a final concentration of approximately 40:1. Studies in vivo showed that the active fraction contained skin reactive factor which, when injected intradermally into normal skin, produced skin lesions in humans resembling delayed-type hypersensitivity reactions but peaking between 10 and 12 hr. This same preparation, when injected intralesionally into cutaneous tumors, induced an inflammatory reaction followed by tumor regression. Only the fraction confined between membranes of pore size 10,000–100,000 daltons was active in promoting tumor regression. Patients with skin lesions from metastatic carcinoma of the breast and other malignancies were studied, and 16 out of 30 treated lesions were judged to have undergone either complete or greater than 50% regression. Of these, 9 were biopsied before and after lymphokine injection and 6 out of 9 were negative for tumor cells.

Node-negative minimal invasive breast cancer patients are not candidates for routine systemic adjuvant therapy

Ninety‐one patients with invasive breast carcinoma with a diameter of 1 cm or less and histologically negative axillary nodes were treated between 1976 and 1986 with radical surgery alone (67), or with conservative surgery (24). Cases were analyzed in relation to tumor size, steroid receptors, histologic and nuclear grade, age, and type of therapy, none of which showed a significant relationship to relapse or survival. There were 22% well‐differentiated, 20% moderately differentiated, and 56% poorly differentiated or anaplastic tumors. Estimated disease‐free survival (DFS) for this group was 91% at 7 years, and overall survival 96% for the same period. There were five relapses (all among poorly differentiated tumors) and three deaths unrelated to breast cancer. With the three deaths censored, 100% of the well‐differentiated and moderately differentiated tumors were disease‐free at 7 years versus 91% for poorly differentiated and anaplastic tumors (P = 0.076). These data suggest that node‐negative patients with minimal invasive breast cancer are highly curable by primary surgical therapy alone, and the authors believe that these patients are not appropriate candidates for adjuvant therapy until such time as subgroups at high risk of recurrence can be identified.

Combination chemotherapy for metastatic breast cancer: comparison of multiple drug therapy with 5-fluorouracil, cytoxan and prednisone with adriamycin or adrenalectomy.

A prospective randomized clinical study to compare 3 treatment modalities, consisting of single‐agent chemotherapy with adriamycin, adrenalectomy, and combination chemotherapy with cytoxan, 5‐FU and prednisone (CFP), was carried out in 94 postmenopausal women with metastatic breast cancer. All of these patients had not received previous hormonal or cytotoxic chemotherapy, and all had measurable disease for response evaluation. Patients were randomized to one of three therapeutic arms: 1) adrenalectomy, CFP, adriamycin, in sequence, or 2) CFP, adriamycin, adrenalectomy, in sequence, or 3) adriamycin, adrenalectomy, CFP, in sequence. Objective response to initial therapy was seen in 9 of 26 adrenalectomy patients (35%), 12 of 32 adriamycin‐treated patients (38%), and 13 of 30 CFP‐treated patients (43%). Duration of remission was significantly better in CFP‐treated patients with a median duration of 21.3 months, as compared to adrenalectomy‐ or adriamycin‐treated patients, with median durations of 9.2 and 7.6 months, respectively. The evaluation of the overall palliative achievement of the three fixed arms, based on response to at least one modality was 13 of 26 in the adrenalectomy sequence (50%), 13 of 30 in the CFP sequence (43%), and 18 of 32 in the adriamycin sequence (56%). There was no response to secondary or tertiary therapies among patients receiving CFP as the initial treatment. The data show that combination therapy with cytotoxic and hormonal agents is superior to single‐agent therapy of adrenalectomy. However, the results also disclose that there is no therapeutic advantage in using CFP as an initial therapy in women with advanced breast cancer.

A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer

Two intensive chemotherapy regimens CFPMV (Cytoxan [cyclophosphamide], 5‐fluorouracil, prednisone, methotrexate, vincristine) and CA (Cytoxan, Adriamycin [doxorubicin]) were tested against a moderate regimen, CFP, in a prospective three‐arm, randomized study with crossover when relapse or failure occurred, in order to assess whether the response, duration of remission, and survival can be altered by using more intensive regimens as first‐line or as rescue therapy. All three regimens were equally effective as initial chemotherapy: CFP 26/46 (57%); CFPMV 31/48 (65%) and CA 26/47 (55%) (P = 0.61) with the least toxicity for the CFP regimen. Median duration of remission were 9.5, 11, and 9 months, respectively. Complete responses were almost identical in all three regimens: 4/46 (9%); 6/48 (12%) and 5/47 (11%) (P = 0.94). CFPMV was an effective regimen as second‐line therapy: 11/33 (33%) or third‐line therapy: 7/21 (33%). The CA regimen was equally effective as second‐line therapy: 8/25 (32%), suggesting that intensive regimens provide an effective rescue therapy, as well in previous responders as in nonresponders. Initial intensive regimens have not substantially altered long‐term survival in the whole group of treated patients, Arm II (CFPMV→CA→CFP) 17.6 months; Arm III (CA→CFP→CFPMV) 12.3 months when compared with initial moderate regimens Arm I (CFP→CFPMV→CA) 16.6 months (P = 0.24). The same lack of difference in survival was noticed in responder patients in each arm: Arm II 19.0 months; Arm III 16.0 months versus Arm I 22.0 months (P = 0.13). Our data suggest that a moderate regimen is as effective as more intense regimens for induction therapy in metastatic breast cancer, with less toxicity, preserving the opportunity for an effective rescue therapy with intensive regimens in second or third‐line chemotherapy. Cancer 59:874‐883, 1987.

Differential response to chemotherapy in metastatic breast cancer in relation to estrogen receptor level. Results of a prospective randomized study

The predictive value of estrogen receptor (ER) level for response to chemotherapy was studied in 182 patients with metastatic breast cancer in a prospective study. Patients were stratified according to ER status and dominant site of disease and randomized to one of three regimens: cyclophosphamide, 5‐Fluorouracil, and prednisone (CFP) versus CFP, methotrexate, and vincristine (CFPMV) versus doxorubicin and cyclophosphamide (AC). There was no significant differences in all response categories (P = 0.21), duration of remission (P = 0.07), and survival (P = 0.17) among the three regimens. When ER status was taken as a predictor for response to chemotherapy, there was no significant difference in overall response (P = 0.61) between ER+ (62/108, 57%) and ER‐patients (31/49, 63%). However, there was a significant trend toward a higher degree of response in ER‐patients (more complete response [CR] nine of 49, 18%, and fewer failures six of 49, 12%) than in ER+ (less CR seven of 108, 7%, and more failures 37/108, 34%) (P = 0.006). Patients with higher measured levels of ER showed worse response (Kendalls tau C, P = 0.026). This trend for ER– patients to have better response than ER+ patients was generally consistent, regardless of the predominant site of metastases or chemotherapy regimen (P = 0.04 for CFP; P = 0.08 for CFPMV; and P = 0.20 for AC). The advantage of a better response for ER– patients was nullified by an earlier relapse which was reflected in longer duration of remission, time to treatment failure, and survival in favor of ER+ patients (12.3 months versus 7.3 months remission duration, 18.7 months versus 13.6 months survival in partial responders). These data suggest that ER– patients respond to a higher extent to chemotherapy but relapse sooner than ER+ patients, suggesting a more rapid growth for ER– tumors. In patients with ER– tumors and poorer prognosis on conventional chemotherapy, new trials of intensive consolidation after response should be considered.