Sequential Adriamycin and CMF in Metastatic Breast Cancer.

PURPOSE: To evaluate the clinical activity of a sequential treatment with Adriamycin followed by CMF (cyclophosphamide, methotrexate, fluorouracil) and the relative therapeutic contribution of the two drug regimens given at full conventional doses in metastatic breast cancer. PATIENTS AND METHODS: From August 1990 to February 1993, 44 patients with advanced breast cancer previously untreated with chemotherapy entered the study. Treatment consisted of the intravenous administration of Adriamycin (75 mg/m² on day 1 every three weeks) for four cycles followed by intravenous CMF (cyclophosphamide, 600 mg/m²; methotrexate, 40 mg/m²; fluorouracil 600 mg/m²) on days 1 and 8 every four weeks for four total courses. RESULTS: In 41 evaluable patients, four cycles of full-dose Adriamycin were able to achieve an overall response rate of 75%, including 17% complete remissions. Four cycles of CMF administered after Adriamycin were able to increase tumor response in 64% of evaluable cases. At the end of the sequential treatment program, 78% of 41 patients achieved an objective remission and in 30% of them a clinical complete response was documented. Main side effects, i.e., leukopenia and gastrointestinal disturbances, were moderate and short-lasting. One patient died because of acute myocardial infarction. CONCLUSION: In untreated metastatic breast cancer patients, the sequential administration of Adriamycin and CMF is highly effective at the expense of a moderate toxicity profile that allows high-dose intensity of both drug regimens. CMF treatment after upfront Adriamycin is able to exert a further therapeutic advantage.

Pilot study of primary chemotherapy with doxorubicin plus paclitaxel in women with locally advanced or operable breast cancer.

A pilot study of primary chemotherapy with bolus doxorubicin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours was performed in 38 women with locally advanced and 41 with stage II/III breast cancer. Patients received four cycles of primary chemotherapy followed by surgery and treatment with cyclophosphamide/methotrexate/5-fluorouracil for six cycles. Preliminary data are available on 73 patients. Doxorubicin plus paclitaxel was well tolerated. Primary toxicity consisted of grade 1 or 2 reversible peripheral neuropathy and grade 3 alopecia. After a median follow-up of 13 months, none of the patients have developed cardiac toxicity or any significant alteration of the left ventricular ejection fraction, which was measured before treatment, at each cycle of doxorubicin plus paclitaxel, and every 3 months thereafter. Major clinical response of the breast tumor was observed in 88% of patients. At pathologic examination of the surgical specimen, 40% were pT1, 15% had no macroscopic tumor residue, and 7% had complete disappearance of invasive neoplastic cells. After a median follow-up of 17 months for patients with locally advanced breast cancer, freedom from progression was 67%, disease-free survival was 71%, and overall survival was 74%. The same end points were 100% for patients with stage II/III disease, with a shorter median follow-up of 10 months. In conclusion, doxorubicin plus paclitaxel is safe, feasible, and effective, and can be used as primary or adjuvant chemotherapy to assess its actual therapeutic role in women with early breast cancer.

Prospective evaluation of pulmonary function in cancer patients treated with total body irradiation, high-dose melphalan, and autologous hematopoietic stem cell transplantation.

Pulmonary function tests (standard vital capacity, SVC; total lung capacity, TLC; forced expiratory volume in 1 second-forced vital capacity ratio, FEV1/FVC; carbon monoxide transfer factor, DLCO) were prospectively evaluated in patients (median age 25 years, 13-52 years; median follow-up 20 months, 6-51 months) with Hodgkin's disease (15 patients), non-Hodgkin's lymphoma (9 patients), and inflammatory breast cancer (3 patients) treated with sequential high-dose therapy comprising the following phases over approximately 2 months: a) cyclophosphamide (7 g/m2); b) vincristine (1.4 mg/m2), methotrexate (8 g/m2), and cisplatinum (120 mg/m2) or etoposide (2 g/m2); c) total body irradiation (TBI; 12.5 gy, 5 fractions over 48 hours), intravenous melphalan (120-180 mg/m2), and transplantation of autologous peripheral blood and/or bone marrow hematopoietic stem cells. Within 2 months after transplantation, 12 patients also received 25 Gy radiotherapy boost to mediastinum and clavicular regions. In vivo dosimetry evaluations of fractionated TBI treatments showed that mean radiation dose absorbed by lungs was 12.18 Gy (97.4% of TBI dose). Despite such a high radiation dose, we observed only transient and subclinical decrease of SVC, TLC, and DLCO. The decrease of SVC, TLC, and DLCO was more evident and prolonged in patients receiving radiotherapy boost. All parameters progressively recovered to normal values within 2 years after transplantation. In contrast, FEV1/FVC remained within normal limits in all patients, thus demonstrating the absence of obstructive ventilatory changes. In addition, no interstitial pneumonia was observed.

Total body irradiation and high-dose melphalan with bone marrow transplantation at Istituto Nazionale Tumori, Milan, Italy.

The technique of total body irradiation (TBI) developed at Istituto Nazionale Tumori, Milan, Italy, is described. This technique consists of i) administration of 12.5 Gy and 14.85 Gy TBI for autologous and allogeneic bone marrow transplantation respectively; ii) in all cases in vivo dosimetry of absorbed TBI dose; and iii) radiation doses to lungs higher than previously described. As of June 1988, seventeen patients with Hodgkin's disease and four with lymphoblastic lymphoma received TBI and 120-180 mg/m2 melphalan. Respiratory function was prospectively evaluated demonstrating moderate and transient reduction of pulmonary function.

Sensitivity and specificity of electrocardiographic ST-T changes as markers of neoplastic myocardial infiltration. Echocardiographic correlation.

We evaluated the correlations between electrocardiographic ST-T changes (negative T waves, ST segment elevation) and echocardiographic diagnosis of neoplastic infiltration of the myocardium in 95 patients with neoplastic masses in contact with the heart. We compared echocardiographic results to computed tomography, nuclear magnetic resonance, surgery or autopsy data in 49 patients: the concordance was 86 percent. Significant ST-T changes were present in 77.7 percent of the patients with myocardial infiltration at echocardiography. The "false negatives" (normal ECG, nonspecific changes) were mainly related to infiltration limited to the right side of the heart; in some of these cases, the appearance of right bundle branch block was observed. The "false positives" (ST-T changes without echocardiographic signs of infiltration) were observed in the older patients and in those with pericardial effusion or other heart diseases. The ST segment elevation was a more specific sign of myocardial infiltration as compared to negative T waves (86 vs 47 percent). A progression or the disappearance of electrocardiographic and echocardiographic abnormalities was observed during follow-up in 24 cases. Serial electrocardiograms are useful for screening in clinical settings in neoplastic patients; the appearance of ST-T changes or of conduction disturbances should suggest the need for two-dimensional echocardiography in order to define the diagnosis.

Intermediate doses of cyclophosphamide alone or following adriamycin in advanced breast cancer. A pilot study.

Cyclophosphamide (CTX) is an active drug in breast cancer and presents a well-established dose-response relationship. To explore further this relationship, the present pilot study investigated the therapeutic efficacy of cyclophosphamide at intermediate dose in two groups of untreated patients with advanced breast cancer. Nine women received the drug alone at 3-4 g/m2 i.v. every 2 weeks for a total of three doses. The same dose schedule was also given to 11 women following the administration of four cycles of Adriamycin, at 75 mg/m2 i.v. every 3 weeks. We documented one partial remission in untreated women and four partial responses in Adriamycin-treated patients. The major toxicity was represented by leukopenia and neutropenia. Myelosuppression was relevant but of short duration, and the use of G-CSF appeared useful in controlling this side effect. In spite of the high dose intensity of the present cyclophosphamide dose schedule (9 g/m2 in 4 weeks), i.e., almost three times superior to that conventionally employed, present results do not suggest its superiority over the current chemotherapeutic regimens utilized in advanced disease.

Mesothelioma of the pericardium: report of a case.

One case of cardiac tamponade from malignant mesothelioma of the pericardium is reported. The tumor was diagnosed by cytology of the fluid drained by pericardial centesis. Necroscopy and histology confirmed the diagnosis.

Surgery for malignant mesenchymal tumors of the breast: a series of 31 cases.

Thirty-one cases of malignant mesenchymal tumors of the breast were analyzed with the purpose of identifying the most suitable type of surgery to be recommended. All the cases considered underwent pathologic review. Even young women were affected, and menopausal status did not seem to influence the development of mesenchymal tumors. Mammography was of little use for diagnosis. All cases underwent surgery and 26 had an adequate follow-up. In 8 cases a relapse occurred with a mean free interval of 6 months. Total mastectomy was sufficient to provide local control, whereas axillary dissection turned out to be not worthwhile. Postoperative radiotherapy did not improve distant results. Relapses mainly consisted of lung metastases. Fifteen patients were alive, free of disease, at a time ranging from 9 months to 13 years after surgery.

Malignant pheochromocytomas: report of 4 cases.

Four cases of pheochromocytomas are reported: 3 cases of malignant pheochromocytomas of the adrenal glands and 1 case of pheochromocytoma, diagnosed on the basis of clinical and biologic signs, whose site and malignant character were not demonstrated. A rare association of pheochromocytoma and stenosis of the renal artery, recorded for one of the cases, is discussed.

Cardiac function evaluation in AMSA-treated patients.

Cardiac function was monitored by means of ECG and systolic time intervals in 13 patients submitted to treatment with 4'-(9-acridinylamino) methanesulfon-m-aniside (AMSA) without the classical reconstitution vehicle N1N-dimethylacetamide. ECG changes were represented by flattening of T waves (100%), sporadic atrial extrasystoles (23%), and sporadic or coupled ventricular premature beats (7.6%). These alterations were transient and not dose related. The systolic time interval ratio, recorded at the end of infusion and 2 h after drug administration, did not change significantly from pretreatment values. Systolic time intervals recorded in 6 patients after the mean cumulative dose of 550 mg/m2, and in 3 patients after the mean cumulative dose of 1000 mg/m2, did not change from mean basal values. Present data failed to confirm the occurrence of a significantly cardiotoxic activity of AMSA.

Relationship between pulmonary function tests and morphologic changes in the lung in bleomycin-treated patients.

The transfer factor of the lung for carbon monoxide (TLCO) and the respiratory response to moderate exercise were determined in 16 patients with pulmonary metastasis pretreated with bleomycin who underwent pulmonary partial resection. The results of pulmonary function tests were related to histologic findings. No significant correlation was found between pulmonary morphologic changes and the TLCO: this questions the usefulness of TLCO as a predictive method for detecting subclinical bleomycin pulmonary toxicity. No significant correlation was found between morphologic findings and cumulative dose of bleomycin: this confirms the limit of a dose limitation strategy. In contrast, evaluation of pulmonary response to exercise seemed to improve the sensitivity of monitoring such patients for clinical evidence of latent pulmonary toxicity; however, it seems that critical morphologic changes must occur before pulmonary performance begins to deteriorate.

Prognostic factors in operable breast cancer.

A series of 743 consecutive cases of operable breast cancer, admitted and treated at the Istituto Nazionale Tumori of Milan from 1969 to 1970, was analyzed by a multivariate statistical method to evaluate a) the variables of the host and the primary tumor associated with the frequency of nodal metastases, b) the variables that significantly affect survival, and c) the identification of homogeneous risk groups. As regards the frequency of regional node metastases, they were more frequently observed in young than in old patients with large tumors (P values 10(-5) and 3 X 10(-5), respectively). Tumors that originated in the axillary tail, upper, outer and central quadrants were significantly associated with a higher rate of node metastases (P = 0.002). Each of these variables maintained its significant value when adjusted by the other two. Survival was affected at a statistically significant level by the age of the patients (P = 2 X 10(-4) ), the pathologic diameter of the primary tumor (P less than 10(-6) ), and the number of metastatic regional nodes (P less than 10(-6) ). The number of involved nodes appears to be the most relevant factor in the assessment of prognosis of patients with positive nodes, Age of the patients, size of the primary tumor, and number of involved nodes maintain their own statistical significance when each is adjusted by the remaining two. The site of origin of the primary tumor, even if associated with the frequency of regional node metastases, did not affect survival. Three groups with a significantly different risk of death were identified in patients with negative lymph nodes and three groups in patients with positive nodes. It is concluded that age, size of the primary, and number of involved lymph nodes are important pieces of information that clinicians should have at hand following radical surgery, not only to make a prognosis, but also to identify groups of patients with high risk of death on which the role of adjuvant treatment should be evaluated.

Phase II study with amsacrines (m-AMSA and m-AMSA lactate) in refractory lymphomas.

A total of 70 patients with malignant lymphomas refractory to one or more chemotherapeutic regimens were treated with iv amsacrines (m-AMSA and m-AMSA lactate). Of 58 evaluable patients, 12 had Hodgkin's disease and 46 had non-Hodgkin's lymphoma. Twenty-nine of the evaluable patients received m-AMSA and 29 received m-AMSA lactate. The amsacrines were recycled every 3 weeks. The doses of m-AMSA were 90-120, 70, and 25-30 mg/m2/day for 3 days, respectively. All patients treated with m-AMSA lactate received a single dose of 225 mg/m2. In Hodgkin's disease, the response rate was 58.3% (one complete response among 12 patients), and in non-Hodgkin's lymphoma, the response rate was 30.4% (six complete responses among 46 patients). The median duration of response was 3 and 5 months, respectively. The response rate was unfavorably affected by the presence of extra-nodal disease and a Karnofsky performance status less than 80. There was no important difference in the incidence and duration of response between m-AMSA and m-AMSA lactate. After vomiting, myelosuppression was the most frequent observed toxic effect. One patient showed an unexpected fatal bone marrow aplasia following the first course of 90 mg/m2. This study indicates that m-AMSA and m-AMSA lactate are active and moderately toxic in previously treated malignant lymphomas. Thus, amsacrines could be effectively incorporated into salvage polydrug regimens.

Heart involvement in lymphomas. The value of magnetic resonance imaging and two-dimensional echocardiography at disease presentation.

BACKGROUND AND METHODS: Thirty-six patients with mediastinal lymphoma were studied with chest magnetic resonance imaging (MRI) and two-dimensional echocardiography at presentation to define the extent of the disease in the paracardiac area. RESULTS: Involvement of cardiac structures was present in 23 of 36 patients (64%). Pericardial contiguity was detected in 23 of 23 patients (100%) by MRI and in 18 of 23 patients (78%) by echocardiography. Pericardial effusion, present in 17 patients (74%), and pericardial infiltration, present in 7 patients (30%), were detected by both techniques in 71% and 86%, respectively. Myocardial infiltration was identified in two of two patients (100%) by MRI and in one of two patients (50%) by two-dimensional echocardiography. Extrapericardial disease was identified in 100% of patients by MRI but only in 30% of patients by echocardiography. CONCLUSIONS: Extracardiac and intracardiac involvement is a frequent event in mediastinal lymphomas and should be carefully evaluated with different imaging modalities, mainly MRI, for correct diagnosis and proper management.

Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients.

The risk of internal mammary chain metastases according to some parameters and its prognostic relevance was evaluated on the basis of the experience collected at the National Cancer Institute of Milan where, from January 1965 to December 1980, 1085 patients were submitted to Halsted mastectomy plus internal mammary chain dissection. A multivariate analysis was carried out, resorting to a multiple linear regression with logistic transformation of the dependent variable. The selection of prognostic factors has been performed with a step-down approach. The frequency of metastases to internal mammary chain nodes was evaluated according to four criteria: age, site and size of primary tumor, and presence of axillary metastases. Data of this series indicate that the frequency of internal mammary node metastases is significantly associated with the age of the patients (younger patients have a higher risk) (p = 0.006) with the size of primary tumor (p = 0.006) with the presence of axillary node metastases (p = 10(-9). Patients with both axillary and internal mammary positive nodes have a very poor prognosis (10-year survival 37.3%) while patients with either axillary metastases only or internal mammary metastases only have an intermediate less grave prognosis (59.6% and 62.4%, respectively). As regards the risk of internal mammary nodes involvement, it appears that knowing the age, the size, and the axillary nodes status, it is possible to calculate with good approximation the probability of their invasion.

Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes.

The results of the analysis carried out on data on 1119 patients with operable breast cancer treated at the National Cancer Institute of Milan from 1965 to 1979 with enlarged mastectomy are reported. Metastases to internal mammary chain were found to be significantly associated with the maximum diameter of primary (16.1% for tumors less than 2 cm and 24.5% for larger tumors, p = 0.007), the age of the patients (27.6% in patients younger than 40 years, 19.7% in patients between 41-50 years, and 15.6% in patients older than 50 years, p = 0.01). The site of origin of the cancer had no impact on internal mammary node metastases. Patients with positive axillary nodes showed metastases to internal mammary nodes in 29.1% of the cases, while 9.1% of patients with axillary negative nodes had positive retrosternal nodes. Survival was significantly affected by the presence of positive internal mammary nodes: the percentage of 10-year survival varied from 80.4% in patients with axillary and internal mammary negative nodes to 30.0% in patients with both nodal basins involved. Intermediate survival rates (54.6% and 53.0%) were found when one or the other of the nodal stations (axillary and internal mammary) was separately affected. Maximum diameter of the primary significantly affected the survival of each group identified by the status of both axillary and internal mammary nodes. In conclusion, the information on the presence or absence of internal mammary node metastases would be of great importance in formulating the prognosis of breast cancer patients. To obtain this information, a biopsy at the first intercostal space may be reasonable in selected patients (age, maximum diameter, and axillary node involvement being the basis for selection) as long as noninvasive methods of diagnosis are available.