Biomedical subjects
G N Hortobagyi
Publications and source records attributed to G N Hortobagyi.
Feasibility of breast-conservation surgery after induction chemotherapy for locally advanced breast carcinoma.
To determine whether preoperative chemotherapy sufficiently downstages disease in patients with locally advanced breast cancer to allow breast-conservation surgery, the clinical, mammographic, and histologic responses were analyzed after three cycles of preoperative vincristine, doxorubicin, cyclophosphamide, and prednisone that were administered to 143 patients with 1988 American Joint Committee on Cancer Stage IIB (17%), IIIA (36%), or IIIB (41%) disease or positive supraclavicular lymph nodes (6%) who had a complete (16%) or partial (84%) clinical response and underwent total mastectomy and axillary node dissection. Thirty-three (23%) were potential breast-conservation candidates based on criteria of complete resolution of skin edema, residual tumor size less than 5 cm, and absence of known tumor multicentricity or extensive intramammary lymphatic invasion. Of these 33, the initial tumor size decreased from a median of 5 cm to less than 1 cm, with 42% having no residual tumor in the mastectomy specimen and 45% having negative nodes. No tumor was found in any other quadrant of the breast, and no patient had a recurrence in the chest wall. After a median follow-up of 34 months, only three patients had distant metastases; two of these died of disease.
Clinical course of patients with breast cancer with ten or more positive nodes who were treated with doxorubicin-containing adjuvant therapy.
Between 1974 and 1986, 283 patients with ten or more positive nodes were treated in four prospective trials using doxorubicin-containing adjuvant chemotherapy. At a median follow-up of 92 months, 182 patients had had a recurrence, and 158 died. An estimated 41% and 37% were disease-free at 5 and 7 years, respectively. Patients with ten positive nodes had a significantly better disease-free survival than those with more than ten such nodes (P = 0.04). The disease-free survival rate and overall survival rate were not influenced by the estrogen receptor status of the tumor, patient age, or disease stage. Long-term data on a large number of patients treated at this institute showed the natural history of this subgroup of patients. Approximately 30% of patient survived disease-free at 10 years after treatment with the systemic therapies used in these protocols. Newer approaches are needed to alter the prognosis of this subgroup of patients further.
A randomized trial of two dosage schedules of mitomycin C in advanced breast carcinoma.
For mitomycin C (MMC), an effective agent in the treatment of metastatic breast cancer, the optimal dosing strategy in responding patients must be defined because of the dose-limiting, long-term hematologic toxic effects. Sixty-seven patients received treatment for metastatic breast cancer (MMC 20 mg/m2, intravenously) and then were selected randomly to receive either "standard doses" (SD) (20 mg/m2, intravenously) or "low doses" (LD) (5 mg/m2, intravenously) of MMC every 6 weeks. The primary objective was to show that the LD regimen would result in fewer toxic effects and at least equal disease control. Response rates in the two arms were similar: there were no complete responses and five partial responses (15%) in the SD group and two complete responses and six partial responses (24%) in the LD group (P = 0.332). In the SD and LD groups, median times to progression (11 versus 12 weeks, respectively), response duration (10 versus 6 1/2 weeks, respectively), and survival (26 versus 26 weeks, respectively) were similar. The hematologic toxicity was significantly less in the LD group. Nine patients in the LD group were treated with SD at disease progression, and one complete response was observed. It is concluded that, in this group of patients, administration of MMC in LD, compared with SD, resulted in fewer hematologic toxic effects and similar disease control.
Complications associated with indwelling catheters.
Between 1983 and 1985, 170 consecutive patients received doxorubicin-containing adjuvant chemotherapy through central venous catheters, and four via a long indwelling catheter in the antecubital fossa. The objective of this retrospective study is to determine the acute and chronic complications associated with indwelling catheters. Ninety-four (56%) patients did not experience any complications. The incidence of acute complications was 2%, which included three pneumothorax. Twenty-nine (17%) patients experienced chronic complications. Of those, 20 (12%) developed infectious complications, and 9 (19%) developed thrombus. In addition, 12 (7%) developed multiple complications, and 32 (19%) patients had other local complications at the catheter site, which included allergic reactions and catheter breakage. Each of these complications was resolved with appropriate treatment. None of the patients died from complications of the indwelling catheter.
Phase II trial of fazarabine (ARA-AC, arabinosyl-5-azacytosine) in metastatic breast cancer.
Fourteen consecutive female patients with metastatic breast cancer received a total of 31 courses of fazarabine at a dose of 2 mg/m2/hour x 72 hours (48 mg/m2/day x 3) as a continuous infusion. There were no responses seen, although one patient achieved stability of her disease for five courses. Because of encouraging in vitro results and the primarily hematologic dose-limiting toxicity, further study in combination with colony stimulating growth factors might be of interest.
Overview of new treatments for breast cancer.
Progress in the treatment of breast cancer developed along multiple directions of research during the last decade. The concept of dose-intensity was addressed through retrospective analyses and prospective randomized trials. It was confirmed that dose-intensity correlates with higher response rates, but the effect of dose-intensive treatments on survival still needs to be established. Several new cytotoxic drugs have appeared during the last several years. Taxol, navelbine, and anthrapyrazole CI-941 have been found to have major efficacy against breast cancer, with response rates exceeding 50%. Amonafide, lonidamine, and elliptinium analogs were also shown to be effective, although to a lesser degree. Antiestrogen analogs, new aromatase inhibitors, and LHRH analogs are recent developments that are changing the face of hormonal therapy. Monoclonal antibodies are being developed and evaluated for tumor imaging applications and as vehicles for specific antitumor agents (cytotoxics, radioisotopes, and toxins). Expanding knowledge about the basic biology of breast cancer has led to the identification of growth factors and their receptors, which may be exploited for therapeutic purposes in the not too distant future.
Local control for locally advanced breast cancer: many opinions, few facts.
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Bone metastasis in breast cancer.
Bone metastases in breast cancer are common and frequently lead to serious skeletal related morbid complications. Metastases develop in areas of metabolically active trabecular bone. It is presumed that breast cancer cells undergo the same stepwise process for metastases development as demonstrated in other tumor types. The specific factor or factors responsible for the osteotropism of breast cancer have not been identified. The morbid events associated with skeletal metastases, such as pathologic fracture, and spinal cord compression, may be assessed objectively by a variety of techniques including skeletal radiography, radionuclide scanning, computed tomographic scanning and magnetic resonance imaging. Biochemical parameters or markers of skeletal metastases are not sensitive enough to detect clinically occult disease. Therapeutic interventions for bone metastases include local and systemic therapies. Surgery and radiation therapy are most frequently used for relief of pain or impending fracture, or when bone fracture or neurologic compromise has already developed. Systemic treatment of bone metastases appears to be as effective as systemic treatment of other metastatic sites. Both hormone and chemotherapy may provide significant palliation. Clinical research suggests that the adjunctive use of bisphosphonates may significantly reduce the incidence of skeletal-related morbid events associated with osteolytic bone disease. Future research efforts directed at determining the osteotrophic factors responsible for bone metastases in breast cancer, the pathophysiology of the bone remodeling process in metastatic disease and the prophylactic use of bisphosphonates may lead to significant clinical benefit for those in whom bone metastases from breast cancer develop.
Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer.
PURPOSE: A prospective study in breast cancer patients was undertaken to determine whether escalating doses of doxorubicin and cyclophosphamide would result in a higher fraction of patients free of disease, and to evaluate the role of leukocyte alpha-interferon. PATIENTS AND METHODS: Between 1982 and 1986, 319 consecutive patients with stage II or III breast cancer with one or more positive nodes were assigned randomly to receive adjuvant chemotherapy that consisted of escalating doses of doxorubicin and cyclophosphamide in combination with vincristine and prednisone or the same chemotherapy regimen followed by 1 year of leukocyte alpha-interferon. Doxorubicin was administered by 72-hour continuous infusion through a central venous catheter (maximum total cumulative dose, 430 mg/m2). All patients with positive or unknown estrogen receptor status were also given tamoxifen for 1 year. RESULTS: The median follow-up was 71 months (range, 35 to 99 months). Correlation of disease-free survival (DFS) with dose-intensity of cyclophosphamide and doxorubicin showed no improvement in DFS for patients who were able to receive escalated drug doses compared with those who were not. Doxorubicin administered by continuous infusion was associated with a negligible risk of cardiotoxicity in this study despite the administration of higher accumulative doses than in our previous adjuvant therapy studies. The DFS rates of patients who did and those who did not receive leukocyte alpha-interferon were similar. CONCLUSIONS: In this study, there was no real evidence that higher drug dose intensity was associated with longer DFS. Leukocyte alpha-interferon as it was used in this study had no therapeutic value. Doxorubicin administered by infusion was associated with a reduced risk of cardiotoxicity.
Activity of ifosfamide in breast cancer.
Ifosfamide is an alkylating agent that has clearly demonstrated efficacy against advanced breast cancer. In broad phase II trials, ifosfamide produced response rates of approximately 15% to 20%, and up to 30% in patients without exposure to previous chemotherapy. In subsequent studies, in which ifosfamide was evaluated in higher doses with mesna uroprotection in advanced breast cancer patients with or without prior chemotherapy, the combined complete and partial response rate was 28%. Ifosfamide has also been used in combination regimens. The ifosfamide/methotrexate/5-fluorouracil (IMF) combination has produced efficacy similar to that of the cyclophosphamide/methotrexate/5-fluorouracil (CMF) combination in both previously treated and untreated metastatic breast cancer. Combinations of ifosfamide/epirubicin, ifosfamide/mitoxantrone, and ifosfamide/etoposide have shown encouraging results. Response rates of approximately 70% have been obtained with regimens that include ifosfamide/doxorubicin or ifosfamide/epirubicin. The dose-limiting toxic reactions of ifosfamide, with administration of mesna uroprotection, are myelosuppression, renal tubular acidosis, and renal insufficiency. Additional studies are needed to determine the role of ifosfamide in well-defined patient subsets, to assess its cross-resistance with other alkylating agents, and to determine the slope of the dose-response curve in patients with breast cancer. Further, the role of ifosfamide in front-line combinations needs to be defined.
Treatment of locally advanced breast cancer.
It is possible to convert most patients with stage III breast cancer to the state of "no evidence of disease." The challenges now are to increase the cure rate by eradicating local and distant micrometastatic disease, and to minimize the mutilation of locoregional treatment.
Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer.
Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5-13+ months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%-76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no allergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).
Ki-67 immunostaining in node-negative stage I/II breast carcinoma. Significant correlation with prognosis.
Prognostic predictors for node-negative breast carcinoma have not been clearly established. Immunostaining with Ki-67 antibody was performed on frozen sections of histologically proved node-negative breast carcinomas from 42 patients to examine its prognostic value and its association with other clinicopathologic and biochemical parameters, i.e., patient age and tumor size, histologic type, nuclear grade, mitotic rate, presence of vascular or lymphatic invasion, DNA ploidy, percentage of cells in S-phase, estrogen content, and c-erbB-2 amplification. Thirty-seven of the 42 tumors showed immunoreactivity with Ki-67 antibody in 1% to 55% of the tumor cells. A strongly significant correlation was observed between Ki-67 staining percentage and, respectively, nuclear grade, age, and mitotic rate. Nuclear grade 1 (the most anaplastic) tumors showed a significantly higher median percentage of cells stained (median, 14; range, 3 to 40) compared with nuclear grade 3 tumors (median, 0.5; range, 0 to 8). Thirteen patients developed recurrence; six of them died of disease. On univariate analysis, both 5-year disease-free and overall survivals were strongly associated with percentage of cells stained with Ki-67 antibody. Our results suggest that Ki-67 immunostaining correlates well with nuclear grade and clinical outcome in node-negative breast carcinoma. Because of small sample size analyzed in this study we were unable to do multivariate analysis. Therefore, further studies with larger number of cases are needed to determine whether tumor proliferative activity determined by Ki-67 immunostaining is an independent prognostic parameter or it merely reflects histopathologic features such as nuclear grade or mitotic activity.
Lack of correlation between histologic findings and response to chemotherapy in metastatic breast cancer.
A retrospective analysis was undertaken to assess the prognostic role of histologic findings in response to chemotherapy and survival in patients with metastatic breast cancer. Histologic material was available for 395 of 1587 patients treated for metastatic breast cancer at the M.D. Anderson Cancer Center between 1973 and 1984. Chemotherapy consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide or similar drugs, with or without tamoxifen. Maintenance cyclophosphamide, methotrexate, and 5-fluorouracil was continued for 2 years after a cumulative doxorubicin dose of 450 mg/m2 was administered. The histologic distribution was as follows: infiltrating ductal carcinoma, 353; invasive lobular, 14; mixed histology, ten; mucinous, seven; signet ring, four; tubular, three; papillary, two; sarcomatoid, one; and apocrine, one. Because individual histologic types occurred infrequently, the patients were divided into infiltrating ductal and nonductal groups. Baseline patient characteristics included age, performance status, estrogen-receptor status, prior hormone response, disease extent, and levels of alkaline phosphatase, bilirubin, and lactate dehydrogenase. These were similar in the two groups. Significantly more patients with nonductal histology had greater than three metastatic sites. There were also more patients with hemoglobin less than 10 mg/dl and albumin less than 3.5 mg/dl in the nonductal group of patients. However, statistically these factors did not have an impact on the results. There was a 63% response rate (17% complete and 46% partial) for the ductal group and a 60% response rate (12% complete and 48% partial) for the nonductal group. The time from initiation of chemotherapy to disease progression was identical (12 months) for the two groups. Survival from initiation of chemotherapy was not significantly different (22 months for ductal and 27 months for nonductal). Based on this study, the authors conclude that histologic findings have no bearing on patient response to chemotherapy or survival in metastatic breast cancer.
Comparison of immunocytochemical and biochemical assays for estrogen receptor in fine needle aspirates and histologic sections from breast carcinomas.
An immunocytochemical assay using a monoclonal antibody specific for estrogen receptor (ER-ICA) was performed on needle aspirates and on histologic sections (mastectomy and biopsy specimens) from 55 patients with breast cancer. A total of 82 ER-ICAs were performed, with matched cytologic and histologic specimens in 27 patients, cytology alone in 15, and histology alone in 13. ER-ICA results were described by a histochemical score (H score) based on intensity-weighted percentages of staining cells. The H scores were compared with results of sucrose density gradient (SDG) analysis of histologic specimens (mastectomy, resection, or biopsy). An H score greater than or equal to 10 and an SDG value greater than or equal to 10 fmol/mg protein were considered positive. The sensitivity of cytologic ER-ICA was 94%, the specificity 100%. The sensitivity of histologic ER-ICA was 67%, the specificity 90%. Correlating cytologic H score with Black's nuclear grade showed that grade 1 (the most anaplastic) carcinomas demonstrated the lowest H scores (mean, 7.3 +/- 29.8), whereas the highest H scores were noted in grade 3 tumors (mean, 150.0 +/- 88.1). Both SDG and ER-ICA showed ER values to be lower in premenopausal than postmenopausal women. There was no correlation between H score and presence of axillary nodal metastases or tumor size. An overall good correlation was demonstrated between immunohistochemical methods and biochemical analysis.
Postoperative adjuvant chemotherapy with fluorouracil, doxorubicin, cyclophosphamide, and BCG vaccine. A follow-up report.
Two hundred twenty-two patients with stage II or III breast cancer following regional therapy were treated with a combination of fluorouracil, doxorubicin hydrochloride (Adrimycin), cyclophosphamide, and BCG vaccine. At 54 months of study (median follow-up, 30 months), the estimated proportions remaining disease-free two and three years after surgery were 83%and 78%, respectively, in the chemotherapy group and 64% and 55%, respectively, in 151 historical control patients. Estimated two- and three-year survival rates were 93% and 89%, respectively, in the chemotherapy group and 84% and 58%, respectively, in the control patients. Congestive heart failure has developed in three patients, possibly related to the use of doxorubicin. Adjuvant chemotherapy with these drugs was effective in prolonging the disease-free interval and survival of patients irrespective of menopausal status, degree of nodal involvement, or stage of the disease.
Tamoxifen. Use in treatment of metastatic breast cancer refractory to combination chemotherapy.
Tamoxifen citrate (Nolvadex [Great Britain]; no comparable US product) is a recently developed antiestrogen with significant activity against metastatic breast cancer in postmenopausal women. We investigated its usefulness in breast cancer patients after conventional endocrine therapy and combination chemotherapy had failed. Of the 50 evaluable patients, four (8%) achieved a complete remission, 14 (28%) achieved a partial remission, and ten showed a less than partial response or stabilization of their disease. Median duration of response was eight months, and the survival of responders was significantly prolonged compared to that of the nonresponders. Side effects of the treatment were mild. These results demonstrate that tamoxifen offers the best choice of therapy for patients with metastatic breast cancer after conventional endocrine therapy and combination chemotherapy have failed.