Treatment Of Metastatic Breast Carcinoma Research Articles

Abstract PO5-16-11: Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers

Abstract The third-generation antibody-drug conjugates, Trastuzumab-Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG), have been approved for the treatment of metastatic breast carcinoma in various subtypes and therapeutic settings based on compelling Phase III study data. (DESTINY-Breast03 (T-DXd; HER2-positive), DESTINY-Breast04 (T-DXd; HER2-low), ASCENT (SG; triple-negative), and TROPiCS-02 (SG; HR+/HER2-negative). The aim of this retrospective study conducted at two major German Breast centers was to evaluate the tolerability, adherence, and efficacy of both substances in the real-world setting. All patients treated outside of clinical trials with T-DXd or SG at the Department of Gynecology and Obstetrics, Ulm University Hospital and the Department of Women’s Health, Tuebingen University Hospital between November 2020 and May 2023 were included in this retrospective analysis. Seventy-five patients were included [T-DXd: 46; SG: 29]. The mean duration of therapy was 5.4 months [T-DXd: 6.2; SG: 4.2]. The real-world cohort was more heavily pretreated than the corresponding study cohorts, with a mean of 4.2 systemic therapies in the metastatic setting prior to T-DXd therapy and 3.6 systemic therapies prior to SG therapy. The administered cumulative dose on average was 87.9% [T-DXd: 94%; SG: 79%] of the theoretical full dose or 95.3% [T-DXd: 98%; SG: 92%] when considering dose reductions that occurred. Hematotoxicities of CTC ≥ 3° occurred in 11% of patients treated with T-DXd and in 41% of patients treated with SG. Neutropenia was the predominant severe hematotoxicity (CTC≥III°) observed during SG therapy, occurring in 38% of patients. The occurrence of neutropenia during SG therapy was reduced with primary prophylactic administration of Granulocyte-Colony Stimulating Factor (GCSF), with a rate of 29% (21/29) of patients experiencing neutropenia ≥CTC-III°, compared to 63% (8/29) without primary prophylactic GCSF. Therapy-associated pneumonitis under T-DXd occurred in 5 out of the 46 included patients and was successfully treated with corticosteroids in all cases (CTC II° in 4 cases, CTC III° in 1 case). The median progression-free survival (PFS) from initial administration was 7.7 months under T-DXd [HER2-positive: 9.0; HER2-low: 6.1], and 4.8 months under SG [TNBC 4.8; HR+/HER2-negative: 2.8]. The median overall survival from initial administration was 27.1 months under T-DXd [HER2-positive: 27.1; HER2-low: not reached], and 11.9 months under SG therapy [TNBC: 11.0, HR+/HER2-negative: not reached]. This analysis provides evidence of the efficacy and tolerability of T-DXd and SG in a heterogeneous and heavily pretreated cohort in a real-world setting. However, a conclusive assessment of progression-free survival (PFS) and overall survival (OS) is not feasible yet, as a substantial number of patients are still under treatment. Updated PFS and OS data, with a specific focus on the therapy indication, will be presented at the meeting. Citation Format: Henning Schäffler, Dominik Dannehl, Kristina Veselinovic, Franziska Mergel, Kerstin Pfister, Brigitte Rack, Visnja Fink, Elena Leinert, Lea Volmer, Tobias Engler, Sara Brucker, Wolfgang Janni, Andreas Hartkopf. Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-11.

Abstract PO5-20-09: LOCOREGIONAL MANAGEMENT OF DE NOVO STAGE IV HORMONE-POSITIVE BREAST CARCINOMA AFTER CDK 4/6 INHIBITOR TREATMENT

Abstract Systemic therapy remains the backbone for treatment of metastatic breast carcinoma. Locoregional treatment of the primary tumor remains controversial. While it has an established role in the palliative setting, its survival benefit remains unclear. The rationale behind locoregional approach is the reduction of tumor burden and the removal of cancer stem cells which may propagate the disease. In previous literature, hormone-positive breast cancer seems to be the best candidate for locoregional treatment in the presence of synchronous metastases. We present a case of a 43 year-old, female, with no known comorbidities, who sought consult due to note of a hard lump on her right breast. Core needle biopsy of the right breast mass was performed which showed invasive breast carcinoma, no special type, Nottingham histologic grade 2. On immunohistochemistry, tumor was ER +8, PR +8, Ki 67 90%, Her-2 neu negative. Baseline positron emission tomography/CT (PET/CT) scan showed hypermetabolic, heterogeneously-enhancing lobulated right breast mass, 3 × 6.7 × 7.7 cm, with smaller hypermetabolic adjacent nodules. There was also note of multiple enhancing, hypermetabolic lung and pleural nodules, and lymphadenopathies in the mediastinal, right axillary, right cardiophrenic and perigastric areas. Well-defined, hypermetabolic heterogeneously hypoenhancing masses were also seen in segments II and VII of the liver. There was also note of right-sided pleural effusion. Ultrasound-guided thoracentesis was done which turned positive for malignant cells on pleural fluid analysis. She underwent 4 cycles of chemotherapy with Doxorubicin and Paclitaxel. Reevaluation PET-CT scan revealed partial response. Patient was then started on Ribociclib plus Letrozole with ovarian function suppression for 18 months. On latest reevaluation PET/CT scan, there was no evidence of hypermetabolic metastatic disease, with demonstration of hypermetabolic activity only in the right breast. The patient then underwent right total mastectomy, with histopathologic findings of residual invasive carcinoma, Nottingham histologic grade 3, residual tumor size of 3.5 cm, with 95% tumor cellularity and lymphovascular invasion identified, ypT2. All surgical margins were negative for tumor. Currently, the patient has no evidence of disease, with ribociclib and letrozole continued until disease progression or unacceptable toxicity. In this case, surgery of the primary tumor was performed in the presence of a responsive metastatic disease, with the primary tumor being the only evidence of disease. With the advent of newer therapy options like cyclin-dependent kinase 4/6 inhibitors offering outstanding survival benefit for metastatic disease, a more aggressive and synergistic approach with locoregional therapy may be done to eradicate the tumor burden, translating to better long-term survival. Locoregional management of the primary tumor should be discussed in the context of a multidisciplinary team approach and should be individualized based on the individual patient’s need. Citation Format: Raye Angeli Abella, Rubi Li. LOCOREGIONAL MANAGEMENT OF DE NOVO STAGE IV HORMONE-POSITIVE BREAST CARCINOMA AFTER CDK 4/6 INHIBITOR TREATMENT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-09.

Third Line Eribulin for Triple-negative Metastatic Breast Ductal Carcinoma Resulting in Extended Progression-free Survival of 57 Months

Eribulin is a non-taxane microtubule inhibitor approved for the treatment of metastatic breast carcinoma after two prior chemotherapeutic regimens. We report a patient with extended progression-free survival (PFS) of more than 57 months with metastatic breast carcinoma treated with eribulin in the third-line setting. A 48-year-old lady was diagnosed with stage IIA (pT2N0M0), high grade, triple-negative, invasive ductal carcinoma (IDC) of the left breast on core needle biopsy. She underwent neoadjuvant chemotherapy with adriamycin, and cyclophosphamide followed by a negative sentinel lymph node (SLN) biopsy. Subsequent mastectomy and axillary lymph node dissection revealed a 2.5 cm, high grade, triple-negative IDC with three additional lymph nodes negative for metastatic carcinoma, consistent with the initial diagnosis. Eight months into the surveillance program, the patient developed a 2.8 cm right lower lobe (RLL) lung mass with standard uptake value (SUV) of 27 on positron emission tomography-computed tomography (PET/CT). Core needle biopsy of the lung lesion revealed sheets of poorly differentiated carcinoma, immunophenotypically compatible with the initial diagnosis of breast pathology. She then commenced single-agent paclitaxel in the 1st line metastatic setting with a significant decrease in RLL lung mass to less than 1 cm with an SUV of 1.7 noted. The patient developed progression after seven months and started 2nd line gemcitabine noting initial improvement and subsequent stable disease for a period of 12 months. Eventual progression of RLL lung nodule measuring 2.1 cm with SUV of 10 noted. Initiated 3rd line eribulin with a notable response on imaging studies within three months and with no evidence of disease (NED) on scans over the subsequent 57 months. Eribulin related mild neuropathy superimposed on previous paclitaxel associated grade 2 neuropathy required a 20% eribulin dose reduction. The patient is currently clinically and radiographically stable with plateaued serum tumor markers. Our patient has shown excellent response and tolerance to eribulin with PFS of over 57 months (nineteen times the norm) which is rare.

Patient with metastatic breast cancer, HER2-positive, trastuzumab- and pertuzumab-resistant responding to lapatinib

Lapatinib is an intracellular tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2) receptors, approved for the treatment of metastatic breast carcinoma pre-treated with anti-HER2 antibodies. We report the case of a 60-year-old woman diagnosed with metastatic breast neoplasm, HER2-positive, progressing after treatment with trastuzumab, pertuzumab and T-DM1, who obtained a regression of hepatic metastases after treatment with lapatinib-capecitabine (Oncology).

Orbital fat regeneration following hormonal treatment of metastatic breast carcinoma

ABSTRACTEnophthalmos in the setting of breast cancer metastatic to the orbit results primarily from the disease pathogenesis, or secondary to treatment effects. Orbital volume restoration and fat regeneration following endocrine treatment monotherapy has not been previously reported. A 76- year-old previously healthy female presented with progressive right enophthalmos secondary to metastatic lobular breast carcinoma. Treatment with an aromatase inhibitor (letrozole) resulted in tumor regression and orbital fat restoration with a corresponding improvement in orbital volume and enophthalmos on clinical exam. The patient is alive on continued letrozole with no progressive disease ten years after diagnosis. This case illustrates the resilience of orbital soft tissues and ability of orbital fat to regenerate in face of breast cancer metastasis. We hypothesize that endocrine monotherapy, and avoidance of radiation therapy, allowed for differentiation of remaining orbital stem cells, and facilitated the fat regenerative process.

Abstract 1664: Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma

Abstract Immunotherapy has now emerged as a promising treatment for metastatic cancer. However, immunotherapy for advanced stage breast carcinoma remains an unmet need. Here we demonstrate that the novel immunomodulator alpha-tocopheryloxyacetic acid (aTEA) synergizes with radiation therapy (RT) in a metastatic murine mammary carcinoma model to improve tumor control more than each individual therapy, and we propose a mechanism based on the stimulation of type I interferons by aTEA. For in-vivo studies, C57BL/6 mice bearing 4T1 murine mammary carcinoma lesions were treated with dietary aTEA, 20 Gy x 2 fractions ionizing radiotherapy, or the combination of aTEA/RT. Immune activation in animals treated with dietary aTEA was determined by analyzing the percentage of proliferating CD4 and CD8 T cells using a Ki-67 assay. Pulmonary metastatic burden was determined using a clonogenic metastasis assay. For in-vitro studies, murine mammary carcinoma cell lines were treated with aTEA or LPS and whole cell lysates were analyzed by Western blot. Expression of interferon regulation factor 3 (IRF3) pathway proteins, including phospho-TANK binding protein kinase 1 (TBK1) and stimulator of interferon genes (STING) were determined. Our results indicate that treatment with the combination of aTEA and RT significantly improves tumor control compared to either treatment alone. Combination therapy resulted in complete and durable tumor regression in a subset of animals treated, an effect not observed with aTEA or RT alone. Dietary administration of aTEA stimulates proliferation of both CD4 and CD8 T cells and significantly reduces metastatic burden in 4T1 tumor bearing mice. This immune stimulatory effect of aTEA appears to be mediated by reactive oxygen species (ROS) production and release of type I interferons through a STING mediated pathway. These preliminary results suggest that the combination of aTEA and ionizing radiation may be a viable therapy for the treatment of metastatic breast carcinoma. This therapeutic combination may provide more durable response to radiotherapy while simultaneously reducing further metastatic spread. Citation Format: Joshua M. Walker, Diego M. Barragan, Melissa J. Kasiewicz, Charles R. Thomas, William L. Redmond. Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1664.

Vinorelbine and fluorouracil plus leucovorin combination (ViFL) in patients with anthracycline and taxane-pretreated metastatic breast cancer: a phase II study

This phase II study was designed in order to evaluate efficacy and safety of the combination of vinorelbine (VNB), fluorouracil (FU) and leucovorin (LV) in patients with metastatic breast carcinoma (MBC) previously treated with anthracyclines and taxanes. From 12/2003 to 12/2007, 51 women (median age 59) were treated. Performance status (PS) (ECOG) was 0-2 (median 0). The chemotherapy consisted of VNB 25 mg/sqm on day 1 added to FU and LV (following De Gramont schedule) on day 1 and 2. Treatment was repeated every 14 days. 518 cycles of CT were administered (median 12). Most common sites of metastatic spread were: bone, liver, lymph nodes, lung. We recorded three cases of G4 neuthropenia and in one case it was febrile; no others G4 toxicities were seen. G3 toxicities were more common, especially neuthropenia (8 patients) asthenia (4) mucositis (2) and Hand-Foot Syndrome (2). Overall response rate was 27.5% (14 patients had a PR) and disease control rate was 76.5%; 12 patients experienced disease progression. Median time to progression (TTP) was 7.70 months and overall survival (OS) was 18.70 months. Results demonstrate that the ViFL regimen has substantial activity in patients with MBC already treated with anthracyclines and taxanes. The combination may be considered a valid choice for the treatment of MBC. Better survival results were seen in patients with visceral metastases than bone involvement. The low response rate shows that the ViFL regimen is not suitable for the neoadjuvant setting.

Docetaxel and Gemcitabine in the Treatment of Metastatic Breast Carcinoma: A Dose Finding Study

Patients with metastatic breast cancer previously treated with anthracyclines for advanced disease are usually refractory to any further treatment with anthracyclines and have a poor prognosis. Therefore, new drugs or new combinations of drugs are needed. One approach has been to focus on the type of chemotherapy with low toxicity that preserves quality of life during treatment, such as weekly drug administration. We designed a dose-finding study to determine the maximum tolerated dose of gemcitabine plus docetaxel, given on a weekly schedule in metastatic breast cancer previously treated with anthracyclines. Three escalating doses of gemcitabine (900, 1000 and 1100 mg/m2) on days 1 and 8 in combination with a fixed dose of docetaxel, 35 mg/m2 on days 1 and 8 were planned. Dose-limiting toxicity included grade > 3 hematologic toxicity, grade > 2 stomatitis, asthenia, diarrhea or organ-specific toxicity (except alopecia). Dose escalation was stopped if 1 out of 3 patients at any dose level experienced dose-limiting toxicity. Nine patients received a mean of 5.1 (range, 1-9) cycles. Gastrointestinal and leukopenia were the main dose-limiting toxicity. No patient experienced dose-limiting toxicity at dose level 1; at dose level 2, 2 out of 3 patients had dose-limiting toxicity and 3 additional patients treated at dose level 2 confirmed that the maximum tolerated dose had been reached. The recommended gemcitabine dose in combination with docetaxel (35 mg/m2 for a phase II study) was established at 900 mg/m2.

Trastuzumab-associated cardiotoxicity.

Trastuzumab is a monoclonal antibody used for the treatment of metastatic breast carcinoma in women whose tumors overexpress the HER2 protein. Cardiotoxicity has been reported to occur with trastuzumab when administered alone and in combination with antineoplastic agents, particularly anthracyclines. The risk of cardiotoxicity with trastuzumab has been reported to be 4% with monotherapy and 27% when administered in combination with an anthracycline and cyclophosphamide, but to the author's knowledge severe outcomes, such as death or permanent disability, are uncommon. The majority of reported cardiac effects are mild to moderate, nonspecific, and medically manageable. Signs and symptoms are similar to those observed in patients who develop anthracycline-induced cardiomyopathy and include tachycardia, palpitations, and exertional dyspnea, which may progress to congestive heart failure. The pathogenesis and histologic changes responsible for trastuzumab-associated cardiotoxicity currently are under investigation. Unlike anthracycline-induced toxicity, trastuzumab-associated toxicity usually responds to standard treatment or the discontinuation of trastuzumab, and there is no evidence that the toxicity is dose related. Current methods for the early detection of cardiotoxicity in trastuzumab-treated patients are similar to those used in anthracycline-treated patients. Cardiac function is established at baseline and monitored regularly during treatment by physical examination and measurement of left ventricular ejection fraction. The majority of patients improve with proper treatment, and some are able to continue to receive trastuzumab.

Cutaneous fibrosis induced by docetaxel

Docetaxel is a taxoid antineoplastic agent approved for use in the treatment of metastatic breast carcinoma. The current study reports an unusual case of generalized cutaneous fibrosis in a 39-year-old white female after treatment with 18 cycles of docetaxel for metastatic breast carcinoma. Cutaneous fibrosis represents a rare and unique reaction associated with the cyclic use of docetaxel. The reaction is manifested by a distinct sequence of events involving pronounced edema followed by the rapid development of cutaneous fibrosis in dependent areas. Cessation of therapy results in dramatic reversal of the fibrotic process. This case report further substantiates the belief that docetaxel represents one of a very limited number of agents that appear capable of giving rise to scleroderma-like features.

Cutaneous fibrosis induced by docetaxel

BACKGROUND Docetaxel is a taxoid antineoplastic agent approved for use in the treatment of metastatic breast carcinoma. The current study reports an unusual case of generalized cutaneous fibrosis in a 39-year-old white female after treatment with 18 cycles of docetaxel for metastatic breast carcinoma. METHODS Cutaneous fibrosis represents a rare and unique reaction associated with the cyclic use of docetaxel. The reaction is manifested by a distinct sequence of events involving pronounced edema followed by the rapid development of cutaneous fibrosis in dependent areas. RESULTS Cessation of therapy results in dramatic reversal of the fibrotic process. CONCLUSIONS This case report further substantiates the belief that docetaxel represents one of a very limited number of agents that appear capable of giving rise to scleroderma-like features. Cancer 2000;88:1078–81. © 2000 American Cancer Society.

Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: a reference.

The authors report results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with doxorubicin-containing combination chemotherapy at a single institution; this report is meant to serve as a reliable reference for single-arm studies of newer therapies in this patient population. Prospectively collected data from 18 successive doxorubicin-containing protocols for the treatment of metastatic breast carcinoma were evaluated. The response rate was 65.0% (95% confidence interval [CI]: 62.5-67.3%), complete response (CR) rate was 16.6% (95% CI: 14.8-18.6%), and partial response (PR) rate was 48.5% (95% CI: 46.0-50.9%). Median progression free survival (PFS) was 11.5 months (95% CI: 10.9-12.3 months) and median overall survival (OS) was 21.3 months (95% CI: 20.3-22.7 months). Survival correlated with response to therapy; median PFS and OS were 22.4 and 41.8 months, respectively, for the patients who achieved CR (n=263) and 14 and 24.6 months, respectively, for PR patients (n=766). The median OS of patients who had progressive disease during chemotherapy was 3.8 months. The response rate, PFS and OS correlated with number of organs involved and especially with tumor burden. Patients with hormone receptor-positive tumors had a similar response rate to that of patients with hormone receptor negative tumors but had significantly longer PFS (medians of 14.3 and 8.7 months, respectively) and OS (medians of 28.6 and 18.1 months, respectively). In patients with metastatic breast carcinoma, doxorubicin-containing chemotherapy had a response rate of 65% and a CR rate of 16.6%. PFS and OS were 11.5 months and 21.3 months, respectively, for all responders and 22.4 months and 41.8 months, respectively, for those who had CR.

Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens

A pilot study of a new chemotherapy, the CIVIC regimen, was performed in 58 patients with metastatic breast carcinoma previously treated with chemotherapy with or without hormonal therapy (n = 41). Cisplatin, 20 mg/m2/day, was given (Days 1-5) every 21 days during a 1-hour intravenous (i.v.) infusion, and vinorelbine (VNB) was delivered at a dose of 6 mg i.v. bolus followed by VNB, 6 mg/m2/day, in continuous i.v. infusion (Days 1-5) every 21 days. Fifty-eight patients were included in this trial between June 1992 and March 1994 (median age, 46.5 years; range, 28-69 years). The number of previous chemotherapy in the adjuvant or metastatic phase were: 1 in 9 patients, 2 in 33 patients, and > or = 3 in 16 patients. Forty-four and 12 patients, respectively, were previously treated in metastatic phase with regimens containing anthracyclines and paclitaxel. Overall, 210 cycles were given (median, 3 cycles; range, 1-6 cycles). Among the 58 patients assessable for tumor response to the CIVIC regimen, 24 patients (41%) (95% confidence interval, 28-54) achieved an objective response (complete response or partial response) with 2 complete response (3%) and 22 partial response (38%). The median time to response was 11 weeks (range, 4-16 weeks). The median survival time from the initiation of the CIVIC regimen was 9.2 months (range, 0-45 months). The response rate was 43% (19 of 44 patients) in patients refractory to anthracyclines and 58% (7 of 12 patients) in patients with disease progression after treatment with anthracyclines and paclitaxel. Myelosuppression was the most frequent side effect. World Health Organization Grade 3 neutropenia occurred in 8 of 58 patients (14%) and in 41 of 210 cycles (20%), Grade 4 neutropenia occurred in 37 of 58 patients (64%) and in 63 of 210 cycles (30%), and Grade 3 and 4 thrombopenia occurred in 7 of 58 patients (12%) and in 9 of 210 cycles (4%). Grade 2 peripheral neuropathy was observed in 6 of 58 patients (10%) and in 12 of 210 cycles (6%), and Grade 3 peripheral neuropathy was observed in 3 of 58 patients (5%) and in 4 of 210 cycles (2%). The risk of Grade 2-3 neuropathy was significantly higher after the fourth chemotherapy cycle (14 of 23 patients vs. 3 of 35 patients: P = 0.00002). The CIVIC regimen is effective and has acceptable tolerance in patients with metastatic breast carcinoma refractory to previous anthracycline- and/or paclitaxel-containing chemotherapy. Four cycles were found to provide the best toxicity-efficacy ratio.

Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline‐ and/or paclitaxel‐containing regimens

Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline‐ and/or paclitaxel‐containing regimens

On the relocation of the amino functionality to the ethyl side chain in aminoglutethimide: Synthesis and aromatase‐inhibitory activity of 3‐(2′‐N,N‐diethyl‐amino)ethyl‐3‐phenylpiperidine‐2,6‐dione

AbstractAminoglutethimide [3‐(4‐aminophenyl)‐3‐ethylpiperidine‐2,6‐dione] has been used clinically in the treatment of metastatic breast carcinoma. Inhibition of tumor growth is due to interference with estrogen biosynthesis. However, its action is not specific and its metabolism gives rise to toxic and non‐inhibitory metabolites. We sought to explore the impact of relocating the amino group in aminoglutethimide to the ethyl side chain. To that end, we now report the synthesis and aromatase‐inhibitory activity of 3‐(2′‐N,N‐diethylamino)ethyl‐3‐phenylpiperidine‐2,6‐dione 5. The introduction of the amino functionality on the ethyl group is accomplished via reductive animation of aldehyde 8, prepared in three steps from benzyl cyanide. The synthetic route presented can be used for the preparation of related derivatives of aminoglutethimide.

Mitoxantrone, 5‐fluorouracil, and high dose leucovorin (NFL) versus intravenous cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) in first‐line chemotherapy for patients with metastatic breast carcinoma

Previous Phase II studies using the combination of mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) in the treatment of metastatic breast carcinoma have shown this regimen to be active and well tolerated. In this randomized Phase II study, the authors compared the NFL regimen with a standard CMF regimen in the first-line therapy of patients with metastatic breast carcinoma. One hundred twenty-eight women receiving their first chemotherapy for metastatic breast carcinoma were entered into this randomized study. Sixty-four patients were treated with NFL: mitoxantrone 12 mg/m2 IV on Day 1; leucovorin 300 mg IV over 30-60 minutes on Days 1, 2, and 3, immediately preceding administration of 5-fluorouracil; and 5-fluorouracil 350 mg/m2 IV bolus on Days 1, 2, and 3. Sixty-four patients received CMF: cyclophosphamide 600 mg/m2 IV on Day 1; methotrexate 40 mg/m2 IV on Day 1; and 5-fluorouracil 600 mg/m2 IV on Day 1. Both regimens were repeated at 21-day intervals; responding patients received at least 8 courses. Patients treated with NFL had a higher response rate than patients treated with the CMF regimen (45% vs. 26%, respectively; P = 0.021). Median duration of response was 9 months with NFL and 6 months with CMF (P = 0.10); 11 patients had long responses (>12 months) with NFL versus 4 patients with CMF (P = 0.06). Median survival was similar for both groups. Both regimens were well tolerated, with infrequent Grade 3 or 4 toxicities. NFL is an active, well-tolerated regimen for the treatment of metastatic breast carcinoma; it produced a higher response rate than the CMF regimen used in this study. Although more intense CMF regimens or regimens containing doxorubicin would likely increase the response rate, they would almost certainly do so with the consequence of greater toxicity as compared with NFL. NFL is an excellent initial palliative treatment option for elderly patients or patients who have exhibited poor tolerance for other chemotherapy regimens.

PP-7-4 Phase study of taxol® (paclitaxel) in combination with epirubicin and cyclophosphamide without G-CSF as a first line treatment of metastatic breast carcinoma (MBC)

PP-7-4 Phase study of taxol® (paclitaxel) in combination with epirubicin and cyclophosphamide without G-CSF as a first line treatment of metastatic breast carcinoma (MBC)

Randomized Trial of Two Doses of Taxol in Metastatic Breast Cancer: An Interim Analysis

<i>Background</i>: Taxol has been shown to be a very effective agent for the treatment of metastatic breast carcinoma (MBC) when given intravenously during 24 h at doses ranging from 200 to 250 mg/m2. <i>Patients and Methods</i>: This multicentric study compares in a randomized setting two doses of taxol – 135 and 175 mg/m2 – given as 3-hour infusions in patients with MBC previously treated with chemotherapy. 471 patients were included and preliminary results of the first 245 patients (123 patients treated with 175 mg/m2 and 122 patients treated with 135 mg/m2) are reported. Pretreatment characteristics were well balanced between the two groups. Overall 31% of the patients had received only adjuvant chemotherapy, 37% had prior treatment for metastatic disease, and 32% had both. None of the patients had received more than one regimen of chemotherapy for metastatic disease. 71 % of the patients had been exposed to anthracyclines. <i>Results</i>: A median of five cycles (range 1-10) was given. Currently 234 patients are evaluable for response. The overall response rate is 26% (8 complete and 52 partial remissions). 106 patients (45%) with stable disease are still on treatment. The response rates were 32% for patients who received only adjuvant chemotherapy, 20% for those with chemotherapy for metastatic disease, and 26% for those who received both. Among the patients considered resistant to anthracyclines, 21% achieved a response with taxol. No patient discontinued taxol therapy because of hypersensitivity reactions. Grade IV neutropenia occurred in 21 and 27% of the patients at 135 and 175 mg/m2, respectively. No severe infection was reported. Neuro-toxicity was dose dependent, but severe manifestations were rare. <i>Conclusions</i>: This interim analysis confirms in a multicentric setting the efficacy of taxol in patients with MBC even after anthracycline failure. Administration of taxol over 3 h with premedication allows outpatient treatment and is very well tolerated at the doses tested in this trial. Based on the demonstrated single-agent activity of taxol in MBC, phase I and phase II trials combining taxol with doxorubicin, cisplatin, cyclophosphamide, or 5-fluorouracil are under way.

Aminoglutethimide‐induced hyperkalaemia

International Journal of Clinical PracticeVolume 43, Issue 7 p. 263-264 Case Report Aminoglutethimide-induced hyperkalaemia J P Davies, Corresponding Author J P Davies Medical Student n/[email protected] Singleton Hospital, Sketty, SwanseaAddress correspondence to Mr J P Davies, 129 Arabella Street, Roath, Cardiff CF2 4SY.Search for more papers by this authorP Bentley MD, BCH, P Bentley MD, BCH House Physician Singleton Hospital, Sketty, SwanseaSearch for more papers by this authorR R Ghose FRCP, R R Ghose FRCP Consultant Physician Singleton Hospital, Sketty, SwanseaSearch for more papers by this author J P Davies, Corresponding Author J P Davies Medical Student n/[email protected] Singleton Hospital, Sketty, SwanseaAddress correspondence to Mr J P Davies, 129 Arabella Street, Roath, Cardiff CF2 4SY.Search for more papers by this authorP Bentley MD, BCH, P Bentley MD, BCH House Physician Singleton Hospital, Sketty, SwanseaSearch for more papers by this authorR R Ghose FRCP, R R Ghose FRCP Consultant Physician Singleton Hospital, Sketty, SwanseaSearch for more papers by this author First published: 01 July 1989 https://doi.org/10.1111/j.1742-1241.1989.tb08738.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1Huggins C, Bergenstal DM. Inhibition of human mammary and prostatic cancers by adrenalectomy. Cancer Res 1952; 12: 134- 139. 2Smith IE, Fitzharris BM, McKinna JA et al. Aminoglutethimide in treatment of metastatic breast carcinoma. Lancet 1978; ii: 646. Volume43, Issue7July 1989Pages 263-264 ReferencesRelatedInformation

Weekly doxorubicin in the treatment of metastatic breast carcinoma.

The introduction of aggressive combination chemotherapy has not been accompanied by any significant prolongation of survival in metastatic breast carcinoma. Hence, there is a need of less toxic but--in terms of palliation--effective chemotherapeutic regimens. This paper concerns 50 patients with progressive metastatic breast carcinoma who were treated with weekly bolus injections of doxorubicin (15-20 mg). All patients were followed until disease progression. A partial response with a mean duration of 6 months was achieved in 7 patients (14%). In addition, stabilization of disease was observed in 24 patients (48%) during 2-34 months. The toxicity was generally mild. It is concluded that weekly doxorubicin with fairly low doses is a moderately effective treatment in stage IV breast carcinoma. It is devoid of severe toxicity which makes it useful even in old and debilitated patients.