Background The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Methods We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). Results The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 ...

Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response ...

Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease

Potential risk factors responsible for development of doxorubicin-induced congestive heart failure were examined through retrospective analysis of 4018 patient records. The overall incidence of drug-induced congestive heart failure was 2.2% (88 cases). The probability of incurring doxorubicin-induced congestive heart failure was related to the total dose of doxorubicin administered. There was a continuum of increasing risk as the cumulative amount of administered drug increased. A weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule. An increase in drug-related congestive heart failure was also seen with advancing patient age. Performance status, sex, race, and tumor type were not risk factors. These data will enable clinicians to better estimate the risk/benefit ratio in individual patients receiving prolonged administration of doxorubicin. They also provide a basis for the investigation of less cardiotoxic anthracycline analogues or for designing measures to prevent doxorubicin-induced cardiomyopathy.

Risk factors for doxorubicin-induced congestive heart failure.

2-D
: two-dimensional
3-D
: three-dimensional
5-FU
: 5-fluorouracil
ACE
: angiotensin-converting enzyme
ARB
: angiotensin II receptor blocker
ASE
: American Society of Echocardiography
BNP
: B-type natriuretic peptide
CABG
: coronary artery bypass graft
CAD
: coronary artery

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2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

Cis-diamminedichloroplatinum (II) (DDP) leads the series of platinum coordination complexes, a new class of cytotoxic agents. The antitumor and toxic effects of this drug are discussed. It has displayed encouraging results in testicular tumors. The drug's therapeutic effectiveness has also been recognized in a variety of other solid tumors, particularly ovarian, bladder, and head and neck malignancies. Gastrointestinal, renal, audiologic, and relatively minor hematologic toxicities may be encountered, but promising methods have been developed to increase the therapeutic index of DDP.

Cis-diamminedichloroplatinum (II): A New Anticancer Drug

Daunomycin-induced cardiotoxicity in children and adults: A review of 110 cases

Administration of cis-dichlorodiammineplatinum(II) may be associated with a number of serious side effects, including nephrotoxicity, gastroeintestinal side effects (nausea, vomiting, and diarrhea), myelosuppression, and occasional transient elevations in liver function tests. In addition, ototoxicity (tinnitus and hearing loss), anaphylactic reactions, peripheral neuropathies, and hypomagnesemia with resulting tetany may also be encountered. The toxic potential of this new agent necessitates careful clinical monitoring during treatment.

Toxic effects of cis-dichlorodiammineplatinum(II) in man.

From the standpoint of chemotherapy, the first progress in the treatment of Hodgkin's disease was the identification of the activity of nitrogen mustard in the 1940's. The initial antitumor effect of the drug created a great excitement. However, when all patients later relapsed, there was subsequent dejection and skepticism about the utility of drug therapy. Fortunately, in the 1950's and 1960's, the development of other effective agents (vinca alkaloids, corticosteroids, and methylhydrazines) in conjunction with the elucidation of the principles of combination chemotherapy led to a marked increase in the antitumor response rate of patients with Hodgkin's disease. The value of many of these drug combinations remains under study. Nonetheless, approximately 75% of all patients with advanced Hodgkin's disease treated today with combination chemotherapy can achieve a complete remission. In addition, over half of these remain disease-free long enough to be considered cured. The development of effective treatment, both local (radiotherapy) and systemic (MOPP chemotherapy), has given the clinical investigator the tools to complete, in the 1970's, the therapeutic experiments necessary to refine both the interrelationship between the treatments and their impact upon the natural history of Hodgkin's disease.

Marcel Rozencweig

Papers

Risk factors for doxorubicin-induced congestive heart failure.

Cis-diamminedichloroplatinum (II): A New Anticancer Drug

Daunomycin-induced cardiotoxicity in children and adults: A review of 110 cases

Toxic effects of cis-dichlorodiammineplatinum(II) in man.

The chemotherapy of Hodgkin's disease: past experiences and future directions.