Donald C. Doll

Cardiotoxicity of Cancer Therapy

Because cancer is a leading cause of mortality in the United States, the number of therapeutic modalities available for the treatment of neoplastic processes has increased. This has resulted in a large number of patients being exposed to a wide variety of cancer therapy. Historically, it has been well recognized that antineoplastic agents may have adverse effects on multiple organs and normal tissues. The most commonly associated toxicities occur in tissues composed of rapidly dividing cells and may spontaneously reverse with minimal long-term toxicity. However, the myocardium consists of cells that have limited regenerative capability, which may render the heart susceptible to permanent or transient adverse effects from chemotherapeutic agents. Such toxicity encompasses a heterogeneous group of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. In some instances, the pathogenesis of these toxic effects has been elucidated, whereas in others the precise etiology remains unknown. We review herein the various syndromes of cardiac toxicity that are reported to be associated with antineoplastic agents and discuss their putative mechanisms and treatment.

Vascular toxicity associated with antineoplastic agents.

Vascular complications associated with antineoplastic agents are being reported with increasing frequency. Such vascular toxicity is clinically heterogeneous, ranging from asymptomatic arterial lesions to a fatal thrombotic microangiopathic syndrome. Mitomycin is most commonly implicated in the thrombotic microangiopathic syndrome, while bleomycin, either alone or in combination with a vinca alkaloid or cisplatin, appears to be an important cause of Raynauds phenomenon. Acute arterial ischemic events, ie, myocardial infarction and cerebrovascular accidents, occur most frequently after cisplatin-based combination chemotherapy. Putative mechanisms for such toxicity include drug-induced endovascular damage, perturbation of the clotting system, platelet activation, an abnormality of thromboxane-prostacyclin homeostasis, autonomic dysfunction, vasculitis, and stimulation of fibroblasts. More than one mechanism may be operative in an individual patient. Better documentation of the incidence and types of vascular toxicity and studies to help elucidate the pathogenesis and management of such toxicity are needed.

Acute Vascular Ischemic Events After Cisplatin-Based Combination Chemotherapy for Germ-Cell Tumors of the Testis

Four patients with germ-cell tumors of the testis had acute vascular ischemic events after treatment with cisplatin-based combination chemotherapy. Two patients had myocardial infarctions and two others cerebrovascular accidents. All patients were less than 30 years old and had no significant risk factors for atherosclerotic cardiovascular disease. Angiographic studies done in three patients showed no endovascular abnormalities. Raynauds phenomenon preceded acute myocardial infarction in one patient with angiographic evidence of ergonovine-induced coronary artery spasm. We suggest that major arterial occlusive events may occur as a result of treatment with cisplatin-based combination chemotherapy.

Mitomycin: ten years after approval for marketing.

Mitomycin was approved for marketing by the Food and Drug Administration in 1974 for use in gastric and pancreatic carcinomas when combined with other chemotherapeutic agents. Since then, mitomycin has been used extensively in combination chemotherapy for a variety of tumors, particularly in the past seven years. However, the contribution of this agent to the various drug regimens has not been adequately defined. Clear evidence of the drugs activity as a single agent has been seen in the intravesical treatment of superficial bladder carcinoma. Common toxicities include anorexia, vomiting, and myelosuppression. Less common, but potentially lethal, toxicities in the form of fibrosing alveolitis and microangiopathic hemolytic anemia with renal failure are being reported with increasing frequency. These potentially severe adverse effects, coupled with the still undefined role of mitomycin in systemic cancer chemotherapy, suggest that selection of this drug for other than investigational use should be made with care.

Bone marrow involvement in small cell lung cancer. Clinical significance and correlation with routine laboratory variables.

Of 129 patients with small cell lung cancer (SCLC) who underwent bone marrow examination for staging, 39 (30%) had bone marrow involvement. Only three of 129 patients (2.3%) had bone marrow involvement as the only site of metastatic disease. When patients with bone marrow metastasis were compared with patients whose bone marrow was normal, there were significant differences in serum levels of lactate dehydrogenase (LDH), glutamic oxalacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), alkaline phosphatase (AP), albumin, and sodium (Na). We found no clinically significant difference in survival between patients with extensive disease with or without bone marrow involvement. Serum Na, albumin, SGOT, and uric acid were important prognostic determinants of survival. Based on the results of this study, we do not recommend routine bone marrow examinations in the staging of SCLC.

Malignant ascites of unknown origin

To determine the clinical characteristics of patients presenting with malignant ascites, as well as means of evaluating the outcome of patients with the disease, a retrospective review was conducted of all cases of malignant peritoneal effusions diagnosed from 1978 to 1987 at a University Hospital and a Veterans Administration Hospital. Of 65 patients with malignant ascites (40 women; 25 men), the primary site was known in 51 cases (80%). Common sites in women were the ovaries, endometrium, and cervix; in men, common sites were the colon, rectum, and stomach. For five women and nine men the primary site was unknown. Median survival from diagnosis was 7.5 days (mean, 43 days; range, 1–256 days). Chest radiograph and abdominal computed tomography (CT) scan did not disclose the occult primary. An occult primary was detected while the patient was alive in only two cases and at autopsy in two other patients. Due to the poor prognosis for this disease, we do not recommend an aggressive approach to malignant ascites of unknown origin, except perhaps in women, in whom ovarian cancer should be suspected.

Neoplasia and the erythron.

Neoplasms may affect the erythroid system in a variety of ways. By far the most common abnormality associated with neoplastic disorders is anemia. It is important to recognize that there are multiple causes of anemia associated with neoplasms, because therapy of the anemia varies according to the causative mechanism. Less commonly, the paraneoplastic syndrome of erythrocytosis may occur in some patients with neoplasia. More subtle abnormalities of the erythrocytes associated with malignant disease include modification of the RBC membrane, changes in erythrocyte enzymes, and abnormalities in hemoglobin production. Clinical awareness of the multiple effects of neoplasms on the erythron will lead to better patient management and may also improve our understanding of erythropoiesis.

Vascular toxicity associated with chemotherapy and hormonotherapy

Vascular complications associated with chemotherapy and hormonotherapy are being reported with increasing frequency. Such vascular toxicity is clinically heterogenous, ranging from asymptomatic venous lesions to fatal hepatic venoocclusive disease of the liver. Putative mechanisms for such toxicity include drug-induced endothelial cell damage, perturbation of the clotting cascade, platelet activation and aggregation, alteration of thromboxane-prostacyclin homeostasis, and dysregulation of cytokines. Better documentation of the incidence and types of vascular toxicity and studies to help elucidate the pathogenesis and management of such toxicity are needed.

Treatment with low-dose oral etoposide in patients with myelodysplastic syndromes.

Forty-three patients with myelodysplastic syndromes (MDS) received treatment with oral etoposide 50 mg/day for 21 consecutive days every 4 weeks. Eighteen patients (42%) experienced hematological responses, including 12 of 17 (70%) patients with chronic myelomonocytic leukemia (CMML). Three of five CMML patients who failed treatment with hydroxyurea experienced major hematological responses with oral etoposide. Median response duration exceeded 9 months (range: 4-49 + months), and one patient remains in an unmaintained complete remission for 4 years. Toxicity included nausea/vomiting in five patients, fever (four patients), infection (three patients), mucositis (two patients), and anorexia (two patients). Two patients had grade 4 neutropenia with sepsis necessitating treatment withdrawal. We conclude that low-dose oral etoposide has remitting activity in MDS and is an effective treatment alternative for patients with CMML.

Lung cancer screening: from imaging to biomarker

Despite several decades of intensive effort to improve the imaging techniques for lung cancer diagnosis and treatment, primary lung cancer is still the number one cause of cancer death in the United States and worldwide. The major causes of this high mortality rate are distant metastasis evident at diagnosis and ineffective treatment for locally advanced disease. Indeed, approximately forty percent of newly diagnosed lung cancer patients have distant metastasis. Currently, the only potential curative therapy is surgical resection of early stage lung cancer. Therefore, early detection of lung cancer could potentially increase the chance of cure by surgery and underlines the importance of screening and detection of lung cancer. In the past fifty years, screening of lung cancer by chest X-Ray (CXR), sputum cytology, computed tomography (CT), fluorescence endoscopy and low-dose spiral CT (LDCT) has not improved survival except for the recent report in 2010 by the National Lung Screening Trial (NLST), which showed a 20 percent mortality reduction in high risk participants screened with LDCT compared to those screened with CXRs. Furthermore, serum biomarkers for detection of lung cancer using free circulating DNA and RNA, exosomal microRNA, circulating tumor cells and various lung cancer specific antigens have been studied extensively and novel screening methods are being developed with encouraging results. The history of lung cancer screening trials using CXR, sputum cytology and LDCT, as well as results of trials involving various serum biomarkers, are reviewed herein.