Showing papers in "Oncologist in 2000"

SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer.

Abstract: We describe a protocol for disclosing unfavorable information—“breaking bad news”—to cancer patients about their illness. Straightforward and practical, the protocol meets the requirements defined by published research on this topic. The protocol (SPIKES) consists of six steps. The goal is to enable the clinician to fulfill the four most important objectives of the interview disclosing bad news: gathering information from the patient, transmitting the medical information, providing support to the patient, and eliciting the patient’s collaboration in developing a strategy or treatment plan for the future. Oncologists, oncology trainees, and medical students who have been taught the protocol have reported increased confidence in their ability to disclose unfavorable medical information to patients. Directions for continuing assessment of the protocol are suggested. The Oncologist 2000;5:302-311

Impact of Cancer-Related Fatigue on the Lives of Patients: New Findings From the Fatigue Coalition

Abstract: Purpose. This survey was designed to confirm the prevalence and duration of fatigue in the cancer population and to assess its physical, mental, social, and economic impacts on the lives of patients and caregivers. Patients and Methods. A 25-minute telephone interview was completed with 379 cancer patients having a prior history of chemotherapy. Patients were recruited from a sample of 6,125 households in the United States identified as having a member with cancer. The median patient age was 62 years, and 79% of respondents were women. Patients reporting fatigue at least a few times a month were asked a series of questions to better describe their fatigue and its impact on quality of life. Results. Seventy-six percent of patients experienced fatigue at least a few days each month during their most recent chemotherapy; 30% experienced fatigue on a daily basis. Ninety-one percent of those who experienced fatigue reported that it prevented a “normal” life, and 88% indicated that fatigue caused an alteration in their daily routine. Fatigue made it more difficult to participate in social activities and perform typical cognitive tasks. Of the 177 patients who were employed, 75% changed their employment status as a result of fatigue. Furthermore, 65% of patients indicated that their fatigue resulted in their caregivers taking at least one day (mean, 4.5 days) off work in a typical month. Physicians were the health care professionals most commonly consulted (79%) to discuss fatigue. Bed rest/ relaxation was the most common treatment recommendation (37%); 40% of patients were not offered any recommendations. Conclusions. Cancer-related fatigue is common among cancer patients who have received chemotherapy and results in substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer. The Oncologist 2000;5:353-360

Management of Cancer in the Older Person: A Practical Approach

Abstract: The management of cancer in the older aged person is an increasingly common problem. The questions arising from this problem are: Is the patient going to die with cancer or of cancer? Is the patient able to tolerate the stress of antineoplastic therapy? Is the treatment producing more benefits than harm? This article explores a practical, albeit evolving, approach to these questions including a multidimensional assessment of the older person and simple pharmacologic interventions that may ameliorate the toxicity of antineoplastic agents. Age may be construed as a progressive loss of stress tolerance, due to decline in functional reserve of multiple organ systems, high prevalence of comorbid conditions, limited socioeconomic support, reduced cognition, and higher prevalence of depression. Aging is highly individualized: chronologic age may not reflect the functional reserve and life expectancy of an individual. A comprehensive geriatric assessment (CGA) best accounts for the diversities in the geriatric population. The advantages of the CGA include:Recognition of potentially treatable conditions such as depression or malnutrition, that may lessen the tolerance of cancer treatment and be reversed with proper intervention; Assessment of individual functional reserve; Gross estimate of individual life expectancy; and Adoption of a common language to classify older cancer patients. The CGA allows the practitioner to recognize at least three stages of aging:People who are functionally independent and without comorbidity, who are candidates for any form of standard cancer treatment, with the possible exception of bone marrow transplant. People who are frail (dependence in one or more activities of daily living, three or more comorbid conditions, one or more geriatric syndromes), who are a candidate only for palliative treatment; and People in between, who may benefit from some special pharmacological approach, such as reduction in the initial dose of chemotherapy with subsequent does escalations. The pharmacological changes of age include decreased renal excretion of drugs and increased susceptibility to myelosuppression, mucositis, cardiotoxicity and neurotoxicity. Based on these findings, the proposal was made that all persons aged 70 and older, treated with cytotoxic chemotherapy of dose intensity comparable to CHOP, receive prophylactic growth factor treatment, and that the hemoglobin of these patients be maintained >/=12 gm/dl.

VEGF Receptor Signaling in Tumor Angiogenesis

Abstract: The growth of human tumors and development of metastases depend on the de novo formation of blood vessels. The formation of new blood vessels is tightly regulated by specific growth factors that target receptor tyrosine kinases (RTKs). Vascular endothelial growth factor (VEGF) and the Flk-1/KDR RTK have been implicated as the key endothelial cell-specific factor signaling pathway required for pathological angiogenesis, including tumor neovascularization. Inhibition of the VEGF tyrosine kinase signaling pathway blocks new blood vessel formation in growing tumors, leading to stasis or regression of tumor growth. Advances in understanding the biology of angiogenesis have led to the development of several therapeutic modalities for the inhibition of the VEGF tyrosine kinase signaling pathway. A number of these modalities are under investigation in clinical studies to evaluate their potential to treat human cancers.

Intracranial Germ Cell Tumors

Abstract: Intracranial germ cell tumors are a heterogeneous group of lesions which occur in children and adults. Within the classification of intracranial germ cell tumors, there are a variety of different tumor types which carry different prognoses. The diagnosis of an intracranial germ cell tumor usually requires histological information, but a subgroup of tumors will secrete specific tumor markers, including α-fetoprotein and β-human chorionic gonadotropin, which may obviate the need for surgical intervention. The management of intracranial germ cell tumors in both children and adults remains unsettled. Germinomas have a good prognosis, as over 90% of patients can be effectively treated with radiation therapy. The dose and volume of radiation therapy needed for disease control is not well established, and controversy exists concerning the need for whole brain or craniospinal radiation therapy for localized tumors. Germinomas are also chemosensitive and recent reports suggest that the dose and volume of radiation therapy required for disease control can be lessened with the addition of adjuvant chemotherapy. The outcome for patients with nongerminomatous germ cell tumors is less favorable. Radiation therapy alone will result in disease control in 40%-60% of patients. The addition of chemotherapy to radiation therapy may improve the rate of survival. The Oncologist 2000;5:312-320

Prognostic Value of Vascular Endothelial Growth Factor in Breast Cancer

Abstract: Angiogenesis, the process leading to the formation of new blood vessels from a preexisting vascular network, is necessary for tumor growth, invasion, and metastasis. Data from experimental and clinical studies indicate that breast carcinoma is an angiogenesis-dependent tumor. Most retrospective studies evaluating the prognostic value of determination of intratumoral microvessel density (IMD) at the vascular "hot spot" (a surrogate marker of angiogenesis) found that IMD is a significant and independent prognostic indicator in patients with both node-negative and node-positive breast cancers. More recently, the expression of certain endothelial growth factors has been tested. Among these, vascular endothelial growth factor (VEGF), the most potent endothelial cell mitogen and also a regulator of vascular permeability, is emerging as a powerful new prognostic tool. Eight of the nine published retrospective studies reported that VEGF is significantly associated with relapse-free survival, overall survival, or both. Patients with early stage breast cancer who have tumors with elevated levels of VEGF have a higher likelihood of recurrence or death than patients with low-angiogenic tumors, even if treated with conventional adjuvant therapy. High levels of VEGF can differentiate the subgroups of patients with breast cancer with poor prognosis who benefit minimally from conventional adjuvant therapy but who may benefit from validated anti-VEGF treatments.

Second-line treatment of ovarian cancer.

Abstract: Patients with epithelial ovarian cancer are often diagnosed with advanced-stage disease. Although clinical complete remissions are obtained in the majority of patients through a combination of cytoreductive surgery and chemotherapy, relapse is common. A number of agents with diverse biologic mechanisms have been identified with activity in the setting of recurrent disease. Strategies for management of patients with recurrent disease, including classification, treatment goals, and therapeutic options will be reviewed.

Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma.

Abstract: Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier Concentrations in the central nervous system are approximately 30% of plasma concentrations Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite These pharmacologic properties make it an ideal agent for treating central nervous system malignancies In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazinetreated patients Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients TMZ may become an important part of treatment regimens for advanced metastatic melanoma The Oncologist 2000;5:144-151

Malignancy in Neurofibromatosis Type 1

Abstract: Neurofibromatosis type 1 (NF1) represents a major risk factor for development of malignancy, particularly malignant peripheral nerve sheath tumors (MPNST), optic gliomas, other gliomas, and leukemias. The oncologist will see NF1 patients referred for treatment of malignancy, and should be alert to the possibility of undiagnosed NF1 among patients with cancer. Brain tumors tend to have a more indolent course in NF1 than in the general population, and hence are best managed conservatively. MPNST, in contrast, do not respond to standard chemotherapy or radiation therapy. The most effective treatment of MPNST appears to be early diagnosis and surgery, but early diagnosis is hampered by frequent occurrence within preexisting large tumors, making new growth or change difficult to detect. New insights into pathogenesis now offer hope of development of specific methods of treatment with reduced toxicity and more precise molecular targeting. There is an urgent need, however, to develop methods to measure tumor growth and monitor outcomes, develop preclinical drug screening systems, and further explore the pathogenesis of the disorder to determine whether mechanisms other than Ras regulation may be important in pathogenesis.

Diet and Cancer

Abstract: The large differences in cancer rates among countries, striking changes in these rates among migrating populations, and rapid changes over time within countries indicate that some aspect of lifestyle or environment is largely responsible for the common cancers in Western countries. Dietary fat has been hypothesized to be the key factor because national consumption is correlated with the international differences. However, detailed analyses in large prospective studies have not supported an important role of dietary fat. Instead, positive energy balance, reflected in early age at menarche and weight gain as an adult, is an important determinant of breast and colon cancers, consistent with numerous studies in animals. As a contributor to positive energy balance, and possibly by other mechanisms, physical inactivity has also been shown to be a risk factor for these diseases and in part accounts for the international differences. Although the percentage of calories from fat in the diet does not appear related to risk of colon cancer, greater risks have been seen with higher consumption of red meat, suggesting that factors other than fat per se are important. In many case-control studies, a high consumption of fruits and vegetables has been associated with reduced risks of numerous cancers, but recent prospective studies suggest these associations may have been overstated. Among the factors in fruits and vegetables that have been examined in relation to cancer risk, present data most strongly support a benefit of higher folic acid consumption in reducing risks of colon and breast cancers. These findings have been bolstered by an association between incidence of colon cancer and a polymorphism in the gene for methylenetetrahydrofolate reductase, an enzyme involved in folic acid metabolism. The benefits of folic acid appear strongest among persons who regularly consume alcohol, which itself is associated with risk of these cancers. Numerous other aspects of diet are hypothesized to influence the risks of cancers in Western countries, but for the moment the evidence is unclear.

Anti-cancer drug discovery and development in Brazil: targeted plant collection as a rational strategy to acquire candidate anti-cancer compounds

Abstract: Throughout medical history, plant products have been shown to be valuable sources of novel anti-cancer drugs. Examples are the VINCA: alkaloids, the taxanes, and the camptothecins, derived from the Madagscan periwinkle plant Catharantus roseus, the Pacific yew Taxus brevifolia, and the Chinese tree Camptotheca acuminata, respectively. For this reason, the South-American Office for Anti-Cancer Drug Development has implemented a large-scale project of acquisition and testing of compounds isolated from South American medicinal plants. The species are selected on the basis of a potentially useful phytochemical composition by consulting ethnopharmacological, chemosystemic, and ecological information. The collected samples are dried and first extracted with an organic solvent, then with distilled water. These crude extracts are evaluated at a concentration of 50 microg/ml for antiproliferative activity against one cell line. Extracts that significantly inhibit the growth of the cells (>/=50%) at relatively low concentrations (

The Initial Results in Muscle-Invading Bladder Cancer of RTOG 95-06: Phase I/II Trial of Transurethral Surgery Plus Radiation Therapy with Concurrent Cisplatin and 5-Fluorouracil Followed by Selective Bladder Preservation or Cystectomy Depending on the Initial Response

Abstract: Purpose. To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer. Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m 2 i.v. and 5-fluorouracil (5-FU) 400 mg/m 2

Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications.

Abstract: Tumor growth and metastasis are dependent on angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in the angiogenesis of numerous solid malignancies including colon cancer. Evidence from preclinical and clinical studies indicates VEGF is the predominant angiogenic factor in human colon cancer and is associated with formation of metastases and poor prognosis. Based on these results, it was hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastasis. To test this hypothesis, the authors evaluated the ability of a small molecule inhibitor specific for the tyrosine kinase VEGF receptor Flk-1/KDR (SU5416) or multiple tyrosine kinase receptors (SU6668) to inhibit tumor angiogenesis and metastasis in a model of colon cancer hepatic metastasis. Both SU5416 and SU6668 inhibited metastases, microvessel formation, and cell proliferation while increasing tumor cell and endothelial cell apoptosis. These results showed that targeting the VEGF receptor/ligand system is a rational approach to inhibiting tumor growth and prolonging survival.

The Impact of Fatigue on Patients with Cancer: Overview of FATIGUE 1 and 2.

Abstract: Fatigue is a complex, multifactorial disorder with physical, mental, and psychological dimensions that has been associated with diminished quality of life (QOL) in patients with cancer. The prevalence and severity of fatigue, however, has only recently been studied systematically. Two national surveys commissioned by The Fatigue Coalition, a multidisciplinary group of medical practitioners, researchers, and patient advocates, whose mission is to study the importance of fatigue for patients with cancer and their caregivers, have assessed the prevalence, severity, and QOL consequences of fatigue in patients with cancer. The most recent survey, initiated in 1998, sought to confirm and extend observations on the prevalence and impact of fatigue in patients with cancer as part of an initiative to develop guidelines for the differential diagnosis and treatment of fatigue. The FATIGUE 2 study probed the emotional, social, physical, and economic impact of fatigue on patients with cancer and their caregivers. Patient perceptions of the professional response to cancer-related fatigue were also assessed. The key findings of these surveys are reviewed.

Childhood Cancers: Hepatoblastoma

Abstract: Hepatoblastoma is the most common primary liver tumor in children, accounting for just over 1% of pediatric cancers. The etiology is unknown, but it has been associated with Beckwith-Weidemann syndrome, familial adenomatosis polypi, and low birth weight. The primary treatment is surgical resection, however, chemotherapy plays an important role by increasing the number of tumors that are resectable. The prognosis for patients with resectable tumors is fairly good, however, the outcome for those with nonresectable or recurrent disease is poor.

Management of Bone Metastases

Abstract: Metastatic bone disease develops as a result of the many interactions between tumor cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signaling mechanisms involved in cancer-induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and its use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.

Translational Research: the role of VEGF in tumor angiogenesis

Abstract: Angiogenesis is defined as the formation of new bloodvessels from preexisting vasculature. Preclinical studieshave shown the major role of angiogenesis in tumor growthand metastasis formation, and therefore, inhibiting tumorangiogenesis may be a promising therapeutic modality [1,2]. Paracrine stimuli derived from tumor cells are the mainpromoters of angiogenesis. Once activated by these stimuli,endothelial cells begin to proliferate and migrate, subse-quently resulting in new tube formation and blood flow.This complex process involves numerous biological activi-ties. Vascular endothelial growth factor (VEGF) is one ofthe most potent and specific angiogenic factors of tumor-induced angiogenesis [3, 4]. Originally identified for itsability to induce vascular permeability and stimulateendothelial cell growth, VEGF is now recognized as a keyfactor required for growth of tumors [5]. The clinicalimportance of VEGF for tumor growth is supported by thefact that most tumors produce VEGF and that inhibition ofVEGF-induced angiogenesis significantly inhibits tumorgrowth in vivo [6-8]. In addition to decreasing the numberof vessels, antiangiogenic drugs may also decrease theinterstitial tumor pressure. This reduction in interstitialpressure may result from the ability of these agents to blockVEGF-induced permeability. VEGF expression has beenshown to correlate with microvessel density in a number ofsolid malignancies including carcinomas of the breast, andtissue concentrations of this growth factor appear to be pre-dictive of mortality associated with breast cancer [9, 10].Similar results have been obtained in studies of solid malig-nancies in various organs including the lung, prostate, andcolon [11-13]. These preclinical and clinical findings sup-port VEGF as a promising target for anticancer therapy.In patients with cancer, antiangiogenic agents, usedalone or combined with chemotherapy, may inhibit tumorgrowth, reduce metastasis formation, prolong survival, andimprove quality of life. Clinicians need to make a majorshift in their thinking if the beneficial effects of these novelagents are to be recognized. Appropriate schedules of suchcombinations need to be developed so that the mechanismof action (i.e., antiangiogenic or cytotoxic) is fully consid-ered. The concern that concomitant administration ofantiangiogenic drugs and chemotherapy will impair cyto-toxic drug delivery is precluded by evidence from animalstudies. Teicher et al.[14-16] clearly demonstrated thatcombination therapy with angiogenesis inhibitors has syn-ergistic antitumor effects in the Lewis lung carcinomaxenograft model. In these studies, addition of the antiangio-genic agents to the cytotoxic therapies reduced not only thenumber of lung metastases formed from the primary tumorbut also the number of large metastases. These results pro-vide evidence that antiangiogenic therapies can potentiatethe efficacy of standard anticancer therapies.This special issue of The Oncologistpresents a diversityof preclinical and clinical studies about anti-VEGF strategiesfor cancer treatment. McMahongives an excellent overviewof the role of VEGF tyrosine kinase receptors in tumor angio-genesis and the strategies being developed to inhibit this sig-naling pathway. Subsequently, Ellispresents preclinical datathat show the role of VEGF in the growth and metastasis ofcolon cancer. He also presents evidence that antiangiogenictherapy with VEGF receptor inhibitors SU5416 and SU6668inhibits the growth of liver metastases. The study by Vajkoczyand coworkers strongly supports the idea that regional differ-ences in Flk-1 activity in vivo may significantly affect tumor

Antiangiogenic Strategies and Agents in Clinical Trials

Abstract: The understanding that the growth of tumors depends on the acquisition of a blood supply has led to the development of new therapies for cancer and other angiogenic diseases based on inhibition of neovascularization. This review examines the role of angiogenesis in cancer progression and describes various strategies for interfering with this process. The developmental status of angiogenesis inhibitors in human clinical trials is presented, including their proposed mechanisms of action. Standard chemotherapeutic agents and angiogenesis inhibitors are compared, noting that different end points might need to be considered in clinical trials and that drug resistance may be less of a problem with antiangiogenic therapy than with conventional chemotherapy regimens. The suggestion is made that cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer.

Development of GnRH antagonists for prostate cancer: new approaches to treatment.

Abstract: Prostate cancer has become the most common cancer among American men and is second only to lung cancer as a cause of male cancer-related death. Several treatment options exist for different stages of prostate cancer including observation, prostatectomy, radiation therapy, chemotherapy, and hormone therapy. Hormone therapy has evolved from the use of estrogens to gonadotropin-releasing hormone (GnRH) agonists and recently, investigational GnRH antagonists. GnRH receptor agonists such as leuprolide, bruserelin and goserelin have been used for the treatment of prostate cancer. These agonists eventually cause the inhibition of lutenizing hormone production, which in turn causes a suppression of testosterone and dihydrotestosterone, on which continued growth of prostate cancer cells depend. Several comparative studies of leuprorelin administered as daily injections or monthly depot injections have been reported. Disease progression was prevented in more than 72% of men administered daily leuprorelin, and in 82% to 89% of those receiving monthly depots. Another synthetic GnRH analog, goserelin, has been studied in a similar population of men with daily injections producing partial responses in 60% to 80% of men with previously untreated prostate cancer. Abarelix, a peptide antagonist of GnRH receptor, is also being studied for the treatment of prostate cancer. The discovery and development of GnRH antagonists may provide an important advance for patients with prostate cancer. Clearly the studies described herein, as well as many others, outline an exciting era of research to define the optimal use of hormonal therapy in prostate cancer.

The Retinoids and Cancer Prevention Mechanisms

Abstract: Carcinogenesis is a multistep process that converts normal cells into malignant cells. Once transformed, malignant cells acquire the ability to invade and metastasize, leading to clinically evident disease. During this continuum from normal to metastatic cells, carcinogenic steps can be arrested or reversed through pharmacological treatments, known as cancer chemoprevention. Chemoprevention strategies represent therapeutic interventions at early stages of carcinogenesis, before the onset of invasive cancer. Effective chemoprevention should reduce or avoid the clinical consequences of overt malignancies by treating early neoplastic lesions before development of clinically apparent signs or symptoms. Preclinical, clinical, and epidemiological data provide considerable support for cancer chemoprevention as an attractive therapeutic strategy. This clinical approach was validated in the recent tamoxifen randomized trial, demonstrating that a selective estrogen receptor modulator reduces the risk of breast cancer in women at high risk for this malignancy. Derivatives of vitamin A, the retinoids, have reported activity in treating specific premalignant lesions and reducing incidence of second primary tumors in patients with prior head and neck, lung or liver cancers. Whether the retinoids will prevent primary cancers at these sites is not yet known. Notably, a carotenoid (beta-carotene) was shown as inactive in primary prevention of lung cancers in high-risk individuals. This underscores the need for relevant in vitro models to identify pathways signaling chemopreventive effects. These models should assess the activity of candidate chemoprevention agents before the conduct of large and costly prevention trials. An improved understanding of cancer prevention mechanisms should aid in the discovery of new therapeutic targets and chemoprevention agents. Ideally, these agents should have tolerable clinical toxicities suitable for chronic administration to individuals at high risk for developing primary or second cancers. This article reviews what is now known from clinical and preclinical studies about the retinoids as cancer prevention agents.

Raloxifene: A Selective Estrogen Receptor Modulator (SERM) with Multiple Target System Effects

Abstract: Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. These compounds were initially called "antiestrogens," but it was subsequently recognized that this inadequately described their spectrum of activities. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis. This review will explore the preclinical and clinical pharmacology of raloxifene, and compare it to other SERMs currently available for clinical use.

Burnout: Caring for the Caregivers

Abstract: The Oncologist 2000;5:425-434 www.TheOncologist.com Correspondence: Richard T. Penson, MRCP, Instructor in Medicine, Hematology-Oncology, Cox 809, 100 Blossom Street, Boston, Massachusetts 02114-2617, USA. Telephone: 617-726-5867; Fax: 617-724-3166; e-mail: rpenson@partners.org Received August 28, 2000; accepted for publication August 28, 2000. ©AlphaMed Press 1083-7159/2000/$5.00/0 The Oncologist Schwartz Center Rounds

MMP-1 is a prognostic marker for hematogenous metastasis of colorectal cancer.

Abstract: Background. Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be an essential step in the complicated process of hematogenous metastasis. MMP-1 is a member of collagenases, a family of MMPs that degrades collagens type I, II, and III, main components of the interstitial stroma. The purpose of this study was to investigate the expression of MMP-1 in colorectal cancer and its correlation with hematogenous metastasis. Patients and Methods. We examined 133 cases of colorectal cancer (Dukes A: 72; Dukes B: 26; Dukes C: 23; Dukes D: 12). Sections were cut from formalin-fixed, paraffin-embedded samples containing the deepest site of cancer invasion and stained immunohistochemically with a monoclonal antibody to MMP-1. According to the area of the tumor that was stained, patients were divided into high- and low-MMP-1 expression groups. Results. MMP-1 expression was observed in the cytoplasm of cancer cells, some stromal cells, and a few normal epithelial cells of colonic mucosa. High MMP-1 expression was found in 47 (35.3%) cases and low in 86 (64.7%). Hematogenous metastasis was identified in 14 (29.8%) of high-MMP-1 groups and 12 (13.9%) of low-MMP-1 groups. MMP-1 expression significantly correlated with hematogenous metastasis of colorectal cancer, but no correlation was found between MMP-1 expression and the other clinicopathological features investigated. Conclusions. MMP-1 expression may be a novel marker for hematogenous metastasis of colorectal cancer, and its inhibition may be a strategy for prevention of metastasis. The Oncologist 2000;5:108-114

Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation

Abstract: Primary Purpose Formation of ascites and pleural effusion (PE) is a common problem for patients with advanced-stage cancer These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue Preclinical models have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the accumulation of malignant PE or ascites This study investigated whether blockade of VEGF activity would reduce biological activity of PE and ascites on endothelial cells of cancer patients Patients and Methods The activity of VEGF in PE and ascites of 58 patients (39 with PE and 19 with ascites) was measured An endothelial cell proliferation assay with human umbilical vein endothelial cells was used to determine the biological activity of ascites and PE Results VEGF concentrations ranged from 67-6,245 pg/ml A significantly higher concentration of VEGF was detected in the ascites and PE of patients with cancer (median, 1,290 pg/ml) than in patients with nonmalignant disease (median, 250 pg/ml; p = 002) Of the 58 PE and ascites samples, 41 were biologically active, based on a two- to fourfold stimulation of endothelial cell proliferation in 72 hours VEGF concentrations were significantly higher in the biologically active samples compared with the 17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 002) Coincubation of the samples with either a neutralizing polyclonal antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and 100%, respectively The inhibition caused by the antibody and that caused by SU5416 correlated significantly (r = 08, p < 0001) Conclusion We conclude that malignant ascites and PE contain high levels of biologically active VEGF This study strongly supports the hypothesis that blockade of VEGF, such as that afforded by SU5416, may benefit cancer patients with recurrent ascites or PE formation The Oncologist 2000;5(suppl 1):45-50

New drugs and novel targets for treatment of invasive fungal infections in patients with cancer.

Abstract: Invasive fungal infections have emerged as important causes of morbidity and mortality in profoundly immunocompromised patients with cancer. Current treatment strategies for these infections are limited by antifungal resistance, toxicity, drug interactions, and expense. In order to overcome these limitations, new antifungal compounds are being developed, which may improve our therapeutic armamentarium for prevention and treatment of invasive mycoses in high-risk patitnts with neoplastic diseases. The Oncologist 2000;5:120-135

Sedation for Intractable Distress of a Dying Patient: Acute Palliative Care and the Principle of Double Effect

Abstract: Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. The case presented is of a young man dying of recurrent epithelioid hemangioendothelioma, distressed with stridor and severe pain, whose poorly controlled symptoms were successfully treated with an infusion of propofol, titrated to provide effective comfort in the last few hours of the patient's life. The tenet of double effect, which allows aggressive treatment of suffering in spite of foreseeable but unintended consequences, is reviewed. The patient's parents were invited and contributed to the Rounds, providing compelling testimony to the power of the presence of clinicians at the time of death and the importance of open communication about difficult ethical issues.

Monoclonal Antibody Therapy in Lymphoid Malignancies

Abstract: The concept of targeted therapy for patients with advanced cancer has intrigued researchers for many years. The lymphoid malignancies are particularly good candidates for this therapeutic approach, due to the identification of multiple lymphocyte-specific antigens. The recent introduction of rituximab marks the beginning of a new era in the treatment of lymphoid malignancies. Rituximab is one of the most active single agents for patients with refractory indolent lymphoma, producing response rates of approximately 50%, with low toxicity and a brief duration of treatment. Additional uses of rituximab are being evaluated in ongoing clinical trials, and are briefly reviewed. As a first-line agent, responses of approximately 70% are produced in patients with indolent lymphoma, with minimal toxicity. A substantial percentage of patients can be successfully retreated with rituximab, with second remission durations longer than the first remission (14-16 months versus 12 months). Multiple combination regimens using rituximab plus chemotherapy are also being evaluated. Although the role of these combined approaches is incompletely defined, high complete response rates can be obtained, with a higher rate of molecular complete remission (i.e., eradication of detectable bcl-2 rearrangements) than has been observed in patients receiving chemotherapy alone. Rituximab is also being evaluated in other CD20(+) lymphoid malignancies including large-cell lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Within the next 12 months, several additional monoclonal antibodies will be available for the treatment of lymphoid malignancies. These include the radioimmunoconjugates tositumomab (Bexxar) and ibritumomab (Zevalin), as well as Campath-1H (anti-CD52) monoclonal antibody. Early clinical data with each of these agents are also briefly reviewed.

Waldenström's macroglobulinemia.

Abstract: Waldenstrom's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma. It has an overall incidence of 2.5/million/year. The median age at diagnosis is 63 years. The clinical manifestations are hepatomegaly (20%), splenomegaly (15%), and lymphadenopathy (15%). The most common symptom is fatigue related to a normochromic, normocytic anemia, and the median hemoglobin value at diagnosis is 10 gm/dl. All patients with Waldenstrom's macroglobulinemia have a circulating tumor marker, the monoclonal IgM protein. Occasionally high levels of the IgM monoclonal protein can produce a hyperviscosity syndrome manifested by oronasal bleeding. Occasionally retinal hemorrhage or serious neurologic complications, such as somnolence or coma, may occur. The most important prognostic factors are hemoglobin, age, weight loss, and a cryoglobulin. Therapy has included alkylating agents, particularly chlorambucil, purine nucleoside analogs such as fludarabine or cladribine, and most recently the use of rituximab. The median survival of symptomatic patients is 65 months. Patients without symptoms should not be treated.

Molecular Abnormalities in Chronic Myeloid Leukemia: Deregulation of Cell Growth and Apoptosis

Abstract: Chronic myeloid leukemia (CML) is a disease of the hematopoietic system, characterized by the presence of the Bcr-Abl oncoprotein. The main characteristics of this disease include adhesion independence, growth factor independence, and resistance to apoptosis. Loss or mutation of the tumor suppressor gene, p53, is one of the most frequent secondary mutations in CML blast crisis. The transition between chronic phase and blast crisis is associated with increased resistance to apoptosis correlating with poor prognosis. This review focuses on the involvement of these two oncoproteins in the development and progression of the apoptotic-resistant phenotype in CML.

Impact of Anemia in Patients With Head and Neck Cancer.

Abstract: Head and neck squamous cell carcinoma, which is comprised of a heterogeneous group of tumors arising from the epithelial lining of the oral cavity, pharynx, and larynx, is a locoregional disease. Tumor hypoxia and anemia are known to adversely effect the efficacy of radiation therapy, a local treatment modality. Therefore, head and neck cancers represent an ideal model for assessing the impact of anemia following treatment with radiation therapy. Various treatment strategies aimed at increasing tumor oxygenation in head and neck cancer patients (including hyperbaric oxygen and hypoxic cell radiosensitizers) have been studied. These studies have been fueled by evidence that hypoxia adversely effects the radiosensitivity of cells. Although the exact mechanism of action of the oxygen effect is not known, in vitro studies with conventional photon radiation therapy under normoxic conditions have shown an effectiveness of 2.5-3.0 times greater than that achieved under anoxic conditions. Recent studies, including large retrospective analyses, have demonstrated the dramatic adverse impact of anemia upon locoregional tumor control and survival. These studies, which have revealed hemoglobin levels as a powerful prognostic factor, provide compelling evidence for the value of reversing anemia and hence tumor hypoxia in head and neck cancer patients.