bluuebunny/crossref_metadata_2025 huggingface dataset:
MMP-1 is a Prognostic Marker for Hematogenous Metastasis of Colorectal Cancer
Authors: Sunami Eiji , Tsuno Nelson , Osada Takuya , Saito Shinsuke , Kitayama Joji , Tomozawa Shigeru , Tsuruo Takashi , Shibata Yoichi , Muto Tetsuichiro , Nagawa Hirokazu
Published: August 2004

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.
Non-Small Cell Lung Cancer: A Study of Long-Term Survival after Vinorelbine Monotherapy
Authors: Julien S. , Jacoulet P. , Dubiez A. , Westeel V. , Depierre A.
Published: August 2004

This study reports the results of 120 patients with inoperable non-small cell lung cancer treated with Navelbine at a dose of 25-30 mg/m2/week in a single-drug chemotherapy regimen. Surgery was contraindicated due to staging or to concomitant morbidity. Twenty patients achieved survival greater than or equal to 18 months, and one patient obtained exceptional survival of more than 120 months. The mean dose intensity of Navelbine in long-term survivors was 21.61 mg/m2/week. Objective response to Navelbine was found by multivariate analysis to be a prognostic factor for survival beyond 18 months. Weight loss of more than 5 kg of corporal weight was an unfavorable prognostic factor in patients with metastatic disease.
New Drugs and Novel Targets for Treatment of Invasive Fungal Infections in Patients with Cancer
Authors: Chiou Christine C. , Groll Andreas H. , Walsh Thomas J.
Published: August 2004

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.
Temozolomide, a Novel Alkylating Agent with Activity in the Central Nervous System, May Improve the Treatment of Advanced Metastatic Melanoma
Authors: Agarwala Sanjiv S. , Kirkwood John M.
Published: August 2004

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 dacarbazine-treated 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.
Communicating Genetic Risk: Pros, Cons, and Counsel
Authors: Penson Richard T. , Seiden Michael V. , Shannon Kristen M. , Lubratovich Marcie L. , Roche Maria , Chabner Bruce A. , Lynch Thomas J.
Published: August 2004

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 non-profit 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.

This case is of a woman with a personal, and a strong family history of breast cancer, who considered genetic testing for mutations in the BRCA1 and BRCA2 genes. The details of the case have been altered to protect the patient's anonymity. The patient was very anxious and there was disagreement between her healthcare providers about the potential benefits of genetic testing. The discussion of the case focused on several controversial issues, particularly the ownership of genetic information, and who is responsible for disseminating information to the family members at risk. The difficulties in communicating risk, providing emotional support and coping with the continuing uncertainties about screening and intervention are reviewed with an overview of the molecular biology, inheritance, and epidemiology of the BRCA1 and BRCA2 genes.
Genetic Immunotherapy for Cancer
Authors: Ribas Antoni , Butterfield Lisa H. , Economou James S.
Published: August 2004

Genetic immunization refers to treatment strategies where gene transfer methods are used to generate immune responses against cancer. Our growing knowledge of the mechanisms regulating the initiation and maintenance of cytotoxic immune responses has provided the rationale for the design of several genetic immunization strategies. Tumor cells have been gene-modified to express immune stimulatory genes and are then administered as tumor vaccines, in an attempt to overcome tumor cell ignorance by the immune system. With the description of well-characterized tumor antigens, multiple strategies have been proposed mainly aimed at optimal tumor antigen presentation by antigen-presenting cells (APC). Among APC, the dendritic cells have been recognized as the most powerful cells in this class, and have become the target for introducing tumor antigen genes to initiate antitumor immune responses. The detailed knowledge of how the immune system can be activated to specifically recognize tumor antigens, and the mechanisms involved in the control of this immune response, provide the basis for modern genetic immunization strategies for cancer treatment.
Anti-Cancer Drug Discovery and Development in Brazil: Targeted Plant Collection as a Rational Strategy to Acquire Candidate Anti-Cancer Compounds
Authors: Mans Dennis R.A. , Rocha Adriana B. , Schwartsmann Gilberto
Published: August 2004

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 μg/ml for antiproliferative activity against one cell line. Extracts that significantly inhibit the growth of the cells (≥50%) at relatively low concentrations (≤50 μg/ml) are submitted to the more comprehensive disease-oriented screen of the U.S. National Cancer Institute. In parallel, these samples are further purified by bioassay-guided purification, involving repeated fractionation by diverse chromatography methods. If the active substance is expected to represent a novel structure, it is identified by appropriate chemical techniques, mechanistic studies are performed with a wide diversity of tumor models and laboratory techniques, and efforts are undertaken for the synthesis of potentially more useful analogs.
Role of Taxoids in Head and Neck Cancer
Authors: Schrijvers D. , Vermorken J.B.
Published: August 2004

Docetaxel and paclitaxel represent a new class of cytotoxic agents having both a specific chemical structure and mechanism of action. They act to promote tubulin polymerization and the formation of stable microtubules. The microtubules produced in the presence of taxoids are resistant to disassembly by physiologic stimuli, and cells exposed to these agents exhibit an accumulation of disorganized microtubule arrays. This affects the normal mitotic process and eventually results in cell death.

Both drugs are active as single agents in patients with head and neck cancer with response rates ranging from 20% to 40%. They may be combined with other cytotoxic agents, radiotherapy, or both. A review is given of the presently available data.
High-Dose Rate Brachytherapy of Bronchial Cancer: Treatment Optimization Using Three Schemes of Therapy
Authors: Muto Paolo , Ravo Vincenzo , Panelli Giancarlo , Liguori Gaetano , Fraioli Gaetano
Published: August 2004

Purpose. Our aim is to demonstrate that a fractionated high-dose rate endobronchial brachytherapy (HDRBT) treatment is tolerable for patients with advanced (IIIA-IIIB) non-small cell lung cancer and gives an improvement of symptoms.

Patients and Methods. From January 1992 to July 1997, we treated 320 patients with external beam radiotherapy (EBRT) and concomitant HDRBT with Ir192. Eighty-four patients received 10 Gy in one fraction from January 1992 to March 1993 (Group A); 47 patients received two fractions of 7 Gy each from April 1993 to December 1993 (Group B), and 189 patients received three fractions of 5 Gy each from January 1994 to July 1997 (Group C).

Results. Mean survival from diagnosis is 11.1 months and mean survival from last HDRBT is 9.7 months. The symptomatic response rate is 90% for dyspnea, 82% for cough, 94% for hemoptysis and 90% for obstructive pneumonia. Performance status was improved in 70% of patients. Follow-up is in the range of 5-36 months with 280/320 evaluable patients (87.5%) (40 patients were lost to follow-up). For the patients treated with three fractions of HDRBT plus EBRT, a smaller number of side effects occurred while relief from symptoms linked to bronchial obstruction and survival was similar for the three groups.

Conclusions. A three-fraction brachytherapy results in fewer side effects, such as bronchial fibrosis with or without stenosis, while survival and symptomatic relief are similar in the three groups treated.
Management of Cancer in the Older Person: A Practical Approach
Authors: Balducci Lodovico , Extermann Martine
Published: August 2004

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; andAdoption 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; andPeople 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.
The Prednisone Dosage in the CHOP Chemotherapy Regimen for Non-Hodgkin's Lymphomas (NHL): Is There a Standard?
Authors: Moreno Alvaro , Colon-Otero Gerardo , Solberg Lawrence A.
Published: August 2004

Purpose. Discrepancies in the quoted prednisone dosages in the regimens reported as the only standard CHOP regimen stimulated our interest in reviewing the medical literature regarding this issue and to assess whether practicing hematologists and oncologists in the U.S. are aware of the different dose schedules of prednisone in the published CHOP programs.

Methods. Sixteen textbooks and chemotherapy reference books were reviewed. A MEDLINE search of English-language articles published between January 1970 and December 1998 was performed. An eight-point questionnaire was sent via e-mail with responses obtained from 421 hematology/oncology physicians in the U.S..

Results. Sixteen textbooks and chemotherapy reference books reviewed quoted only one prednisone dosage as part of the standard CHOP regimen; the prednisone dosages quoted as standard varied between publications. More than 4,000 eligible non-Hodgkin's lymphoma patients have been treated with the CHOP chemotherapy as part of 43 different clinical trials reviewed. The dosages of prednisone and prednisolone used varied among six different levels. Thirty percent (127/421) of practicing U.S. physicians were not aware of the existence of more than one prednisone dose schedule as part of the CHOP regimen. The three most frequently used dosages are 100 mg/days 1-5 (67%), 100 mg/m2/days 1-5 (17%), and 60 mg/m2/days 1-5 (13%).

Conclusions. Discrepancies in steroid dosages used as part of the reported standard CHOP regimens are common and not well recognized in the medical literature nor by practicing U.S. hematologists/oncologists. Based on this study, a prednisone dose of 100 mg/day for five days should be considered the standard dose.
The Consequences of Diarrhea Occurring During Chemotherapy for Colorectal Cancer: A Retrospective Study
Authors: Arbuckle R.B. , Huber S.L. , Zacker C.
Published: August 2004

Purpose. Diarrhea is one of the dose-limiting toxicities associated with chemotherapy agents in treatment regimens for colorectal cancer. The objectives of this study were to analyze the impact of all grades of diarrhea on clinical decisions for patients receiving treatment for colorectal cancer by characterizing the diarrhea that occurred, quantifying changes in chemotherapy treatment, identifying methods to treat diarrhea, and determining the economic impact.

Patients and Methods. We retrospectively reviewed the treatment of 100 consecutive patients with colorectal cancer who experienced diarrhea during the course of chemotherapy. The diarrhea was documented in the progress notes and graded according to National Cancer Institute Common Toxicity Criteria. Changes in chemotherapy treatment and resource utilization associated with diarrhea were recorded.

Results. The 100 patients received 673 chemotherapy cycles, of which 45% ± 2% were associated with diarrhea. Approximately 52% of patients experienced diarrhea of grades 3 or 4, and 56 patients underwent 66 modifications in their chemotherapy treatment, such as dose reductions (22), delays in therapy (8), discontinuations of therapy (15), or multiple changes (11). Thirty-seven patients consumed resources beyond oral antidiarrheals to control diarrhea: 14 patients received emergency outpatient treatment, 23 patients were hospitalized, 21 patients received intravenous fluids, and one death due to dehydration was reported.

Discussion and Conclusion. Diarrhea was a significant consequence of colorectal chemotherapy, with the majority of patients experiencing grades 3 or 4 diarrhea and 56% of all patients also modifying their chemotherapy treatment. Even mild diarrhea of grades 1 and 2 was associated with changes in treatment in 11% of patients; thus, diarrhea of all grades should be recognized and treated appropriately to maintain full-dose chemotherapy.
The Role of Behavioral and Psychosocial Science in Reducing Cancer Morbidity and Mortality
Authors: Burish Thomas G.
Published: August 2004

Behavioral and psychosocial science has the potential to contribute much to the overall effort to reduce cancer morbidity and mortality and to improve the quality of life for cancer patients and their families. However, for a variety of reasons, including a lack of sustained funding for research and training and a lack of confidence by some in the potential payoff for investments in the area, this potential has not only not been realized but also not been adequately explored. A special subcommittee of “The March” Research Task Force studied research in this area and issued a report making several recommendations for future funding for psychosocial and behavioral research in cancer. This article reports those recommendations and the reasons the committee supported them.
Highlights in Ovarian Cancer
Authors: Seiden Michael
Published: August 2004

The ovarian cancer presentations at the 2000 ASCO meeting did not yield any major paradigm shifts in the treatment of women with epithelial ovarian cancer. Emphasis at this year's meeting focused on the potential incorporation of drugs such as topotecan, oxaliplatin, doxil, and gemcitabine into the initial treatment strategies of women with advanced ovarian cancer. These studies included the introduction of several active and tolerable regimens that are potentially worthy of direct comparison to the carboplatin and paclitaxel combination. In the woman with recurrent or persistent ovarian cancer there was a greater focus on phase III studies directly comparing various chemotherapy strategies in the treatment of women with recurrent disease. This included the comparisons of single-versus two-drug salvage regimens, alternate salvage schedules, and direct comparison of agents active in taxane- and platinum-resistant disease. Finally, several early studies of novel non-chemotherapeutic strategies were presented.
Hematologic Malignancies: Selected Abstracts and Commentary
Authors: Grossbard Michael L.
Published: August 2004

ASCO 2000 did not offer revolutionary new advances in the treatment of hematologic malignancies. However, reports at the meeting built incrementally on gains established over the past several years. The meeting continued to highlight advances in the targeted therapy of hematologic malignancies. Excitement abounds regarding the clinical development of STI 571, a rationally designed tyrosine kinase inhibitor, for the treatment of chronic myelogenous leukemia. Studies further defined the role monoclonal antibody treatment for non-Hodgkin's lymphoma and more mature data were presented on both unconjugated antibody therapy and radioimmunoconjugates. In disease detection, important data were presented to clarify the role of positron emission tomography scans in the staging and follow-up of lymphoid malignancies. The following review summarizes key abstracts presented at the 2000 ASCO meeting and will elaborate on the implications of these findings for disease management.
Breast Cancer Update
Authors: Kuter Irene
Published: August 2004

The large number of excellent presentations on breast cancer at this year's ASCO meeting reflects the enormous interest in clinical trials of this common disease. In the reports of adjuvant hormonal therapy, the most interesting included Abstract 273 by Boccardo et al., who reported that postmenopausal women with estrogen receptor positive (ER+) cancers who had already completed three years of tamoxifen experienced better overall survival if treated with two years of subsequent aminoglutethimide (a first-generation aromatase inhibitor) rather than another two years of tamoxifen. This whets our appetite for studies currently under way to define the role of third-generation aromatase inhibitors in the adjuvant setting. A report by Fisher from the National Surgical Adjuvant Breast and Bowel Project B-23 study (Abstract 277) provided confirmation of what is rapidly becoming accepted, that the addition of tamoxifen to chemotherapy does not benefit breast cancer patients with negative lymph nodes who have ER– cancers. In premenopausal women, another report of the benefit of hormonal therapy, this time by the French Adjuvant Study Group using complete hormonal blockade with a luteinizing hormone-releasing hormone agonist and tamoxifen (Abstract 279) showed that hormonal therapy can be at least as good as, if not better, than six cycles of 5-fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2 in terms of disease-free survival and overall survival.

Among the papers on adjuvant chemotherapy, a controversial paper from the German Adjuvant Breast Cancer Group reported that three cycles of CMF (a dose-intense regimen with all three drugs being given on days 1 and 8) were as good as six cycles (Abstract 283). Another report, from the International Breast Cancer Study Group, raised the controversial question of whether there really is much added benefit from the addition of chemotherapy to tamoxifen in postmenopausal women with negative lymph nodes if their tumors have ERs (Abstract 281). A second study (the first was the CALGB study reported at ASCO in 1998) showing a benefit to the addition of Taxol to an anthracycline-based adjuvant regimen, was reported from the M.D. Anderson Cancer Center (Abstract 285), giving further impetus to the inclusion of Taxol in standard adjuvant treatment.

Finally, there were a number of interesting presentations on HER-2. Reported here are three of these, all addressing the effect of HER-2 overexpression on the response to hormonal therapy. Taken together, they uphold the emerging concern that women with ER+ cancers may not benefit significantly from endocrine treatment if the tumors also overexpress HER-2. Observations such as these will afford us the ability to predict more accurately which women will benefit from specific treatments.
Prophylactic Cranial Irradiation in Small-Cell Lung Cancer
Authors: Yang Gary Y. , Matthews Richard H.
Published: August 2004

Prophylactic cranial irradiation is now known to improve survival to a significant degree in small-cell lung cancer (SCLC) patients; this is in addition to its established role in preventing the disabling symptoms of brain metastases. New information indicates that it confers a survival benefit for limited or extensive stage SCLC patients gaining a complete response in the chest. A review of causes of cerebral dysfunction as a complication indicates that such problems can be due to suboptimal radiation fractionation, chemotherapy, or an inappropriate combination of prophylactic brain irradiation with chemotherapy. Optimum treatment with prophylactic brain irradiation has been shown not to cause adverse effects with detailed psychometric testing. Several additional sources of information can be drawn together to suggest a dose-response pattern for prophylactic brain irradiation, leading to the recommendation that a dose of 25-36 Gy is optimal, delivered in 2-3 Gy daily fractions after the completion of chest irradiation and chemotherapy. This will be better defined in future clinical trials.
SPIKES—A Six-Step Protocol for Delivering Bad News: Application to the Patient with Cancer
Authors: Baile Walter F. , Buckman Robert , Lenzi Renato , Glober Gary , Beale Estela A. , Kudelka Andrzej P.
Published: August 2004

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 Role of Prognostic Features in the Treatment of Childhood Acute Lymphoblastic Leukemia
Authors: Friedmann Alison M. , Weinstein Howard J.
Published: August 2004

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and is among the most curable of the pediatric malignancies. Many clinical, biological, genetic, and molecular features have been identified as having prognostic significance in the outcome of patients with ALL. The standard features are age and WBC at diagnosis, with infants (less than one year), adolescents (greater than nine years), and children with WBC above 50,000/μl being at higher risk. Certain chromosomal abnormalities are also strong predictors; in particular, the Philadelphia chromosome and MLL gene rearrangements (especially in infants) are adverse features, while TEL-AML1 is favorable. It is important to note, however, that even the most important known predictors explain only a small proportion of the variability in outcome. These features are currently used to tailor the intensity of treatment so that the toxicity of treatment can be minimized and cure rates can continue to improve. This article reviews time-honored prognostic features, recent advances, and future directions in this field.
Fox Chase Network: Fox Chase Cancer Center's Community Hospital Affiliation Program
Authors: Higman Susan A. , McKay Francis J. , Engstrom Paul F. , O'Grady Margaret A. , Young Robert C.
Published: August 2004

Fox Chase Cancer Center developed a format for affiliation with community providers in 1986. Fox Chase Network was formed to establish hospital-based community cancer centers to increase access to patients involved in clinical research.

Under this program, the Fox Chase Network now contributes 500 patients per year to prevention and clinical research studies. As relationships with community providers form, patient referrals have increased at Fox Chase Cancer Center and for each Fox Chase Network member.

A dedicated staff is required to operate the central office on a day-to-day basis as well as at each affiliate. We have found this to be a critical element in each program's success.

New challenges in the cancer business—increasing volumes with declining revenue—have caused us to reconfigure the services offered to affiliates, while maintaining true to our mission: to reduce the burden of human cancer.
Impact of Cancer-Related Fatigue on the Lives of Patients: New Findings From the Fatigue Coalition
Authors: Curt Gregory A. , Breitbart William , Cella David , Groopman Jerome E. , Horning Sandra J. , Itri Loretta M. , Johnson David H. , Miaskowski Christine , Scherr Susan L. , Portenoy Russell K. , Vogelzang Nicholas J.
Published: August 2004

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 Retinoids and Cancer Prevention Mechanisms
Authors: Dragnev Konstantin H. , Rigas James R. , Dmitrovsky Ethan
Published: August 2004

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 (β-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.
The Status of High-Dose Chemotherapy in Breast Cancer
Authors: Rodenhuis S.
Published: August 2004

High-dose chemotherapy in breast cancer is a subject of considerable controversy. Preliminary results from several randomized trials have shown that it is certainly not the breakthrough hoped for in the early 1990s. The available data are, however, compatible with a modest but potentially important effect on relapse-free survival in the adjuvant treatment of high-risk breast cancer. To prove such an effect, several more years of maturation are required for a number of randomized studies. At this point in time, there is no justification for the use of high-dose chemotherapy in breast cancer outside clinical studies.
Monoclonal Antibody Therapy in Lymphoid Malignancies
Authors: Hainsworth John D.
Published: August 2004

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.
Raloxifene: A Selective Estrogen Receptor Modulator (SERM) with Multiple Target System Effects
Authors: Muchmore Douglas B.
Published: August 2004

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.
Diet and Cancer
Authors: Willett Walter C.
Published: August 2004

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.
Pediatric Oncology: Regulatory Initiatives
Authors: Hirschfeld Steven , Shapiro Alla , Dagher Ramzi , Pazdur Richard
Published: August 2004

The majority of children with cancer receive therapy as participants in clinical research protocols coordinated by national pediatric cooperative groups. One of the highest priorities of these groups is the development of novel therapies. Due to differences in the biology of pediatric and adult tumors and in physiology between adults and children, it is usually necessary to evaluate the safety and effectiveness of new drugs separately in adult and pediatric populations. To stimulate the development of new therapies for pediatric indications and encourage the submission of clinical data to support pediatric product labeling, the U.S. Food and Drug Administration has undertaken two initiatives. In 1998 the FDA issued a regulation (The 1998 Final Pediatric Rule) that mandated if a drug or biological is under review for a claim and the disease exists in both pediatric and adult populations, pediatric studies must be performed. Section 111 of the FDA Modernization Act of 1997 states that if a drug product has exclusivity based on a patent or marketing license, the exclusivity can be extended by six months for the submission of pediatric data to the FDA. The incentive applies to both approved drugs and those under development. These initiatives are intended to enhance access to new anticancer therapies and promote labeling for pediatric oncology indications.
Childhood Cancers: Hepatoblastoma
Authors: Herzog Cynthia E. , Andrassy Richard J. , Eftekhari Farzin
Published: August 2004

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.
Induction of Differentiation and Apoptosis— A Possible Strategy in the Treatment of Adult Acute Myelogenous Leukemia
Authors: Bruserud Øystein , Gjertsen Bjørn Tore , Huang Tien-sheng
Published: August 2004

A differentiation block with accumulation of immature myeloid cells characterizes acute myelogenous leukemia (AML). However, native AML cells often show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, e.g., all trans-retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment for the acute promyelocytic leukemia variant of AML. Several agents can induce leukemic cell differentiation for other AML subtypes, although these effects differ between patients. Differentiation may then be associated with induction of apoptosis, and differentiation-inducing therapy may therefore become useful in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. However, it should be emphasized that differentiation and apoptosis can occur as separate events with different regulation in AML cells, and future studies in AML should therefore focus on: A) the identification of new agents with more predictable effects on differentiation and apoptosis; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation/apoptosis induction has a predictable and beneficial effect, and C) further characterization of how AML blast sensitivity to drug-induced apoptosis is modulated by differentiation induction.
Management of Bone Metastases
Authors: Coleman Robert E.
Published: August 2004

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.
Malignancy in Neurofibromatosis Type 1
Authors: Korf Bruce R.
Published: August 2004

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.