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Fatigue is the most common problem experienced by oncology patients.[1-2] In this issue of ONCOLOGY, Drs. Lesage and Portenoy present an excellent overview of the potential etiologies, assessment parameters, and treatment options for this complex, multidimensional symptom. As they note in their comprehensive review, research on this symptom, which has a significant impact on oncology patients’ ability to function and quality of life, is limited. Therefore, one is left to consider what important research questions need to be answered regarding cancer-related fatigue.

The article by Drs. Lesage and Portenoy is an excellent overview of current knowledge regarding the etiology, diagnosis, and treatment of fatigue in the cancer patient. Although we still have much to learn about cancer-related fatigue, noteworthy progress has been made over the past 10 years in identifying the problem, describing its consequences, establishing it as a recognized diagnostic entity, understanding its causes, and offering treatments.

Increasing data suggest that rituximab may have activity in a variety of uncommon B-cell malignancies. Although earlier preliminary data suggested a high response rate in hairy cell leukemia (HCL) (Thomas et al: Blood 94:705a[abstract 3116], 1999), the complete response rate of 20% in patients who had previously failed cladribine (Leustatin) therapy reported by Nieva et al was considered disappointing (abstract #1535). A more promising approach to patients with refractory HCL is the BL-22 immunotoxin, in which anti-CD22 is linked to a Pseudomonas exotoxin (Kreitman et al: N Engl J Med 345:241-247, 2001). Of 16 patients treated on a phase I study who had failed at least one purine analog, 13 responded, including 11 complete remissions. At a median of 16 months, only three complete responders relapsed and these were successfully reinduced.

Rituximab has been combined with a number of biological agents, including alpha-interferon (Davis et al: Clin Cancer Res 6:2644-2652, 2000; Kimby et al: Blood 96:577a[abstract 2479], 2000) and interleukin (IL)-12 (Ansell et al: Blood 99:67-74, 2002). The current design of combination trials is often based more on the availability of active agents than on any scientific rationale. The bcl-2 protein is overproduced in 60% to 80% or more of follicular NHL patients and in more than 80% of patients with CLL. A result is decreased apoptosis related to the prevention or slowing of activation of caspases. A resulting effect is a form of multidrug resistance. bcl-2 knockout mice have severe immunodeficiency and lymphocytopenia, suggesting that bcl-2 may be required for the viability of these cells. G3139 is an antisense bcl-2 oligonucleotide currently in clinical trials for a variety of solid tumors and hematologic malignancies.

Several reports have focused on other interesting monoclonal antibodies under evaluation in patients with lymphoid malignancies. Apolizumab (Hu1D10) is a humanized monoclonal antibody directed at an human leukocyte antigen epitope on malignant and benign B cells. The expression is somewhat variable by disease, but cells from about 40% to 60% of patients are positive for the 1D10 antigen.

The initial experience with rituximab in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) was disappointing. In the first six papers, primarily including patients with relapsed and refractory SLL, there were no complete remissions, with an overall response rate of about 12%, of brief duration (McLaughlin et al: J Clin Oncol 16:2825-2833, 1998; Maloney et al: Blood 90:2188-2195, 1997; Nguyen et al: Eur J Haematol 62:76-82, 1999; Piro et al: Ann Oncol 10:655-661, 1999; Winkler et al: Blood 94:312a [abstract 1396], 1999; Foran et al: J Clin Oncol 18:317-324, 2000).

Rituximab as a single agent induces responses in about 32% of patients with aggressive B-cell NHL, although these responses tended to be partial and brief (Coiffier et al: Blood 92:1927-1932, 1998). Nevertheless, because of its favorable toxicity profile, the antibody was rapidly incorporated into combination chemotherapy regimens, most often with CHOP, the standard program for this histology. Vose and coworkers (J Clin Oncol 19:389-397, 2001) published the results of a multicenter phase II trial in which the antibody was administered on day 1 of each 21-day cycle, with CHOP beginning on day 3, in contrast to the schedule reported by Czuczman et al (J Clin Oncol 17:268-276, 1999).

How the monoclonal antibodies work in lymphoid malignancies remains unclear. Several studies presented at the 2001 American Society of Hematology (ASH) meeting provided insight into their mechanisms of action, and also into how cells become resistant to their effects.

Radioimmunotherapy is another promising area of lymphoma therapy. The two radioimmunoconjugates (RICs) that have been the most widely studied in patients with follicular, low-grade NHL are tositumomab/iodine-131 tositumomab (Bexxar) and yttrium-90 ibritumomab tiuxetan (Zevalin). Both have demonstrated a high level of activity in patients who have failed chemotherapy and rituximab (Witzig et al: J Clin Oncol 17:3793-3803, 1999; Kaminski et al: J Clin Oncol 19:3918-3928, 2001).

Rituximab was approved by the US Food and Drug Administration largely on the basis of the pivotal trial conducted in 166 patients with follicular/low-grade NHL who had failed a median of two prior chemotherapy regimens (McLaughlin et al: J Clin Oncol 16:2825-2833, 1998). The response rate was 48%, including 6% complete remissions (CR), lasting a median of about a year. Attempts to improve on these results by using rituximab as initial therapy have not provided convincing evidence for improved patient outcome (Hainsworth et al: Blood 95:3052-3056, 2000; Colombat et al: Blood 97:101-106, 2001). The high response rates in the French trial by Colombat and co-workers are related in large part to the favorable nature of the patient population. Moreover, median duration of response was only about a year. In the study from Hainsworth et al mentioned above, response rates when calculated by standard methods were comparable to those seen in relapsed and refractory patients.

Based on its B-cell-depleting properties, rituximab as a single agent or in combination with immunosuppressive chemotherapy drugs has been used to successfully treat nonmalignant hematologic conditions such as immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia, cold agglutinin disease, and pure red cell aplasia (Hegde et al: Proc Am Soc Clin Oncol 20:305a[abstract 1218], 2001; Perrota and Abuel: Blood 92:88b[abstract 3360, 1998; Saleh et al: Blood 96:252a[abstract 1086], 2000; Lee et al: Blood 96:596a[abstract 2560], 2000; Rai et al: Blood 96:754a[abstract 3264, 2000; Zecca et al: Blood 97:3995-3997, 2001; Stasi et al: 98:952-957, 2001), with encouraging success. Anecdotal reports also suggest activity for rituximab in systemic lupus erythematosus, rheumatoid arthritis, inflammatory arthropathy, and paraneoplastic pemphigus (Edwards and Cambridge: Rheumatology 40:205-211, 2001; Protheroe et al: Rheumatology 38:1150-1152, 1999; Heizmann et al: Am J Hematol 66:142-144, 2001).

The treatment of patients with acute myelogenous leukemia (AML) ranges from palliative care only, to standard therapy, to investigational approaches. Acute myelogenous leukemia is, in fact, several different diseases, and the percentage of clinical responses varies with disease and prognostic subsets.

This phase II trial investigated the safety and efficacy of a combined-modality treatment with rituximab (Rituxan) and fludarabine (Fludara) in patients with fludarabine- and anthracycline-naive chronic lymphocytic lymphoma (CLL).

Rituximab (Rituxan) is a chimeric IgG1 anti-CD20 monoclonal antibody increasingly used in the treatment of non-Hodgkin’s lymphoma (NHL). Previous in vitro studies have suggested the role of antibody-dependent cellular cytotoxicity (ADCC) and FcgR-positive effector cells (natural killer and macrophage) in the antitumor effects of anti-CD20 antibodies, but the actual mechanism of rituximab action in vivo remains largely unknown. The FCGR3A gene coding for the FcgRIIIa receptor displays a functional dimorphism with either a phenylalanine (FCGR3A-158F) or a valine (FCGR3A-158V) at amino acid 158, with a higher affinity of human IgG1 and increased ADCC for the latter. The aim of this study was thus to determine the influence of this FCGR3A polymorphism on clinical and molecular responses to rituximab.

Intravenous immunoglobulin (IVIG) is prepared from large pools of plasma from healthy donors and is widely used to treat autoimmune diseases, especially immune thrombocytopenic purpura (ITP). Human polyclonal antierythrocyte antibodies, such as anti-D, can also be effective at treating ITP in individuals expressing the appropriate antigen. The demand for IVIG and anti-D exceeds the supply, and the development of a recombinant product to replace these human-derived blood products would be highly desirable. We have hypothesized that monoclonal antibodies directed against red cells may be effective in inhibiting immune forms of thrombocytopenia.

ROCKVILLE, Maryland-The Food and Drug Administration (FDA) has approved the use of Gleevec (imatinib mesylate, Novartis) for the treatment of c-kit-positive inoperable and metastatic malignant gastrointestinal stromal tumors (GISTs).

WASHINGTON-Most states get a failing grade in the latest assessment of spending on antitobacco programs. The updated report on how the states are allocating the money they receive from legal settlements with the tobacco industry shows that only five states are providing funds for tobacco prevention programs at or above the lowest amounts recommended by the Centers for Disease Control and Prevention (CDC).

In this second portion of a two-part interview, Linda L. Emanuel, MD, PhD, discusses the future of bioethics. Part I highlighted end-of-life care and physician-assisted suicide, while part II focuses on organizational ethics and future issues in bioethics.

A recent report on obesity released by US Surgeon General Dr. David Satcher said that about 300,000 people in the United States die each year from diseases related directly to being overweight, including heart disease and cancer.

STANFORD, California-The cost-effectiveness of rituximab (Rituxan) combined with CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) in the treatment of patients with diffuse large B-cell lymphoma compares favorably to other oncology therapies in this setting, according to a study presented at the 43rd Annual Meeting of the American Society of Hematology.

ANN ARBOR, Michigan-Tositumomab with radioactive I-131 attached (Bexxar) is more effective than the unlabeled antibody in relapsed or refractory CD20-positive non-Hodgkin’s lymphoma (NHL), according to Mark S. Kaminski, MD. Dr. Kaminski reported data from a randomized, open-label, multicenter study comparing the two formulations at the 43rd Annual Meeting of the American Society of Hematology. He is professor of internal medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

HOUSTON-The combination of fludarabine (Fludara) and cyclophosphamide (Cytoxan, Neosar) plus rituximab (Rituxan), known as FCR, produces "a higher complete remission rate than prior regimens tested" against chronic lymphocytic leukemia (CLL), reported William Wierda, MD, of the department of leukemia at The University of Texas M. D. Anderson Cancer Center in Houston. In addition, molecular remissions can be demonstrated in a significant number of those responding to the FCR combination.

WASHINGTON-"The search for cancer prevention agents is hampered by the fact that only one biomarker-the prostate-specific antigen (PSA)-now offers a simple, noninvasive measure of the cancer process in the body," Robert W. Day, MD, PhD, said at a meeting of the Cancer Prevention Working Group, sponsored by the Cancer Research Foundation of America (CRFA). "The need for cancer biomarkers is critical, not only for their diagnostic benefits but also to provide endpoints for judging the effectiveness of any proposed chemopreventive agents."

ORLANDO, Florida-Adding rituximab (Rituxan) to standard chemotherapy for follicular lymphoma regimens improves the rate and quality of responses and increases clearance of the bcl-2/IgH chimeric gene, according to studies from US and Italian cooperative groups reported at the 43rd Annual Meeting of the American Society of Hematology.

BUFFALO, New York-Final data from a phase II study of rituximab (Rituxan) plus fludarabine (Fludara) in low-grade lymphoma show that this combination is associated with excellent antitumor activity, clears bcl-2-positive cells from blood and/or bone marrow in most patients, and is well tolerated, according to Myron S. Czuczman, MD. Dr. Czuczman, who is chief of the Division of Lymphoma at Roswell Park Cancer Institute in Buffalo, New York, presented this single-institution study in a poster session at the 43rd Annual Meeting of the American Society of Hematology.

COLUMBUS, Ohio-Concurrent administration of rituximab (Rituxan) and fludarabine (Fludara) produced higher complete response rates in previously untreated patients with chronic lymphocytic leukemia (CLL) than sequential administration, according to results of a phase II Cancer and Leukemia Group B study.

The National Cancer Institute (NCI) recently released Cancer Progress Report 2001-the first in a new series of reports designed to make scientific information on cancer more accessible and understandable. The new report describes and illustrates the nation’s progress in reducing the cancer burden across the full cancer continuum, from prevention through death.

BUFFALO, New York-Median progression-free survival has still not been reached after 6 years median follow-up of 40 patients with low-grade or follicular non-Hodgkin’s lymphoma (NHL) treated in the first clinical trial of rituximab (Rituxan) in combination with CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], and prednisone), Myron S. Czuczman, MD, reported.

ERFURT, Germany-Interim data from a randomized phase III study show that MCP (mitoxantrone [Novantrone], chlorambucil [Leukeran], prednisolone) with or without rituximab (Rituxan) is active in advanced indolent lymphomas. Michael Herold, MD, reporting for the Ostdeutsche Studiengruppe Haematologie/Oncologie (OSHO), said, "The response rate of 81% is within the range of that seen with standard therapies. The complete response (CR) rate of 40% was highly encouraging, particularly given the multi-institutional setting of this study. To date, no significant change in response has been seen with the addition of rituximab to MCP, but further follow-up is needed to determine if the addition of rituximab will improve the duration of response."

BETHESDA, Maryland-The National Cancer Institute’s Cancer Progress Report 2001-a living document that the Institute will update once or twice a year online and every few years in printed form-renders a mixed judgment about the nation’s success in reducing the burden of cancer.