ONCOLOGY Vol 16 No 3

In this day of encyclopedic oncology texts, frequently updated online reference sites, and literature searches at the click of a button, is there a place for a basic medical oncology textbook? The second edition of the Textbook of Medical Oncology, edited by Drs. Cavalli, Hansen, and Kaye, is approximately 50% longer than the first edition, due in large part to the inclusion of newer therapeutic approaches.

In this report, we present our results of the biochemotherapy combination of rituximab (Rituxan), a monoclonal antibody against CD20, with fludarabine (Fludara) and cyclophosphamide (Cytoxan, Neosar).

Epratuzumab (hLL2 [LymphoCide]), a humanized monoclonal antibody directed against the B-cell specific antigen CD22, has been demonstrated to be a safe and active monotherapy in phase I/II trials for the treatment of relapsed and refractory non-Hodgkin’s lymphoma (NHL).

Rituximab (Rituxan), a chimeric human-mouse anti-CD20 antibody, and alemtuzumab (Campath), a humanized rat anti-CD52 antibody, have each shown activity in chronic lymphocytic leukemia (CLL).

Although patients with small lymphocytic lymphoma and chronic lymphocytic leukemia (SLL/CLL) have CD20 expression on malignant lymphocytes, response rates with standard rituximab (Rituxan) courses in refractory patients have been low.

Monoclonal antibodies demonstrate impressive response rates in lymphoid diseases, and treatment indications are expanding. Both alemtuzumab (Campath) (anti-CD52) and rituximab (Rituxan) (anti-CD20) are active in chronic lymphocytic leukemia (CLL) and low-grade lymphomas.

The first clinical trial of rituximab (Rituxan) in combination with CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) was initiated in April 1994 (J Clin Oncol 17:268, 1999). This study showed the safety and efficacy of the combination in low-grade non-Hodgkin’s lymphoma (NHL) and enabled progression to phase II trials in intermediate-grade NHL (J Clin Oncol 19:389, 2001). In addition, the Groupe d’Etude des Lymphomes de l’Adulte (GELA) randomized phase III study has shown a statistically significant increase in progression-free survival for rituximab/CHOP as compared with CHOP alone (Blood 96:223a [abstract 950]).

Despite a tight proposed domestic budget for fiscal 2003, President Bush wants to increase spending on the National Breast and Cervical Cancer Early Detection Program administered by the Centers for Disease Control and Prevention (CDC).

The increasing frequency of diagnosis and death of patients with follicular cell-derived carcinoma of the thyroid substantiates the need for a broad understanding of the optimal diagnostic and treatment strategies for this disease. Dr. Angelos has provided a good overview of the treatment modalities and approaches to follow-up for these patients. However, several points require additional emphasis or detail.

There have been significant advances in our understanding of the biology of acute myelogenous leukemia (AML), and to a lesser extent, in its treatment. Dr. Estey has provided an excellent overview of the current state of the clinical management of the disease. He has described both the standard therapeutic approaches, including allogeneic hematopoietic stem cell transplantation, as well as the role of investigational therapy. The present state of clinical research in AML is reviewed in some detail in the context of the broad clinical investigation of the disease at the M. D. Anderson Cancer Center. Dr. Estey makes a strong argument for the early consideration of investigational therapy, focusing on patients for whom "standard" therapy is demonstrably inadequate.

Glioblastoma multiforme remains virtually incurable, with reported median survivals of less than 2 years with standard treatment.[1] In recent years, thalidomide (Thalomid) has shown activity in high-grade gliomas as a single agent and in combination with nitrosoureas and carboplatin (Paraplatin).[2-4] I will describe three cases in which patients with recurrent, multicentric glioblastoma responded to thalidomide plus chemotherapy after failing initial treatment with conventional radiation and chemotherapy for a single malignant glioma.

Therapeutic strategies are evolving for the treatment of patients with newly diagnosed acute myelogenous leukemia (AML), as well as for those with relapsed or refractory disease. Clinical and laboratory studies have demonstrated that AML is not a single disease, but a heterogeneous group of diseases with different clinical features and natural histories. There are variable responses to therapy depending on both the biologic characteristics of the disease and the clinical characteristics of the patient. Nevertheless, studies evaluating the outcomes of relatively large numbers of patients with newly diagnosed AML show that the majority still die of their disease.[1-3]

The Lesage and Portenoy article fulfills several important purposes. First, the authors remind us of the critical need to become more systematic and diligent in assessing and monitoring fatigue, a potentially debilitating symptom that is now recognized as the most common adverse effect experienced by cancer patients undergoing active treatment.[1] In the assessment of fatigue, the authors acknowledge that "the gold standard of evaluation is the patient’s self-report."

The use of complementary and alternative medicine is a well-known phenomenon among cancer patients, and prostate cancer patients are no exception. The review article by Drs. Das and Kaplan nicely summarizes most of the data available on the use of PC-SPES, selenium, and vitamin E by prostate cancer patients. These three agents are probably the most widely used complementary approaches in prostate cancer, and they are the ones that have been studied most extensively. However, true data on efficacy, careful toxicity analyses, dose-response analysis, or pharmacokinetic analyses of these agents are extremely limited.

A number of molecularly targeted agents directed at critical pathways involved in cell survival and cell proliferation have recently entered clinical evaluation in children with cancer. These agents offer the potential for more effective anticancer therapy while diminishing acute and long-term toxic effects. Systematic evaluations of agents such as these are essential if continuing improvements in outcome are to be achieved in children with cancer. Brief summaries of the rationale for conducting studies of several agents in children are provided below. Following these summaries is a listing of phase I, phase I/II, phase II, and pilot studies of these agents in pediatric populations

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).

Fatigue is one of the most common symptoms experienced by patients with cancer and other progressive diseases. Although reported to be a major obstacle to maintaining normal daily activities and quality of life, remarkably few studies of this syndrome have been conducted.

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.

The management of well-differentiated thyroid cancer requires a multidisciplinary approach. The majority of patients are diagnosed only after a nodule is palpable. A cytologic evaluation can readily diagnose a papillary thyroid carcinoma but a follicular carcinoma requires determination of capsular or vascular invasion.

Prostate cancer patients commonly use complementary and alternative medications. There has been growing interest in recent years in the role of the herbal medication PC-SPES and the essential nutrients selenium and vitamin E in the prevention and treatment of prostate cancer. This article reviews the preclinical and clinical studies of these therapies.