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Breast cancer is the most common noncutaneous malignancy inwomen in industrialized countries. Chemotherapy prolongs survival inpatients with early-stage breast cancer, and maintaining the chemotherapydose intensity is crucial for increasing overall survival. Manypatients are, however, treated with less than the standard dose intensitybecause of neutropenia and its complications. Prophylactic colonystimulatingfactor (CSF) reduces the incidence and duration of neutropenia,facilitating the delivery of the planned chemotherapy doses.Targeting CSF to only at-risk patients is cost-effective, and predictivemodels are being investigated and developed to make it possible forclinicians to identify patients who are at highest risk for neutropeniccomplications. Both conditional risk factors (eg, the depth of the firstcycleabsolute neutrophil count nadir) and unconditional risk factors(eg, patient age, treatment regimen, and pretreatment blood cell counts)are predictors of neutropenic complications in early-stage breast cancer.Colony-stimulating factor targeted toward high-risk patients startingin the first cycle of chemotherapy may make it possible for fulldoses of chemotherapy to be administered, thereby maximizing patientbenefit. Recent studies of dose-dense chemotherapy regimens with CSFsupport in early-stage breast cancer have shown improvements in disease-free and overall survival, with less hematologic toxicity than withconventional therapy. These findings could lead to changes in how earlystagebreast cancer is managed.

Risk Models for Chemotherapy-Induced Neutropenia in Non-Hodgkin’s Lymphoma

Andrew D. Zelenetz, MD, PhD

November 1st 2003

Non-Hodgkin’s lymphoma is primarily a disease of the elderly, with61% of the new cases reported in patients 60 years old or older. Aggressivecombination chemotherapy can cure some patients, but there arefrequently treatment failures and overall survival is low. Retrospectivestudies have found that treatment with less than standard chemotherapydoses is associated with lower survival, and surveys of practice patternshave found that many patients, especially elderly ones, are treated withsubstandard regimens and doses. Neutropenia is the major dose-limitingtoxicity of chemotherapy in patients with non-Hodgkin’s lymphoma.First-cycle use of colony-stimulating factor (CSF) can reduce the incidenceof neutropenia and its complications and help maintain the chemotherapydoses. Researchers have investigated risk factors in patientswith non-Hodgkin’s lymphoma to determine which patients are at highestrisk for neutropenia and would benefit from targeted first-cycle CSFsupport. It has been shown in several studies that advanced age, poorperformance status, and high chemotherapy dose intensity are risk factors.Other trials suggest that low serum albumin levels, elevated lactatedehydrogenase levels, bone marrow involvement, and high levelsof soluble tumor necrosis factor receptor are also risk factors. Doseintensity has also been shown in many studies to be an important predictorof survival in patients with non-Hodgkin’s lymphoma. Managingthe toxicity of chemotherapy with CSF has facilitated the deliveryof planned dose on time, as well as dose-intensified chemotherapy regimens.The promising results from recent clinical trials of dose-denseregimens with CSF support suggest that this could prove to be the beststrategy for improving patient outcomes.

Emerging Technology in Cancer Treatment: Radiotherapy Modalities

James M. Hevezi, PhD

October 1st 2003

This is a period of rapid developments in radiotherapy for malignantdisease. New methods of targeting tumors with computed tomography(CT) virtual simulation, magnetic resonance imaging (MRI), andpositron-emission tomography (PET) fusion provide the clinician withinformation heretofore unknown. Linear accelerators (linacs) withmultileaf collimation (MLC) have replaced lead-alloy blocks. Indeed,new attachments to the linacs allow small, pencil beams of radiation tobe emitted as the linac gantry rotates around the patient, conforming tothree-dimensional (3D) targets as never before. Planning for these deliverysystems now takes the form of "inverse planning," with CT informationused to map targets and the structures to be avoided. In thearea of brachytherapy, techniques utilizing the 3D information providedby the new imaging modalities have been perfected. Permanentseed prostate implants and high-dose-rate (HDR) irradiation techniquestargeting bronchial, head and neck, biliary, gynecologic, and otheranatomic targets are now commonplace radiotherapy tools. CT-guidedpermanent seed implants are being investigated, and a new method oftreating early breast cancer with HDR brachytherapy via a ballooncatheter placed in the lumpectomized cavity is coming to the forefront.Newer modalities for the treatment of malignant and benign diseaseusing stereotactic systems and body radiosurgery are being developed.Targeted radionuclides using microspheres that contain radioemittersand other monoclonal antibody systems tagged with radioemitters havebeen recently approved for use by the Food and Drug Administration.

The New Generation of Targeted Therapies for Breast Cancer

Frank A. Scappaticci, MD, PhD;Robert D. Mass, MD

October 1st 2003

Syed and Rowinsky present acomprehensive review of newtargeted therapies for breast cancer.This is an important review thatsummarizes new biologic targets andcurrent drugs in development for thetreatment of breast cancer-a rapidlyevolving field. Among the targets addressedin the article are epidermalgrowth factor receptor (EGFR), Ras/Raf/mitogen-activated protein (MAP)kinase, phosphatidylinositol 3-kinase(PI3K)/protein kinase B (AkT)/moleculartarget of rapamycin (mTOR), tumorangiogenesis, apoptosis, andhistone deacetylases. The list shouldalso be expanded to include differentiatingagents and inhibitors of invasionand metastasis. It is critical toemphasize the future of customizedtherapy and the use of biologic agentsalone, together, or in combination withchemotherapy for the treatment ofbreast cancer.

Emerging Technology in Cancer Treatment: Radiotherapy Modalities

George T. Y. Chen, PhD

October 1st 2003

Dr. Hevezi provides a broadoverview of the numeroustechnical innovations thathave been commercialized and arenow available to many centers for theradiation treatment of cancers. Hisreview describes computed tomography(CT) simulation, stereotactic radiosurgery,intensity-modulated radiotherapy(IMRT), and advances inbrachytherapy. The article's breadth ofcoverage necessarily limits details.

IMPAC Medical Provides Integrated Oncology-Specific Management Systems for Ca Hospitals, Private Practices

September 1st 2003

MOUNTAIN VIEW, California-IMPAC Medical Systems, Inc., an oncology management software company launched 13 years ago in a Silicon Valley garage, now has almost 1,700 clients worldwide, in 52 countries, including many of the leading US cancer centers, as well as specialty treatment centers and private practices.

Cancer Websites You Can Use:People Living With Cancer

J. Sybil Biermann, MD

September 1st 2003

People Living With Cancer(www.plwc.org, Figure 1), thepatient-oriented website postedby the American Society for ClinicalOncology (ASCO), has emergedas one of the preeminent cancer patienteducation sites, and for goodreason: It offers excellent site organization,easy navigability, and usefulinformation.

Commentary (Berenson): Bisphosphonates in the Prevention and Treatment of Bone Metastases

James R. Berenson, MD, FACP

September 1st 2003

Oncologists have increasinglyrecognized that bone loss andits resultant complicationshave a major impact on the lives ofcancer patients. Bone loss in this populationmay be a consequence of directcancer involvement in the boneor of treatments that affect gonadalfunction or otherwise have a negativeimpact on bone.

Irinotecan and Fixed-Dose-Rate Gemcitabine in Advanced Pancreatic and Biliary Cancer: Phase I Study

Weijing Sun, MD, FACP;Daniel G. Haller, MD

September 1st 2003

It is a continuing challenge for oncologists to effectively treatadvanced/metastatic pancreatic and biliary cancer. Both irinotecan(CPT-11, Camptosar) and gemcitabine (Gemzar) have shown activityagainst these diseases with different mechanisms. Preclinical andclinical data also suggest additive or synergistic effects of the combinationof these two agents with few or no overlapping toxicities. Phosphorylationof gemcitabine, a process of intracellular activation of theagent, is dose-rate dependent. It has been suggested that the fixed-doserateinfusion of gemcitabine increases the concentration of intracellulartriphosphate gemcitabine, which in turn may result in more objectiveresponses and longer median survival compared to the standard infusion.This phase I study tests the toxicity of the combination of irinotecanwith fixed-dose-rate infusion of gemcitabine, and determines thedose of the combination for phase II investigation.

Gemcitabine and Irinotecan in Locally Advanced or Metastatic Biliary Cancer: Preliminary Report

Pankaj Bhargava, MD;Chirag R. Jani, MD;Diane M. F. Savarese, MD;Judith L. O’donnell, RN;Keith E. Stuart, MD;Caio Max S. Rocha Lima, MD

September 1st 2003

Chemotherapy has had limited success in biliary tract cancer. Of thenewer agents, gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar)both have single-agent activity in patients with advanced disease.We conducted a phase II trial to study the efficacy and toxicity of thecombination of gemcitabine plus irinotecan in patients with locallyadvanced or metastatic biliary tract cancer. The study has enrolled 14patients with histologically or cytologically documented cancer of thebiliary tract or gallbladder with bidimensionally measurable disease,Eastern Cooperative Oncology Group performance status 0 or 1,decompressed biliary tree, and no prior exposure to chemotherapy.Gemcitabine at 1,000 mg/m2 and irinotecan at 100 mg/m2 were bothadministered on days 1 and 8, every 21 days. In patients who had lessthan grade 3 hematologic and less than grade 2 nonhematologic toxicityfollowing cycle 1, the dose of irinotecan was increased to 115 mg/m2 forsubsequent cycles. A total of 65 cycles of chemotherapy have beenadministered, with an average of 4.5 cycles per patient (range: 1 to 11cycles). The median treatment duration was 3 months (range: 0.75 to 8months). An objective partial response was determined radiographicallyin two patients (14%) while stable disease for periods ranging from 4to 11.5 months was noted in six patients (43%). Toxicity consisted ofgrade 3/4 neutropenia in seven patients (50%) with no episodes offebrile neutropenia, grade 3/4 thrombocytopenia in four (28%), grade3 diarrhea in two (14%), and grade 3 nausea in one patient. Thecombination of gemcitabine plus irinotecan appears to possess modestclinical activity, and it is well tolerated in patients with advanced biliarycancer. Patient accrual is ongoing to this study.

Cervical Cancer: Issues of Sexuality and Fertility

Jeanne Carter, PhD;Sarah Auchincloss, MD;Yukio Sonoda, MD;Michael Krychman, MD

September 1st 2003

Cervical cancer rates have fallen in the United States; regardless, thedisease remains a significant concern for women, especially those whoare premenopausal. The management of cervical cancer is dependenton stage of disease at diagnosis, and specific needs emerge for patientsboth during and following treatment. Over the past decade, the focus hasbeen to maintain adequate tumor control while reducing long-termnegative consequences. However, problems with sexuality and fertilitypersist for women treated for cervical cancer despite these advances.Sexual dysfunction following treatment for gynecologic cancer hasbeen well documented in the literature, and recent studies demonstratethe success of brief psychosexual interventions. Treatment of sexualdifficulties in cancer patients can be achieved through the provision ofinformation, support, and symptom management, ideally as part of asexual health program. Resources are not always available to developsuch a program. However, medical professionals can identify individualsand organizations with expertise in treating sexual and fertilityconcerns, which can be provided to their patients, making help withthese problems more accessible as needs arise.

Commentary (Fanale/Hortobagyi): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Michelle Fanale, MD;Gabriel N. Hortobagyi, MD, FACP

September 1st 2003

Drs. Ramaswamy and Shapiropresent a timely and comprehensivereview of the potentialuses of bisphosphonates and theirindications in the prevention and treatmentof bone metastasis. The reviewprovides a concise summary of thepathophysiology of skeletal metastasesand describes emerging biologicprinciples that open the door for novel,highly targeted therapeutic interventions.It is generally accepted thatrelative osteoclast hyperactivity resultsin excess bone resorption, which isthe basic process behind bone metastasis,osteoporosis, and hypercalcemiaof malignancy. Osteoprotegerin,the receptor activator of nuclear factor–kappa B (RANK), and the kappa Bligand (RANK-L) have critical rolesin osteoclastogenesis. In addition,parathyroid hormone–related proteinalso plays a major role in osteoblastactivation and production of RANKLas well as terminal osteoclast differentiationand activation.

Commentary (Hillner): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Bruce E. Hillner, MD

September 1st 2003

In this issue, Ramaswamy and Shapiroprovide another excellent reviewof the recent literature on therole of bisphosphonates in the managementof bone metastases frombreast cancer and selected other cancers.Bisphosphonates and bone metastaseshave been the subject ofnumerous similar publications. In aquick Medline search of papers publishedsince January 2002, I found 12different review articles including asimilar manuscript in this journal.[1]

Bisphosphonates in the Prevention and Treatment of Bone Metastases

Bhuvaneswari Ramaswamy, MD;Charles L. Shapiro, MD

September 1st 2003

Bisphosphonates have an established role in treating tumor-inducedhypercalcemia and decreasing the incidence of skeletal-related events.Recent data suggest that these agents may also prevent skeletal metastases.This review explains how cancer metastasizes to bone and howbisphosphonates may block this process, with a summary of clinicaltrials supporting the use of bisphosphonates to treat and prevent bonemetastases. For skeletal metastases in patients with breast cancer,multiple myeloma, or other solid tumors, bisphosphonates are importantadjuncts to systemic therapy. Despite promising results in metastaticprostate cancer, additional trials are needed before bisphosphonatesbecome part of standard treatment in this setting. Ongoing trials areevaluating the preventive role of the third-generation bisphosphonatesin breast cancer patients. Until the results of these trials are presented,bisphosphonates should only become a component of adjuvant treatmentin the context of a clinical trial. Bone loss, a common consequenceof cancer treatment, should be treated with the usual measures indicatedfor the management of osteoporosis, including bisphosphonates.

Capecitabine Shows Substantial Activity and Comparable Efficacy When Combined With Either Irinotecan or Oxaliplatin