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This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

Myelosuppression and neutropenia represent the major dose-limitingtoxicity of cancer chemotherapy. Chemotherapy-induced neutropeniamay be accompanied by fever, presumably due to life-threateninginfection, which generally requires hospitalization for evaluationand treatment with empiric broad-spectrum antibiotics. The resultingfebrile neutropenia is a major cause of the morbidity, mortality, andcosts associated with the treatment of patients with cancer. Furthermore,the threat of febrile neutropenia often results in chemotherapydose reductions and delays, which can compromise long-term clinicaloutcomes. Prophylactic colony-stimulating factor (CSF) has been shownto reduce the incidence, severity, and duration of neutropenia and itscomplications. Guidelines from the American Society of Clinical Oncologyrecommend the use of CSF on the basis of the myelosuppressivepotential of the chemotherapy regimen. The challenge in ensuring theappropriate and cost-effective use of prophylactic CSF is to determinewhich patients would be most likely to benefit from it. A number ofpatient-, disease-, and treatment-related factors are associated with anincreased risk of neutropenia and its complications. A number of clinicalpredictive models have been developed from retrospective datasetsto identify patients at greater risk for neutropenia and its complications.Early studies have demonstrated the potential of such models toguide the targeted use of CSF to those patients who are most likely tobenefit from the early use of these supportive agents. Additional prospectiveresearch is needed to develop more accurate and valid riskmodels and to evaluate the efficacy and cost-effectiveness of modeltargeteduse of CSF in high-risk patients.

Cancer is a disease of the elderly, and its incidence and mortalityincrease with age. The number of persons with cancer is expected todouble between 2000 and 2050, from 1.3 million to 2.6 million, withthe elderly accounting for most of this increase. Studies have shownthat otherwise-healthy older patients treated with chemotherapy of similarintensity obtain benefits comparable to those obtained by youngerpatients. However, chemotherapy-induced neutropenia and its complicationsare more likely in older patients; they are also more often hospitalizedbecause of life-threatening infectious complications. Furthermore,most neutropenic episodes in elderly patients occur in the earlycycles of chemotherapy. To minimize the occurrence of chemotherapyinducedneutropenia, older patients are often treated with less-aggressivechemotherapy and with dose reductions and delays, which maycompromise treatment outcome. The proactive management ofmyelosuppression is therefore essential in elderly patients. Research todetermine the predictors for neutropenia has found that age itself is asignificant risk factor. The benefit of treating elderly patients withcolony-stimulating factors is well established, with their use beginningin the first cycle of chemotherapy being crucial for minimizing neutropeniaand its complications and facilitating the delivery of full-dosechemotherapy. Such prophylaxis should be routinely considered in elderlypatients with cancer treated with myelosuppressive chemotherapy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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 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.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

ROCKVILLE, Maryland-Bex-xar (tositumomab and iodine I-131 tositumomab) has received FDA approval for the treatment of patients with CD20-positive follicular non-Hodgkin’s lymphoma (NHL), with and without transformation, whose disease is refractory to rituximab (Rituxan) and has relapsed following chemotherapy. Bexxar will be co-marketed in the United States by Corixa Corporation, Seattle, and GlaxoSmith-Kline, Philadelphia.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.