Palliative and Supportive Care

Dr. Cherny’s article on the managementof cancer pain is acomprehensive review thatshould prove to be a helpful resource.As physicians in a palliative care andoncology program, we discuss howwe utilize these principles and whatwe see put into practice by others.Cherny and Catane have already documentedthat the great majority ofoncologists do a substantial amountof palliative care, whether they call itthat or not, and that most oncologistswould be willing to work with palliativecare or symptom managementspecialists.[1] Knowledge is only onepart of the solution, and must be pairedwith better practice by health-care professionalsand help from our patients.Articles like this will only help if oncologistspay attention.

Delirium is highly prevalent in cancer patients with advanced disease.Frequently a preterminal event, the condition is a sign of significantphysiologic disturbance, typically involving multiple medical etiologiesincluding infection, organ failure, adverse medication effects,and in rare situations, paraneoplastic syndromes. Unfortunately, deliriumis frequently underrecognized or misdiagnosed and, therefore,inappropriately treated or untreated in terminally ill patients. The clinicalfeatures of delirium are numerous and encompass a variety of neuropsychiatricsymptoms common to other psychiatric disorders. Threeclinical subtypes of delirium, based on arousal disturbance and psychomotorbehavior, have been described: hyperactive, hypoactive, andmixed. The differential diagnosis for delirium includes depression,mania, psychosis, and dementia. Numerous instruments have been developedto aid the clinician in rapidly screening for the disorder. Standardmanagement requires an investigation of the etiologies, correctionof the contributing factors, and management of symptoms. Symptomaticand supportive therapies, including numerous pharmacologicapproaches, are important, but several aspects of the use of neurolepticsand other agents in the management of delirium in the dying patientremain controversial.

Severe, debilitating fatigue is common in cancer patients. For many,it is the symptom that interferes most with normal routines. Virtuallyevery modality used to treat cancer may cause fatigue, as can complicationsof the disease such as sleep disturbances, infections, malnutrition,hypothyroidism, and anemia. There is a significant overlap betweendepression and fatigue in many patients. Given the high prevalenceof cancer-related fatigue, frequent assessment of patients is essential.The evaluation should include an attempt to identify reversiblecauses of fatigue, and screening for depression. However, many cancerpatients suffer from fatigue even in the absence of any identifiable,reversible cause. For these patients, consideration can be given to suitableexercise programs, educational support and counseling, and energyconservation strategies. A trial of a stimulant medication is alsoreasonable. Given the heterogeneity of patients, individualized approachesare needed. For anemic patients undergoing chemotherapy,erythropoietic agents can increase hemoglobin levels. The impact ofthese drugs on fatigue and quality of life is uncertain. Recent reports ofincreased mortality and thrombotic events in cancer patients treatedwith epoetin require further investigation.

The management of cancer pain requires familiarity with a rangeof therapeutic strategies, including antineoplastic therapies, analgesicpharmacotherapy, and anesthetic, neurosurgical, psychological, andrehabilitation techniques. Successful pain management is characterizedby implementation of the techniques with the most favorable therapeuticindex for the prevailing circumstances, along with provision forrepeated evaluations, so that a favorable balance between pain reliefand adverse effects is maintained. For most patients, pain managementinvolves the administration of specific analgesic approaches. In all cases,these analgesic treatments must be skillfully integrated with the managementof other symptoms.

NEW ORLEANS-Palonosetron (Aloxi) prevented chemotherapy-induced nausea and vomiting in older patients better than two other 5-HT3 receptor antagonists-ondansetron

Only a minority of elderly patientswith advanced non–small-cell lung cancer(NSCLC) have been offered palliativechemotherapy, as indicated by clinicalsurveys beginning in the 1980s.Lilenbaum’s thorough review of thetreatment of locally advanced and metastaticNSCLC studies in two specialpopulations (elderly and Eastern CooperativeOncology Group [ECOG]performance status [PS] 2 patients)highlights a new trend seen with theadvent of better-tolerated chemotherapyregimens.

Guidelines for the management of chemotherapy-induced emesisare necessary to help clinicians match the emetogenicity of antineoplasticagents with the abundance of antiemetic agents now available. Numerousguidelines for antiemetic therapy currently exist, but compliancewith them is inconsistent, in part because optimal antiemetic protectionis not yet possible, even with the best guidelines. For this reason,guidelines must be dynamic and evolve as knowledge increases.Revision of antiemetic guidelines should be prompted by changes ingeneral principles of treatment, not changes in specific details. Recentrecognition of the unique benefits of incorporating selective neurokinin-1 receptor antagonists into regimens for the prevention of nauseaand vomiting caused by highly emetogenic chemotherapy, particularlyin delayed emesis, justifies modification of existing antiemeticguidelines.

Improved understanding of the physiologic and neuropharmacologicmechanisms underlying chemotherapy-induced nausea andvomiting (CINV) has driven significant progress in the treatment ofCINV over the past 2 decades. Recognition of the role of neurotransmittersand their receptors in the process of CINV has been central tothis progress. Initial attention focused on dopamine, then on serotonin,and most recently on substance P, which has yielded a usefulnew class of antiemetic medications known as selective neurokinin-1receptor antagonists. Preclinical studies of these neurokinin-1 receptorantagonists suggested that they would demonstrate broad antiemeticactivity in acute emesis, demonstrate activity against cisplatininduceddelayed emesis, be well tolerated, and contribute to enhancedefficacy when used in combination with other classes of antiemetics.These suggestions appear to have been largely borne out in clinicaltrials. Pharmacogenomics may offer a means to further extend andapply our understanding of CINV by enabling more selective targetingof antiemetic therapies. To date, the application of pharmacogenomicsto CINV has focused on variations in the metabolism of serotoninreceptor antagonists by CYP 450 genotype and variations in the5-HT3 receptor gene itself.

Hand-foot syndrome is a localized cutaneous side effect associatedwith the administration of several chemotherapeutic agents, includingthe oral fluoropyrimidine capecitabine (Xeloda). It is never life-threateningbut can develop into a painful and debilitating condition thatinterferes with patients' normal daily activities and quality of life. Severalsymptomatic/prophylactic treatments have been used to alleviatehand-foot syndrome, but as yet there is insufficient prospective clinicalevidence to support their use. The only proven method of managinghand-foot syndrome is treatment modification (interruption and/or dosereduction), and this strategy is recommended for patients receivingcapecitabine. Retrospective analysis of safety data from two largephase III trials investigating capecitabine as first-line therapy in patientswith colorectal cancer confirms that this strategy is effective inthe management of hand-foot syndrome and does not impair the efficacyof capecitabine. This finding is supported by studies evaluatingcapecitabine in metastatic breast cancer. Notably, the incidence andmanagement of hand-foot syndrome are similar when capecitabine isadministered in the metastatic and adjuvant settings, as monotherapy,or in combination with docetaxel (Taxotere). It is important that patientslearn to recognize the symptoms of hand-foot syndrome, so thatprompt symptomatic treatment and treatment modification strategiescan be implemented.

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

Cancers of the gallbladder andbile ducts are uncommon, aggressivemalignancies thatpresent both a diagnostic and therapeuticchallenge. With an annual incidenceof 7,200 cases in the UnitedStates, and the difficulty in diagnosingbiliary tract tumors, there is a paucityof data supporting therapeuticoptions. This comprehensive updateby Daines et al demonstrates the advancesin diagnostic and staging techniques,which have led to appropriatesurgical resection. Despite these advances,the prognosis of gallbladderand cholangiocarcinoma remains bleak,without significant improvement in survival,contrary to the author's optimisticintroduction. There is a lack of activechemotherapy and clinical trials exploringadjuvant and palliative therapy.Guidelines such as those advocated bythe National Comprehensive CancerNetwork (NCCN) help to establish standardsfor the evaluation and treatmentof these uncommon tumors and providea framework for the developmentof clinical trials.[1]

Gallbladder carcinoma and carcinoma of the bile ducts are relativelyrare cancers in the United States. These cancers are often diagnosedin an advanced stage due to their nonspecific symptomatologyand until recently have been associated with a dismal prognosis. Recentadvances in imaging and surgical techniques along with emergingoptions in palliative chemotherapy have improved the outlook inthese cancers. While complete surgical resection remains the only hopeof cure in both these cancers, palliative biliary decompression and chemotherapyresult in substantial improvement in quality of life. Part 1 ofthis review, which appeared in last month’s issue, provided a relevantand comprehensive update of molecular pathology, imaging modalities,and surgical care. In part 2, we examine palliative care and systemictherapy in gallbladder and biliary tract carcinomas, as well asthe use of liver transplantation in the treatment of cholangiocarcinomas.These strategies are of relevance to internists as well as oncologistscaring for these patients.

Gallbladder carcinoma and carcinoma of the bile ducts are relativelyrare cancers in the United States. These cancers are often diagnosedin an advanced stage due to their nonspecific symptomatologyand until recently have been associated with a dismal prognosis. Recentadvances in imaging and surgical techniques along with emergingoptions in palliative chemotherapy have improved the outlook inthese cancers. While complete surgical resection remains the only hopeof cure in both these cancers, palliative biliary decompression and chemotherapyresult in substantial improvement in quality of life. Part 1 ofthis review provides a relevant and comprehensive update of molecularpathology, imaging modalities, and surgical care. In part 2, which willappear next month, we will review palliative care and systemic therapyin gallbladder and biliary tract carcinomas, as well as the use of livertransplantation in the treatment of cholangiocarcinomas. These strategiesare of relevance to internists as well as oncologists caring forthese patients.

The options available for patients with recurrent prostate cancerare limited. Men who have failed external-beam irradiation as the primarytreatment are rarely considered for potentially curative salvagetherapy. Traditionally, only palliative treatments have been offered withhormonal intervention or simple observation. A significant percentageof these patients have only locally recurrent cancer and are thus candidatesfor curative salvage therapy. Permanent brachytherapy withiodine-125 or palladium-103 has been used in an attempt to eradicatethe remaining prostate cancer and prevent the need for additional intervention.It is critical in this population to identify patients most likelyto have distant metastases or who are unlikely to suffer death or morbidityfrom their recurrence, in order to avoid potential treatmentmorbidity in those unlikely to benefit from any intervention. Followingsalvage brachytherapy, up to 98% of these cancers may be locally controlled,and 5-year freedom from second relapse is approximately 50%.With careful case selection, relapse-free rates up to 83% may beachieved. A schema is presented, suggesting that it may be possible toidentify the patients most likely to benefit from salvage treatment basedon prostate-specific antigen (PSA) kinetics and other features. Suchfeatures include histologically confirmed local recurrence, clinical andradiologic evidence of no distant disease, adequate urinary function,age, and overall health indicative of at least a 5- to 10-year life expectancy,prolonged disease-free interval (> 2 years), slow PSA doublingtime, Gleason sum ≤ 6, and PSA < 10 ng/mL.

SALT LAKE CITY-A single fraction of 8 Gy of radiation therapy is as efficacious as 30 Gy delivered in 10 fractions for palliation of painful bone metastases and causes less acute toxicity, reported William F. Hartsell, MD, at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (plenary session, abstract 1).

As the major regulator of erythropoiesis in man, erythropoietin inhibitsthe programmed cell death of committed erythroid precursors.In cancer patients, a relative erythropoietin deficiency is coupled witha decreased responsiveness to the substance mediated by the effects ofinflammatory cytokines on the marrow and on ferrrokinetics, leadingto a high incidence of anemia. Two recombinant human erythropoietin(rhEPO) preparations-epoetin alfa (Epogen, Procrit) and epoetinbeta (Marogen)-as well as a modified erythropoietic compound(darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-partseries on hematopoietic agents reviews the use of these erythropoieticfactors and their effect on the anemia that develops in cancer patients.Thrombopoietic factors and progenitor cell-mobilizing factors are alsobriefly addressed.

Oropharyngeal mucositis is a common and treatment-limiting sideeffect of cancer therapy. Severe oral mucositis can lead to the need tointerrupt or discontinue cancer therapy and thus may have an impacton cure of the primary disease. Mucositis may also increase the risk oflocal and systemic infection and significantly affects quality of life andcost of care. Current care of patients with mucositis is essentially palliativeand includes appropriate oral hygiene, nonirritating diet andoral care products, topical palliative mouth rinses, topical anesthetics,and opioid analgesics. Systemic analgesics are the mainstay of painmanagement. Topical approaches to pain management are under investigation.The literature supports use of benzydamine for prophylaxisof mucositis caused by conventional fractionationated head andneck radiotherapy, and cryotherapy for short–half-life stomatoxic chemotherapy,such as bolus fluorouracil. Continuing studies are investigatingthe potential use of biologic response modifiers and growth factors,including topical and systemic delivery of epithelial growth factorsand agents. Progress in the prevention and management of mucositiswill improve quality of life, reduce cost of care, and facilitate completionof more intensive cancer chemotherapy and radiotherapy protocols. Inaddition, improved management of mucositis may allow implementationof cancer treatment protocols that are currently excessively mucotoxicbut may produce higher cure rates. Continuing research related to thepathogenesis and management of mucositis will undoubtedly lead to thedevelopment of potential interventions and improved patient care.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.

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.

Anumber of novel and targeted agents for treating cancer have been introducedin recent years. Nevertheless, chemotherapy remains the mainstayof treatment in the majority of patients, and myelosuppression-especially neutropenia-represents the primary dose-limiting toxicity of chemotherapy.Therefore, chemotherapy-induced neutropenia remains a central concernin the safe and effective delivery of chemotherapy.

Hematopoietic growth factors have transformed the practice of oncology.The two major factors in clinical use are recombinant human(rh) granulocyte colony-stimulating factor (G-CSF, filgrastim[Neupogen]) and granulocyte-macrophage colony-stimulating factor(GM-CSF, sargramostim [Leukine]). These factors differ significantly intheir role in hematopoiesis and the regulation of mature effector cell function.G-CSF regulates both basal and neutrophil production and increasedproduction and release of neutrophils from the marrow in response toinfection. GM-CSF mediates its effects on the neutrophil lineage throughits effects on phagocytic accessory cells and its synergy with G-CSF, but itdoes not appear to have a role in basal hematopoiesis. Part 1 of this twopartseries focuses on the use of the myeloid growth factors rhG-CSF andrhGM-CSF to shorten the duration of chemotherapy-induced neutropeniaand thus prevent infection in cancer patients. In randomized trials,rhG-CSF has consistently decreased the duration of neutropenia duringall cycles of chemotherapy and reduced the risk of infection by 50% ormore. Trials of rhGM-CSF have not reported consistent results.

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.

Mycosis fungoides is a low-grade lymphoproliferative disorder ofskin-homing CD4+ lymphocytes that may produce patches, plaques,tumors, erythroderma, and, ultimately, systemic dissemination. Treatmentselection is generally guided by institutional experience, patientpreference, and toxicity profile, as data from phase III clinical trials arelimited. Effective topical treatments currently include mechlorethamine(Mustargen), carmustine (BCNU, BiCNU), corticosteroids, bexarotene(Targretin, a novel rexinoid), psoralen plus ultraviolet A, ultraviolet B,and total-skin electron-beam radiotherapy. Effective systemic treatmentsinclude interferon, retinoids, bexarotene, denileukin diftitox(Ontak), extracorporeal photopheresis, chemotherapy, and high-dosechemotherapy with allogeneic bone marrow transplant. Each of thesetreatments is discussed in detail, followed by specific recommendationsfor each stage of mycosis fungoides.

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.

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.

Approximately 70% of patientswith life-threatening diseasestreatable with allogeneic bloodstem cell transplantation do not havematched related donors. The NationalMarrow Donor Program (NMDP) wasestablished in 1986 to provide humanleukocyte antigen (HLA)-matched,volunteer unrelated donors for thesepatients. The NMDP performs thistask by maintaining a registry of morethan 4.9 million volunteer donors ofmarrow and peripheral blood stemcells (PBSC) and 12 cord blood bankscontaining more than 25,000 units ofumbilical cord blood.