Palliative and Supportive Care

WASHINGTON-Older cancer patients who received the colony-stimulating factor (CSF) pegfilgrastim (Neulasta) during each cycle of chemotherapy, including the first, had significantly less febrile neutropenia than patients who received it only after the first cycle, according to the results of a large, community-based clinical trial. Those receiving the drug in the first cycle also had fewer hospitalizations and other neutropenia-related complications, said Lodovico Balducci, MD, head of the senior adult oncology program at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Dr. Balducci reported the findings at the Geriatric Oncology Consortium annual meeting (abstract 3).

The number of older adults in the general population continues togrow. As their numbers rise, the elderly and the management of theirmedical problems must be of increasing concern for health-care professionals.Within this older population, cancer is a leading cause ofmorbidity and mortality. Although many studies have looked at the psychiatricimplications of cancer in the general population, few studiestackle the issues that may face the older adult with cancer. This articlefocuses on the detection and treatment of depression, anxiety, fatigue,pain, delirium, and dementia in the elderly cancer patient.

Dr. Khatcheressian and colleagueshave nicely reviewedboth barriers to palliative andsupportive care and remedies.

The management of ovarian cancer entails a complex blend of medicaland surgical interventions. Managing patients with recurrent ovariancancer increases the complexity of therapies and adds palliative interventions.The presence of recurrent ovarian cancer is both emotionally andphysically taxing for patients as well as their caregivers. With an increasinglyinformed patient population, a balance must be achieved betweeneasily accessible information enabling patients to know that they nowhave an incurable disease and support for their hopes and desires to stillovercome their cancer. The decision tree in the management of recurrentovarian cancer blends many different factors. This discussion will separatethose factors as if they are pure elements. We will address managementbased on response to primary therapy and time to recurrence, thelocation of recurrence, symptoms of recurrence, the patient’s histopathology,and the patient’s primary stage as it relates to the extent of diseasepresent at the start of chemotherapy.

In their article, Drs. Michener andBelinson make the case for treatingrecurrent ovarian cancer as achronic disease, with limiting morbidityand providing palliation of symptomstheir major goals. A review ofrecent literature would support their contention and management strategy.The cure rate for patients with recurrentovarian cancer is < 5%, and theaverage patient in the United Statesreceives more than five separate regimensof chemotherapy for recurrentdisease. Previous attempts at aggressivetreatment for recurrent disease haveshown, at best, very modest benefitwith significant expense and morbidity.What we are left with is a strategy oftrying to determine which patients maybenefit from aggressive salvage therapyand which are better managed witha chronic palliative attempt.

Despite major advances in cancerbiology and therapeutics,cancer and its treatment continueto cause devastating suffering,not only for the more than half a millionpatients who will die this yearfrom cancer, but also for many ofthose who will be successfully treated.[1] Symptom burden has a profoundimpact on the quality of life ofcancer patients across all stages of disease.Routine screening of ambulatorycancer patients identifies an average of7 to 10 distressing physical and psychologicalsymptoms per patient.[2]Even patients with a good performancestatus have a median of nine or moresymptoms.[3,4] Not surprisingly, theseverity and burden of symptoms nearthe end of life is even greater.[4]

Twenty years of research in controlling symptoms such as pain andnausea have shown persistent suboptimal performance by the US oncologysystem. The data suggest that some of the tools of palliative careprograms can improve physical symptoms of seriously ill patients at acost society can afford. To fix these problems will require recognitionof the symptoms or concerns, a system such as an algorithm or careplan for addressing each, measurement of the change, and accountabilityfor the change. Symptom assessment scales such as the EdmontonSymptom Assessment Scale or Rotterdam Symptom Check List work tomake symptoms manifest. Listing symptoms on a problem list is a necessarystep in addressing them. Physical symptoms such as pain can beimproved by use of computer prompts, algorithms, dedicated staff time,team management, or combinations of these strategies. Less concreteproblems such as medically appropriate goal-setting, integrating palliativecare into anticancer care sooner, and informing patients aboutthe benefits and risks of chemotherapy near the end of life require morecomplex solutions. We review what is known about symptom control inoncology, how and why some programs do better, and make suggestionsfor practice. Finally, we suggest a practical plan for using symptomassessment scales, listing the problems, and managing them accordingto algorithms or other predetermined plans.

The field of palliative care hasgrown rapidly in recent yearsin response to patient need andclinician interest in effective approachesto managing chronic andlife-threatening illness. The article byKhatcheressian et al reviews the datathat make the case for palliative careas a core component of modern oncologypractice. They point out thatthe issue is not whether we have aquality problem here-it is clear thatwe do. Rather, the focus of this articleis on how best to address that problemin the context of the very real time andfinancial constraints in which we nowpractice oncology in the United States.

Significant improvements in the management of patients with endstagerenal disease (ESRD) who are on chronic renal replacementtherapy (CRRT), has led to an increased prevalence of this populationamong older Americans. Since cancer is also common in the elderly,oncologists are likely to be faced with patients who suffer from bothcancer and ESRD. There is a paucity of information regarding issuessurrounding the optimal management of such patients, especially thoseneeding chemotherapy. This review surveys the relevant problemsoncologists may encounter in such patients and summarizes the availableliterature on chemotherapeutic management of common cancers.The reader is strongly urged to consult the original references for detailsof chemotherapy administration prior to use in an individualpatient.

Advanced cancer in the setting of liver dysfunction poses a dilemmafor physicians, as many cancer chemotherapeutic agents undergo hepaticmetabolism. Most cytotoxic drugs have a narrow therapeutic index,and the administration of chemotherapy to patients with liver impairmentresults in complicated safety issues. We present a concise reviewof cancer chemotherapy dosing in the setting of liver dysfunction.Although caution in treating all patients with hepatic failure is essential,the use of certain agents provokes greater concern than others.Continuous-infusion fluorouracil, capecitabine (Xeloda), mechlorethamine(Mustargen), cyclophosphamide, topotecan (Hycamtin), andoxaliplatin (Eloxatin) appear to be relatively well tolerated. On thecontrary, taxanes, vinca alkaloids, irinotecan (Camptosar), andanthracyclines may cause unacceptable toxicity if administered to patientswith poor hepatic function. For many anticancer agents, the paucityof data prohibits formal dosing recommendations, and most guidelinesremain empiric.

Cappuzzo and colleagues havereviewed the present optionsof salvage therapy for advancednon–small-cell lung cancer(NSCLC). This issue is highly relevantnowadays, as many patients whofail palliative chemotherapy are stillin sufficiently good condition to receiveadditional therapy. It is ratherinstructive to note that 10 years agothe use of systemic chemotherapy foradvanced NSCLC was advocated butstill not standard, and today we haveseveral options for treating patients inthe second- and even third-line setting.Among these options are agents thatspecifically target molecular featuresof lung cancer, such as the epidermalgrowth factor receptor (EGFR)

Thromboembolism affects many patients with solid tumors and clonalhematologic malignancies. Thromboprophylaxis with low-molecularweightheparin (LMWH) is indicated for surgery and other high-risksituations, but not routinely for central venous catheters or nonsurgical,ambulatory management. Thrombotic events require full anticoagulationfor the duration of active disease and/or the prothromboticstimulus. LMWHs are safe and more effective than both unfractionatedheparin for initial therapy and warfarin for secondary prevention. Antiinflammatoryand antiangiogenic properties might account for thisadvantage and for a survival benefit of chronic LMWH in subgroupsof cancer patients. Ongoing studies are characterizing the cost-effectivenessand antitumor mechanisms of LMWHs, the potential utility ofnewer anticoagulants, and the ability of predictive models to identifyhigh-risk candidates for thromboprophylaxis.

Thromboembolism affects many patients with solid tumors and clonalhematologic malignancies. Pathogenetic mechanisms include inflammatory-and tissue factor-mediated coagulation, natural anticoagulantdeficiencies, fibrinolytic alterations, hyperviscosity, and activationof platelets, endothelial cells, and leukocytes. High rates of venousthromboembolism (VTE) occur with advanced pancreatic, breast, ovarian,germ cell, lung, prostate, and central nervous system cancers.Hodgkin disease, non-Hodgkin's lymphoma, myeloma, paroxysmalnocturnal hemoglobinuria, and certain leukemias also predispose tovenous thromboembolism. Arterial and venous events occur with polycythemiavera and essential thrombocythemia. Central venous cathetersand prothrombotic antitumor regimens augment the risk in somepatients. Part 1 of this two-part article addresses pathophysiology, clinicalpresentations, and risk of malignancy-associated thrombosis. Part 2,which will appear in next month's issue, covers prophylaxis and treatmentof these thromboembolic complications.

PHOENIX-Between 17.5% and 29.8% of 57 nonmetastatic breast cancer patients had cognitive impairment prior to starting chemotherapy in an ongoing study exploring the effects of chemotherapy on cognitive functioning among breast

SAN ANTONIO-Prophylactic pegfilgrastim (Neulasta) for patients undergoing myelosuppressive chemotherapy should be used at lower levels of febrile neutropenia risk than are currently recommended by guidelines, according

Approximately 70% to 80% of all patients who receive chemotherapyexperience nausea and vomiting, which can disrupt their lives in numerousways. Chemotherapy-induced nausea and vomiting (CINV) hastraditionally been classified according to three patterns: acute, delayed,and anticipatory. Additional classifications include refractory and breakthroughnausea and vomiting. The mechanisms by which chemotherapycauses nausea and vomiting are complex, but the most common isthought to be activation of the chemoreceptor trigger zone. An appreciationof the risk factors for developing CINV is important when matchingantiemetic treatment to risk. The emetogenicity of the chemotherapyregimen-generally categorized as high, moderate, low, or minimal-greatly affects a patient’s risk for developing CINV. In addition to establishedand emerging pharmacologic approaches to managing CINV,many complementary and integrated modalities may be options.Progress in CINV management must include a better understanding ofits etiology and a focus on prevention. This review will consider theetiology, assessment, and treatment of patients with CINV.

Colony-stimulating factors are glycoproteins that act on hematopoietic cellsby binding to specific cell surface receptors and stimulating proliferation,differentiation commitment, and a degree of end-cell functional activation.Granulocyte colony-stimulating factor (G-CSF), produced by monocytes,fibroblasts, and endothelial cells, regulates the production of neutrophils within thebone marrow and affects neutrophil progenitor proliferation.[1,2]

Renal-cell carcinoma (RCC) is curable only in patients presenting with resectable, early-stage disease. Advanced local or metastatic disease carries an approximate 15% 5-year survival rate. However, the natural history of metastatic RCC is heterogeneous, and aggressive palliative treatment is recommended, especially for patients with a solitary metastatic site and good performance status.

Opioid rotation involves changing from one opioid to another usingcorrect equianalgesic conversion techniques to achieve better analgesiaand/or fewer side effects. The strategy appears to work because ofsignificant interindividual variations in response to both analgesic activityand toxicity. Although there are many retrospective studies, fewprospective controlled trials of opioid rotation have been published.The practical and theoretical advantages of opioid rotation includeimproved analgesia, reduced side effects, cost reduction, and improvedcompliance. Disadvantages include problems related to inaccurate conversiontables, limited availability of certain opioid formulations, druginteractions, and the possibility of increased expense. Weighing theadvantages and disadvantages is essential prior to making a decisionabout opioid rotation selection.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2004, asreported in ONI. Guest editor Dr. Roy Herbst discusses these advances in clinicalmanagement, with a focus on developments in adjuvant therapy for early disease,targeted therapy, and new chemotherapy findings.

Malnutrition plays a key role in the morbidity of head and neckcancer patients receiving surgery, chemotherapy, radiotherapy, or combined-modality therapy. In addition to weight lost prior to the diagnosisof head and neck cancer, the patient may lose an additional 10% ofpretherapy body weight during radiotherapy or combined-modality treatment.A reduction of greater than 20% of total body weight results inan increase in toxicity and mortality. Severe toxicity can result in prolongedtreatment time, which has been implicated in poor clinical outcome.Early intervention with nutritional supplementation can reducethe chance of inferior outcome in patients at high risk of weight loss.The preferred route of nutritional support for these patients is enteralnutrition. Two commonly used methods for enteral feedings arenasoenteric and percutaneous endoscopic gastrostomy. It is importantto take into account the ethical considerations involved in providinglong-term nutritional support, particularly for patients with terminalconditions. Nutritional directives are best evaluated throughmultidisciplinary efforts, including input from the patient as well asmembers of the nursing, nutritionist, and medical staff.

The emergence of resistance and changes in the spectrum ofCandida infections have led to an increased interest in susceptibilitytesting of antifungal drugs. Such testing may be particularly useful inpatients with invasive candidiasis who have been previously treated withazole antifungals, those whose infections are not responding to treatment,and those with infections caused by non-albicans species of Candida.The choice of a specific antifungal depends on the clinical statusof the patient, the relative toxicity and efficacy of the drug in the givenpatient population, the infecting species and antifungal susceptibilityof the isolate, and the patient’s prior exposure to antifungal agents.Infectious Diseases Society of America recommendations for the initialmanagement of candidemia and acute disseminated candidiasisinclude an azole, caspofungin, amphotericin B (AmB), or a combinationof fluconazole plus AmB. Caspofungin and voriconazole show goodactivity against most Candida species and may be good alternatives forpatients with Candida glabrata and Candida krusei infections and forthose with relapsing infections.

Candida is recognized as the fourth most common cause of bloodstreaminfection in the United States, with a high attributable mortalityrate. While Candida albicans remains the most common pathogen, nonalbicansCandida species, including Candida glabrata and Candidakrusei, with greater resistance to triazoles are being increasingly isolated.These epidemiologic changes are attributable to a combinationof factors, such as the use of fluconazole prophylaxis, changes in patientdemographics and underlying diseases, and use of therapeuticstrategies that may pose unique risks. Of particular concern is the increasedprevalence of species that are resistant to the azole antifungals.Candida glabrata, for example, is often resistant to fluconazole,and its ability to become cross-resistant to newer azole antifungals is arecent concern. Increasing evidence underscores the need to carefullyevaluate antifungal treatment options, according to both host and therapeuticrisks for drug resistance.

There has been a remarkable explosion in medicalinformation over the past several years.The rate of new discoveries and improved understandingof the biology and treatment ofcancer is ever-increasing. The same is true inthe area of supportive cancer therapy.[1]

Oxaliplatin (Eloxatin) is a novel platinum compound that has activityin a wide variety of tumors. Several hypersensitivity reactions distinctfrom laryngopharyngeal dysesthesia have been described. We retrospectivelyanalyzed 169 consecutive patients who received oxaliplatinfor esophageal or colorectal cancer between 1/1/00 and 7/31/02 andreviewed any significant adverse reactions labeled as hypersensitivityreactions. Thirty-two patients (19%) reportedly experienced hypersensitivity.Skin rash was the most common event (22 patients), occurringafter a median of three infusions. Fever was seen in five patients aftera median of two infusions. Five patients experienced respiratory symptomsat median infusion number 6. Ocular symptoms of lacrimationand blurring of vision were seen in two patients. Five patients experiencedmore than one type of reaction. Treatments prescribed forhypersensitivity were antihistamines, steroids, and topical emollients.One patient developed grade 4 hypersensitivity during cycle 6, characterizedby laryngeal edema, tongue swelling, and labored breathing.This patient underwent a desensitization procedure, adapted from guidelinesfor carboplatin (Paraplatin) allergy. Subsequently, three cycleswere administered over 6 hours and were well tolerated. However,during the fourth infusion postdesensitization, the patient developedrecurrent signs of hypersensitivity. In conclusion, hypersensitivity isfrequently seen with oxaliplatin, but most reactions are mild.

Considering the significant morbidity and mortality associated withinvasive fungal infections in immunocompromised patients, it is particularlyimportant to make the diagnosis as early as possible and tomake best use of the available antifungal drugs for prophylaxis andtreatment. The newer antifungal drugs include the lipid products ofamphotericin B, such as amphotericin B lipid complex (ABLC) andliposomal amphotericin B; voriconazole (a triazole); and caspofungin(an echinocandin). ABLC and liposomal amphotericin B are as effectiveas amphotericin B deoxycholate but are less nephrotoxic; ABLC isprobably the drug of choice for zygomycosis. Voriconazole is approvedfor use in the treatment of invasive aspergillosis and may have a role inpreventing breakthrough fungal infections in patients with persistentfever and neutropenia. Caspofungin is effective against both invasiveaspergillosis and invasive candidiasis.

Combination therapy with amphotericin B and flucytosine is consideredto be the treatment of choice for cryptococcal infections. However,for other infections and combinations of antifungal infections,the data are less clear-cut. The concurrent use of amphotericin B withan azole has elicited controversy, given the potential of antimicrobialantagonism. The results of one recent candidemia study suggest thatthe potential antagonism may not be an issue; the combination of amphotericinB and fluconazole provided more effective clearance of Candidafrom the bloodstream than did fluconazole used alone. Several invitro and animal studies have shown antagonism between the azolesand amphotericin B for aspergillosis. However, introduction of the newclass of agents that target β-glucan synthase (echinocandins) has invigoratedthe prospects of combination therapy. The echinocandins andpolyenes are not antagonistic, and there is evidence that theechinocandins may provide additive to synergistic activity in combinationwith triazoles. For patients whose aspergillosis is progressing despitemonotherapy, the addition of a second agent, such as anechinocandin, may be reasonable.

Delirium in the setting of terminalillness is common; moreover,it can create extremehardships for patients and their families,who are already facing the mostdifficult of circumstances. However,delirium that develops in the contextof comorbid medical conditions maybe readily reversible with thoughtfulevaluation and effective management.Friedlander, Brayman, and Breitbartdescribe important factors to considerwhen assessing and treating deliriumin the context of end-stage illness.We will elaborate on their discussionand emphasize some common pitfallsassociated with the management ofdelirium.

Depression is seen in many cancer patients. It is an especially importantissue in palliative care, as depression can be more common inpatients who are at the end of life. Accurate assessment and treatmentcan have a powerful impact on improving a patient's quality of life.This article reviews the definition and the differential diagnosis of depressionin cancer patients. It then focuses on some of the treatmentoptions available, including pharmacotherapy and psychotherapy.

Miriam Friedlander, YanaBrayman, and WilliamBreitbart have produced anexcellent review of delirium in thepalliative care setting. Their paper isthorough, readable, and thoughtful,and will be helpful to oncologists caringfor patients with advanced illness.I particularly like the fact that theauthors make it clear that delirium isnot only a very common complicationof advanced cancer, but that it isalso a major source of suffering anddistress for both patients and families.In view of the problems deliriumpresents and the frequency with whichdelirium arises as death approaches,this complication of advanced and terminalillness has received inadequateattention. My thanks and congratulationsgo to the authors for providingsuch a clear and helpful review of thischallenging clinical problem.