ONCOLOGY Vol 19 No 14

Drs. Perez and Muss provide acomprehensive review of therole of adjuvant chemotherapyin the management of breast cancerpatients. The benefits of anthracyclinevs nonanthracycline regimens are discussed,the taxanes are reviewed indetail, and data regarding dose intensity,dose density, and optimal numberof chemotherapy cycles areexplored. Data on newer agents andbiologic agents also are presented.Debate continues regarding the subsetsof patients who will derive thegreatest benefit from chemotherapyand which regimen is most appropriate.While the review indicates theefficacy of several regimens as definedby randomized clinical trials, itdoes not emphasize patient-specificfactors in determining the optimaltherapy for a given patient.

In 2005, an estimated 29,370 newcases of oral cavity and pharyngealcancers were diagnosed inthe United States, accounting for2.14% of all cancer cases.[1] Over7,000 individuals will die from thesecancers in this country in 2005-approximately one death per hour.Many advances have been made inthe diagnosis and treatment of thesecancers, yet the mortality rate remainshigh (5-year survival rate of ~50%).Probably the most important approachis early detection, since early-stagetumors are associated with markedlybetter survival rates than late-stagecancers that have already spread toregional tissues and lymphatics.

Treatment options for patientswith myeloma have movedfrom the relatively ineffectivecombinations of cytotoxic agents andcorticosteroids, to the widespread useof high-dose therapy and autologousbone marrow or peripheral blood stemcell transplant. Through this transition,the overall survival for patientshas nearly doubled from a previousmedian survival of 2 to 2.5 years, upto 4 to 5 years based on the transplantarms of several large randomizedclinical trials.[1-3] In this issue ofONCOLOGY, Dr. Richardson andcolleagues extensively detail the recentadvances in myeloma therapythat involve the use of more “modern”or novel agents such as thalidomide(Thalomid), lenalidomide (Revlimid),and bortezomib (Velcade). Theseagents are of monumental importance in the assault on myeloma as theyhave provided much needed advancesfor patients with relapsed and refractorymyeloma and, in doing so,have set the stage for the next majorrevolution in myeloma therapy.

Xerostomia is a permanent and devastating sequela of head and neckirradiation, and its consequences are numerous. Pharmaceutical therapyattempts to preserve or salvage salivary gland function through systemicadministration of various protective compounds, most commonlyamifostine (Ethyol) or pilocarpine. When these agents are ineffective orthe side effects too bothersome, patients often resort to palliative care, forexample, with tap water, saline, bicarbonate solutions, mouthwashes, orsaliva substitutes. A promising surgical option is the Seikaly-Jha procedure,a method of preserving a single submandibular gland by surgicallytransferring it to the submental space before radiotherapy. Improved radiationtechniques, including intensity-modulated radiotherapy andtomotherapy, allow more selective delivery of radiation to defined targetsin the head and neck, preserving normal tissue and the salivary glands.Acupuncture may be another option for patients with xerostomia. All ofthese therapies need to be further studied to establish the most effectiveprotocol to present to patients before radiotherapy has begun.

In 2004, multiple myeloma was diagnosed in more than 15,000 peoplein the United States and will account for approximately 20% of deathsdue to hematologic malignancies. Although traditional therapies suchas melphalan (Alkeran)/prednisone, combination chemotherapy withVAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), andhigh-dose chemotherapy with stem cell transplantation have shownsome success, median survival remains between 3 to 5 years. Treatmentoptions for patients with multiple myeloma have increased in recentyears, with the promise of improvement in survival. New agents, suchas the proteasome inhibitor bortezomib (Velcade), the antiangiogenicand immunomodulator thalidomide (Thalomid) and its analogs, suchas lenalidomide (Revlimid), together with other small molecules, includingarsenic trioxide (Trisenox), and other targeted therapies, havebeen studied alone and in combination with other antineoplastic therapies,either as induction therapy prior to stem cell transplantation or inpatients with relapsed disease. Bortezomib recently was approved inthe United States for the treatment of multiple myeloma in patientswho have received at least one prior therapy. The use of bortezomibbasedregimens as front-line therapy as well as the use of other agentsin multiple myeloma remain under investigation, and approvals forboth thalidomide and lenalidomide are hoped for soon, with the overallprospect of patient outcome continuing to be increasingly positive.

The review by Kahn andJohnstone published in this issueof ONCOLOGY is comprehensiveand interesting. A fewpoints deserve emphasis, the first ofwhich is the issue of how we shouldmeasure and report xerostomia. Accurateand reliable measurements ofxerostomia are necessary in order toproperly assess its severity, timecourse, dose-response relationships,and the efficacy of measures to protectthe glands or to stimulate salivaryproduction following irradiation. Xerostomiaencompasses the objectivereduction in salivary output andchanges in its composition, as well asthe subjective symptoms reported bythe patient. Currently available measurementsof xerostomia include(1) functional imaging of gland activity,(2) measurements of the salivaryoutput, (3) observer-assessed toxicitygrading, and (4) instruments assessingpatient-reported evaluation of thevarious xerostomia-related symptoms.

In the past decade there has been arapid increase in our understandingof the biology of multiple myelomaand the development of newtreatment strategies.[1] In the currentissue of ONCOLOGY, Richardson etal provide an excellent overview ofnew agents in the treatment of multiplemyeloma. Two of these agentsare currently available in the UnitedStates outside of clinical trials: thalidomide(Thalomid) and bortezomib(Velcade). The thalidomide analog-lenalidomide (Revlimid)-will likelybe available in the near future,while several other novel agents arebeing evaluated in clinical trials.Richardson and colleagues haveplayed a major role in the developmentof bortezomib and lenalidomide,as well as numerous novel agentscurrently in clinical trials. Their reviewis therefore particularly enlightening,and provides a first-handaccount of the clinical developmentof various new drugs for the treatmentof myeloma.

Improvements in early diagnosisand treatment of breast cancer overthe past few decades have clearlyreduced disease-related mortality. The2000 Oxford Overview published recentlyby the Early Breast Cancer Trialists’Cooperative Group (EBCTCG)highlights some of the widely practicableadjuvant drug treatments thatwere under investigation in the 1980s,and have substantially reduced 5-yearrecurrence rates as well as 15-yearmortality rates.[1] Optimal adjuvanthormone therapy is associated with asubstantial improvement of diseaseoutcomes in hormone receptor–positivewomen. Chemotherapy is alsoassociated with considerable benefitsin women with breast cancer, regardlessof age, stage, or hormone receptorstatus. However, chemotherapy isnot without risks. The treatment isassociated with many adverse eventsthat may significantly affect a patient’squality of life while she is receivingtreatment. Other effects may be longstanding,permanent, and, rarely, lifethreatening.

Malignant glioma, the mostcommon primary centralnervous system (CNS) tumorin adults, remains one of the greatesttherapeutic challenges in oncologytoday due to the limited impact ofconventional cytotoxic therapies onoverall survival for patients with thesetumors. Although surgery and external-beam radiotherapy (XRT) can prolongsurvival, the value of adjuvantchemotherapy has been negligible formost malignant glioma patients. Theexception has been those patients withanaplastic oligodendroglioma and accompanyingchromosomal 1p and 19qloss-a fairly uncommon subset ofmalignant glioma patients who respondvery favorably to alkylatorbasedchemotherapy.[1]

The treatment of malignant gliomashas received significant attentionover the past decade.This likely represents recognition ofthe poor prognosis associated withthese cancers combined with the challengeof developing a treatment strategyfor a neoplasm that, although itrarely metastasizes, has not proven tobe curable by surgical resection. Infact, debate continues about the roleof aggressive surgery in this disease,given that an image-guided biopsycan provide accurate diagnosis whileminimizing any procedure-relatedmorbidity and mortality. Some studieshave strongly suggested a therapeuticbenefit with surgical resection,but the extent of resection is a criticalcomponent.

This review of adjuvant chemotherapyby Perez and Muss isconcise and complete. For themost part, the authors present the datain a balanced way. The role of adjuvantchemotherapy has been establishedin breast cancer. Appropriateutilization of adjuvant chemotherapycan significantly reduce the risk ofdisease recurrence and improve survival.These benefits are associatedwith adjuvant chemotherapy regardlessof the age of the patient, nodalstatus, or hormonal status of cancer.

Mortality in breast cancer has declined in the past decade, owing toadvances in diagnosis, surgery, radiotherapy, and systemic treatments.Adjuvant chemotherapy has had a major effect on increasing survivalin women with locoregional breast cancer. Like all treatments, adjuvantchemotherapy is a work in progress, and it has evolved from singleoral agents to complex multidrug regimens. The choice of regimens isnot without controversy, however, and several have been shown to bemore effective than others, especially in patients who are at high riskfor recurrence. The taxanes paclitaxel and docetaxel (Taxotere) havebeen shown to be effective in the adjuvant setting, and they have alsobeen shown to improve the outcomes in node-positive disease. Bothdisease-free and overall survival are greater with doxorubicin,paclitaxel, and cyclophosphamide given in a dose-dense, every-2-weekschedule with growth factor support than with the same agents givenin an every-3-week schedule. Disease-free and overall survival in patientswith node-positive disease are greater with docetaxel, doxorubicin(Adriamycin), and cyclophosphamide (TAC) than with fluorouracil,doxorubicin, and cyclophosphamide (FAC). Febrile neutropenia iscommon with the TAC regimen, but it can be minimized with growthfactor support. Based on these findings, dose-dense therapy and TAC arethe current adjuvant treatments of choice in patients with node-positivedisease; other, less-intense regimens may be appropriate in patientswith lower-risk disease. Ongoing trials are investigating the efficacy ofcommonly used regimens, new chemotherapeutic and biologic agents,and novel doses and schedules of currently available agents.

Glioma is the most common form of primary brain tumor, as well asthe most lethal. Primary treatment strategies for glioma, includingcytoreductive surgery, external-beam irradiation, and systemic chemotherapyhave had generally disappointing results for these tumors. Limitationsof these approaches include tumor invasion into functional braintissue, lack of chemosensitivity, and shortcomings of systemic delivery.Recent attention has focused on locoregional strategies for treatment,as well as new methods for delivering therapy. Identification of tumorspecificsurface targets, biologic agents, and more sophisticated meansto deliver macromolecules to the brain is offering new promise in thetreatment of these tumors. This paper will review the current state ofthe art of available locoregional therapies for glioma, with a particularfocus on convection-enhanced delivery, targeted toxin, and other biologicstrategies.