ONCOLOGY Vol 18 No 7

The rationale for graft purging-that infusion of malignant cellscontained within the hematopoieticprogenitor cells (HPC) infusedback to patients who have receivedhigh-dose therapy will contribute torelapse-seems very sound. Whowould willingly be infused with cancercells, and who would ever suggestthat infusion of such cancer cells couldever be thought of as a good idea?Nonetheless, Alvarnas and Forman arecorrect in their conclusion that purginghas never been demonstrated tolead to improved outcome in randomizedtrials.

Virtually every management decisionrelated to prostate canceris highly controversial.Should we screen men for prostatecancer with prostate-specific antigen(PSA)? If so, what are the proper cutoffvalues? If we detect an early prostatecancer, is treatment warranted? Ifwe find an aggressive cancer, is treatmenteffective? If treatment is deemedwarranted, what is the optimal managementstrategy (radical prostatectomyvs radiation therapy)? If radicalprostatectomy is selected, should theprocedure be performed roboticallyor via an open approach? If radiationtherapy is selected, does eitherbrachytherapy or external-beamirradiation offer an advantage? Isthere a role for neoadjuvant hormonaltherapy in men undergoing definitiveintervention?

Locally advanced non–small-cell lung cancer represents 30% to 40%of all pulmonary malignancies. Most patients will die of the diseaseafter aggressive contemporary treatments. Therefore, significant improvementin therapeutic methods must be implemented to improveoverall survival rates. The arrival of a new generation of chemotherapeuticagents-including the taxanes, gemcitabine (Gemzar), andtopoisomerase inhibitors such as irinotecan (Camptosar) and topotecan(Hycamtin)-offers the hope of significant advances in the treatmentof lung cancer. Irinotecan and topotecan are camptothecin derivativesthat inhibit topoisomerase I enzyme. It is believed that topoisomerase Iinhibitors stabilize a DNA/topoisomerase I complex and interact withreplication machinery to cause cell death. A significant amount of datademonstrates that these topoisomerase I inhibitors also act asradiosensitizers. With the increasing data that support concurrentchemoradiation treatment for malignancies, including lung cancer andhead and neck cancers, there is an impetus to pursue the additionaldrugs that may potentially improve local control and survival. Irinotecanis undergoing early clinical trials in the combined-modality setting inseveral different disease sites. This paper will review the data on therole of camptothecin derivatives as a radiosensitizer and as a componentof combined-modality therapy for lung cancer. It is hoped thatnewer treatment strategies, like the combination of radiation andtopoisomerase I inhibitors, will have a significant impact on cure ratesin the future.

Not so long ago, therapeutic decisionsin chronic myeloid leukemia(CML) were ratherstraightforward: Allogeneic bonemarrow transplantation was performedin all patients with a donorwho were deemed fit enough for theprocedure, interferon-alfa was administeredto all others able to tolerate it,and the remainder received hydroxyurea.The advent of imatinibmesylate (Gleevec) and, to a lesserdegree, the development of reducedintensityconditioning regimens, haveradically changed the approach totreating CML and have considerablyincreased the complexity of treatmentdecisions.

In the early 1990s, a few Europeanphysicians met to design a trialassessing the value of high-dosetherapy followed by autologous stemcell transplantation in relapsed follicularnon-Hodgkin’s lymphoma(NHL). Extensive discussions werealso devoted to the topic of purgingthe stem cell graft. Some of us felt itdid not make sense to reinfuse tumorcells after the application of high-dosetherapy including total-body irradiation:“The tumor cells were clearlyvisible in the bone marrow.” Othersfelt there may be a difference betweenmonoclonal cells visible in the marrowand clonogenic cells that maygive rise to a relapse. It was the era ofthe first positive data on purging inAML[1] and NHL.[2,3] In those discussions,it was apparent that therewere believers and nonbelievers.

In order to understand the controversiesin chronic myeloid leukemia(CML), one must understandthe current status of the disease. Withthe introduction of imatinib mesylate(Gleevec), our knowledge of the biologyof the disease, as well as treatmentmodalities, has changed. AsMughal and Goldman illustrate, wecurrently know extensive detail aboutthe mechanisms involved in the developmentand progression of this disease.Short of developing a cure forCML, continuing investigation is un-coveringimportant and useful informationregarding the prognostic variablesto be considered when makingtreatment decisions. Ironically, the olddilemma of who should receive atransplant and when is now more difficult.Managing a seemingly straightforwardcase is complex, andestablished clinical investigators havebeen humbled by their decisions.

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.

In this issue of ONCOLOGY, Daviset al provide a succinct overviewof the contemporary managementof high-risk prostate cancer patients.[1] As the authors point out, theintroduction and widespread implementationof prostate-specific antigen(PSA) as a tumor marker hasdriven a remarkable stage migrationin how patients present with prostatecancer, yet a significant number ofmen continue to present with featuresplacing them at high risk for localtreatment failure, development ofprostate cancer metastases, and ultimately,death.

The analysis, “Graft Purging inAutologous Bone MarrowTransplantation: A Promise NotQuite Fulfilled,” by Drs. Joseph Alvarnasand Stephen Forman, is verytimely. The authors’ conclusion is succinctlypresented in their title.

The article by Davis et al is importantfor several reasons.First, it reminds us about themost lethal phenotype in patients withapparently localized prostate cancer.This subgroup is easily forgotten intoday's era of PSA screening becausethe majority of patients now diagnosedwith prostate cancer are classified aslow risk. Second, there have been few,if any, good reviews that define theissues, including the definition ofhigh-risk disease, the effectiveness ofthe major treatments (ie, radical prostatectomy,radiation therapy, and theirneoadjuvant or adjuvant supplementaltherapies), and the current gaps inour knowledge of these issues.

Clonogenic tumor cells contained within hematopoietic stem cell(HPC) grafts may contribute to relapse following autologous transplantation.Graft purging involves either in vivo or ex vivo HPC manipulationin order to reduce the level of tumor cell contamination.Some phase II trials suggest that patients who receive purged productsmay have a superior transplant outcome. Phase I trials demonstratethe feasibility of purging methods including ex vivo graft incubationwith chemotherapeutic drugs, monoclonal antibodies and complement,and CD34+ cell selection. A phase II trial in follicular non-Hodgkin’slymphoma demonstrates that patients who receive HPC products purgednegative for bcl-2 gene rearrangements have a superior outcome, comparedwith patients who receive polymerase chain reaction (PCR)-positiveproducts. This finding, however, has not been confirmed in a randomizedtrial. HPC purging has demonstrated no benefit in a phase IIItrial in myeloma. Phase II trials in acute myelogenous leukemia showcomparable outcomes for patients who receive either purged orunpurged HPC grafts. Limitations of purging include possible progenitorcell loss, delayed engraftment, and qualitative immune defects followingtransplant. Data to justify routine use of HPC graft purging areinsufficient. Phase I and II data support development of phase III trialsof both in vivo and in vitro purging methods.

Among patients with lung cancer, approximately 15% have smallcelllung cancer (SCLC). The clinical characteristics of SCLC tend tobe more aggressive, but also more sensitive to chemotherapy and radiationtherapy than those of non-SCLC. Irinotecan (Camptosar) is aderivative of camptothecin, an inhibitor of the nuclear enzymetopoisomerase I. Irinotecan has been shown to exhibit excellent antitumoractivity against SCLC in monotherapy regimens and in combinationwith cisplatin. A phase III trial comparing irinotecan and cisplatin(IP) with etoposide and cisplatin (EP) in patients with previously untreatedextensive-stage SCLC (ED-SCLC) was conducted. Patients inthe IP arm responded significantly better than patients in the EP arm.In the IP arm, the response rate was 84%, and median overall survivalwas 12.8 months. A phase II trial of irinotecan, cisplatin, and etoposide(IPE) administered weekly (arm A) or every 4 weeks (arm B) for EDSCLC(JCOG 9902-DI) was also performed. In arm B, the responserate was 77% and the median overall survival was 12.9 months. A randomizedtrial comparing IP with IPE administered every 3 weeks inpatients with previously untreated ED-SCLC is presently being performedin Japan.

New agents with improved systemic activity are needed for the treatmentof lung cancer. Irinotecan (Camptosar) is a promising agent inadvanced non–small-cell (NSCLC) and small-cell lung cancer (SCLC).In a Japanese phase III trial of advanced NSCLC, irinotecan oririnotecan/cisplatin demonstrated a significant survival advantage comparedto the standard of vindesine/cisplatin. Similar North Americanphase III trials focusing on irinotecan’s role in NSCLC are under way.Ongoing trials have also been launched to corroborate the significantsurvival advantage reported by a Japanese phase III trial for irinotecan/cisplatin vs standard etoposide/cisplatin in extensive SCLC. Currentand planned trials in NSCLC with irinotecan in combination withgemcitabine (Gemzar), the taxanes, and other new agents, and thoracicradiotherapy should also provide useful clinical data. Moreover,trials in SCLC are investigating the rationale of combining irinotecanwith a platinum agent as a component of chemoradiotherapy regimens.Promising data from these and other studies will further elucidate arole for irinotecan in the management of lung cancer.

Until recently, the standard treatment for newly diagnosed patientswith chronic myeloid leukemia (CML) in chronic phase who were noteligible for allogeneic stem cell transplant was interferon-alfa alone orin combination with low-dose cytarabine. Moreover, about 20% to 25%of patients who were relatively young and had suitable HLA-matcheddonors have in recent years been offered treatment by allogeneic stemcell transplantation, a procedure that can cure CML but is associatedwith an appreciable risk of morbidity and mortality. However, followingthe recognition in the 1980s that the p210 oncoprotein encoded bythe BCR-ABL fusion gene on the Philadelphia chromosome had greatlyenhanced tyrosine kinase activity and was probably the initiating eventin the chronic phase of CML, much effort was directed toward developmentof drugs that would selectively inhibit this kinase activity. In 1998these efforts culminated in the first clinical use of imatinib mesylate(Gleevec), which has since been shown to produce impressive results intreatment of patients with CML in chronic phase. In previously untreatedpatients, the incidence of complete cytogenetic responses exceeds80%, and the majority of responses appear thus far to be durable.Imatinib also proved active in patients with accelerated phase and blasticphase disease, but in most of these cases, the benefits have been relativelyshort-lived. The advent of imatinib has thus necessitated a fundamentalreappraisal of the approach to the initial management of CML.

Lung cancer is a major health problem worldwide. Non–small-celllung cancer (NSCLC) accounts for 80% to 85% of all lung cancers,while small-cell lung cancer (SCLC) accounts for 15% to 20% of cases.For early-stage and locally advanced NSCLC (stages I through III), amultimodality treatment approach is appropriate because it improvessurvival. Combination chemotherapy is currently the standard treatmentfor good performance patients with metastatic disease. Elderlypatients (≥ 70 years) with metastatic NSCLC also benefit from treatment.In SCLC, concurrent radiation therapy and chemotherapy is thestandard for limited disease, while chemotherapy is the treatment forextensive disease. Novel innovative therapies, which could includemolecular targeting agents, are needed to treat both NSCLC and SCLC.

Screening for prostate cancer by determining serum prostate-specificantigen (PSA) levels has resulted in a stage migration such thatpatients with high-risk disease are more likely to be candidates for curativelocal therapy. By combining serum PSA, clinical stage, and biopsyinformation-both Gleason score and volume of tumor in the biopsycores-specimen pathologic stage and patient biochemical disease-freesurvival can be estimated. This information can help patients and cliniciansunderstand the severity of disease and the need for multimodaltherapy, often in the context of a clinical trial. While the mainstays oftreatment for local disease control are radical prostatectomy and radiationtherapy, systemic therapy must be considered as well. A randomizedtrial has shown a survival benefit for radical prostatectomy inpatients with positive lymph nodes who undergo immediate adjuvantandrogen deprivation. Clinical trials are needed to clarify whether adjuvantradiation therapy after surgery confers a survival benefit. PSAis a sensitive marker for follow-up after local treatment and has proventhat conventional external-beam irradiation alone is inadequate treatmentfor high-risk disease. Fortunately, the technology of radiationdelivery has been dramatically improved with tools such as three-dimensionalconformal radiation, intensity-modulated radiation therapy,and high-dose-rate brachytherapy. The further contributions of pelvicirradiation and neoadjuvant, concurrent, and adjuvant androgen deprivationtherapy have been defined in clinical trials. Future managementof high-risk prostate cancer may be expanded by clinical trialsevaluating neoadjuvant and/or adjuvant chemotherapy in combinationwith androgen deprivation.