editorial

Integrating Support into Cancer TherapyJeffrey Crawford, MDChief of Medical OncologyDivision of MedicineDuke University Medical CenterDurham, North Carolina

Volume 3, Number 2 • January 2006

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When we began this journal in 2003, our editorial staffspent a great deal of time deciding on the name of our jour-nal, Supportive Cancer Therapy. In the past, many of us havebelieved that cancer treatment and supportive care were 2distinct domains in the management of patients with can-cer. Although at one point in the history of oncology thismight have largely been true, during the past decade, majorresearch advances have been made in these areas. In addi-tion, advances in clinical practice have been equallydependent upon the development of new cancer therapies aswell as agents and approaches that lessen the side effects oftreatments and improve their overall efficacy. So in 2006, inorder to provide our patients with state-of-the-art care, it iscritical that we look at supportive care and cancer thera-peutics as one integrated approach. Because so many jour-nals focus on the therapeutic end of cancer therapy, thisjournal is developed to ensure that equal emphasis is placedon the supportive therapy that enables patients to receivetheir cancer treatments more safely and effectively.

The articles in the current issue of Supportive Cancer Therapyare excellent examples of that emphasis. Bisphosphonates havehad an important impact on reducing bone-related complica-tions in patients with cancer, and Body addresses the renaleffects of this important class of agents. In addition, Langeraddresses a case report of a rare but increasingly recognizedcomplication of bisphosphonate therapy, osteonecrosis of thejaw. It is of critical importance for us to recognize this compli-cation in our patients and to develop preventive strategies.

Regarding the management of hot flashes, Barton and col-leagues present some interesting results in their pilot stud-ies with dehydroepiandrosterone. A common complicationfor patients with breast cancer with a central venous catheteris the risk of deep vein thrombosis. The frequency of FactorV Leiden mutations in this population is explored byCurigliano and colleagues.

Whether this represents an increased biologic effect ofchemotherapy in these patients, causing hematologic andnonhematologic toxicities, and whether there are uniquecytokine cascades that occur in the presence of neutropeniathat trigger these symptoms is an unanswered question butone that clearly requires further exploration.

Loibl and colleagues address an interesting and still con-troversial area of prophylaxis of anemia in patients withbreast cancer in the preoperative setting using darbepoetinalfa. After 2 earlier randomized trials suggested that anadverse consequence from preventive strategies was high

hemoglobin levels, there was clearly a need to continueprospective trials to look at the risk-benefit ratio. In addi-tion to the work of the current authors, there are severalongoing randomized trials that are eagerly awaited. Some ofthese issues are explored further by Schwartzberg in hisLetter to the Editor discussing erythropoietic therapy.

In order for new information to be developed and deliv-ered into the clinical arena, it is important that we do every-thing possible to maximize clinical trial participation andorganize our clinics in a manner that supports excellent clin-ic practice and research. In this regard, there are interestingarticles exploring reasons for poor accrual in the palliativesetting of radiation therapy clinical trials as well as a reviewabout organizing and implementing group medical appoint-ments in the bone marrow transplantation clinic.

Thus, all of these articles are thematically organizedaround the concept of integration of advances in support-ive therapy of patients with cancer with therapies targetingthe cancer itself. Perhaps the best example of this is theResearch in Brief review that addresses the role of plerix-afor (AMD3100) in mobilizing hematopoietic progenitorcells in patients with hematologic malignancies. The devel-opment of this agent is based on > 2 decades of laboratoryand clinical investigations of hematopoiesis and cytokines insupport of standard- and high-dose cytotoxic chemotherapyregimens. This is perhaps the ultimate integration of sup-portive strategies with cancer treatment to achieve the ben-efits that have been seen in the management of patients withhematologic malignancies.

The history of bone marrow transplantation in the settingof solid tumors dates back decades, but as recently as the late1980s, there was no effective strategy to support the pro-longed periods of cytopenia, infection, and often consequentorgan damage that developed in these patients, leading tounacceptable rates of morbidity and mortality. The advent ofmyeloid growth factors reduced the duration of neutropeniawith standard-dose chemotherapy and, to a lesser extent,with high-dose chemotherapy, which modified some of theseoutcomes. However, it was really the discovery that admin-istration of these cytokines caused release of earlyhematopoietic progenitor cells into the peripheral bloodthat dramatically changed the field. The observation thatseveral different colony-stimulating factors and other early-acting hematopoietic growth factors, as well as chemother-apy per se, could lead to the release of progenitor cells fromthe bone marrow into the peripheral blood was largely an

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empirical observation. Detailed studies of different dosesand schedules of chemotherapy with and without growthfactors and different dosing schedules of growth factors weredone in an attempt to optimize the release of these progeni-tor cells. It became increasingly clear that one could dra-matically reduce the period of neutropenia and thrombocy-topenia after high-dose therapy with reinfusion of an ade-quate number of progenitor cells.

In recent years, we have come to understand the biologyof this process. Specifically, it appears that CXCR4/stro-mal-derived factor−1 is pivotal in the receptor-ligand inter-action, resulting in stem cell retention in the bone marrow.It seems clear that cytokines, such as granulocyte colony-stimulating factor (G-CSF), interrupt this axis, leading toprogenitor cell release into the peripheral blood. The devel-opment of plerixafor represents the next generation ofagents that allow us to enhance progenitor cell mobiliza-tion. It appears that plerixafor acts synergistically withG-CSF in targeting the interaction between STF1 and itsreceptor, CXCR4. The initial phase I trials not only demon-strated an enhancement of the release of CD34+ cells intothe peripheral blood but also identified benefit of thisapproach in patients who initially showed poor mobiliza-tion of progenitor cells with G-CSF therapy alone.

Our current Research in Brief reviews phase II trials with

patients with multiple myeloma and non-Hodgkin’s lym-phoma that were reported at the December 2005 meeting ofthe American Society of Hematology. These studies impres-sively demonstrated that plerixafor in combination with G-CSF resulted in the successful mobilization of CD34+ cells in60% of the patients whose cells had previously failed tomobilize with G-CSF alone or in combination with chemo-therapy. These encouraging results have led to the develop-ment of 2 phase III trials to confirm the safety and efficacyof the combination strategy of G-CSF plus plerixafor versusG-CSF plus placebo. The endpoints to be evaluated includethe generation of CD34 cells, the number of aphereses, andultimately, the percent of patients with successful plateletand neutrophil engraphment. If successful, this will repre-sent a further technologic advance in the area of stem celltransplantation. This approach demonstrates promise notonly to further reduce the morbidity and potential mortalityfrom high-dose chemotherapy but also to broaden the patientpopulation that might be eligible for such an approach in thefuture. By building on the advances in our understandingof the biology of hematopoiesis coupled with new develop-ments in clinical investigation of high-dose therapy inhematologic malignancies, we have an ideal example of whatsupportive cancer therapy is all about.