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The Rationale for Performing Autologous Peripheral Blood Stem Cell Transplants in Community Cancer Centers

Clinical Research Division of Response Oncology, Inc., Memphis, Tennessee, USA

Correspondence: C. Dean Buckner, M.D., Response Oncology, Inc., 600 Broadway, Suite 112, Seattle, Washington 98122, USA; Telephone: 206-726-8921; Fax: 206-726-9068; e-mail: dbuckner{at}jetcity.com

	Abstract

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There is debate over whether or not the technology of peripheral blood stem cell (PBSC) support of high-dose chemotherapy (HDC) should be disseminated to practicing oncologists or continue to be administered only in academic referral centers. High-dose therapy with stem cell support is now the standard of care for selected patients with lymphoma, multiple myeloma and possibly breast cancer. Such therapies, delivered in a clinical trials setting, need to be more widely available to eligible patients. This manuscript presents the rationale for performing HDC with PBSC support in community cancer centers. The availability of PBSC has made the delivery of well-established HDC regimens safe and effective in an outpatient setting. Delivery of such therapy where the patient lives has many economic and social advantages to the patient compared to referral to a transplant center. In addition, more patients can be treated more cost effectively if such therapy is administered locally where the patient lives. From the scientific point of view, improved access to HDC in the community should increase accrual to clinical trials, allowing the generation of outcome data more rapidly.

Key Words. Autologous peripheral blood transplants

	Introduction

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The infusion of autologous hematopoietic stem cells allows the administration of higher than normal doses of marrow toxic chemotherapeutic agents. Further escalation of drug doses with stem cell support is ultimately limited by nonhematopoietic toxicities, primarily to the mucous membranes, lungs, and liver. The source of stem cells for support following the administration of high-dose chemotherapy (HDC) was originally from bone marrow (BM), which essentially limited this technology to transplant referral centers. However, the emergence of peripheral blood stem cells (PBSC) over the past decade as the preferred source of hematopoietic stem cells has made HDC with stem cell support widely available. Peripheral blood stem cells can be collected following the administration of chemotherapy plus a growth factor, or a growth factor alone by apheresis in an outpatient or blood bank setting [1], and cryopreservation technology is relatively simple and widely available [2].

Although there is controversy regarding the relative effectiveness of HDC with PBSC, most published randomized trials have shown superiority over lower-dose treatments [3-9]. No randomized trial has shown HDC with stem cell support to be inferior to conventional dose chemotherapy, but some have shown equivalency or differences in favor of HDC that were not statistically significant, possibly due to small numbers of patients evaluated [10, 11].

There has been debate over whether or not the technology of hematopoietic stem cell support of HDC should be disseminated to practicing oncologists, especially when performed under the auspices of a clinical trials company [12-14]. The arguments against performing PBSC transplants in community cancer centers have been reported and will not be discussed here [12, 14, 15].

The purpose of this manuscript is to present the rationale for performing HDC with PBSC support in community cancer centers under the supervision of practicing oncologists. Data presented here were derived from protocols developed since 1989 by the Clinical Trials Division of Response Oncology Inc. (ROI), involving over 4,000 patients treated with HDC and PBSC support. Approximately 1,200 patients/year are evaluated, and 650 are treated with HDC and PBSC support in 50 centers by 400 medical oncologists in the ROI network.

Requirements for Performing HDC in Community Cancer Centers
Autologous PBSC transplants can be performed within a private practice setting if appropriate steps have been taken to assure quality of treatment and the generation of meaningful data. All patients should be treated on protocols with well-defined selection criteria. It can be assumed, in this context, that no private practice will be large enough to generate meaningful data and that a regional or national network for providing protocols will be necessary. This network can be provided by a large established NCI-sponsored cooperative group, a regional affiliation with an academic or nonacademic institution, or a clinical trials company. In any of these situations, there has to be on-site data collection, monitoring of data for accuracy, and means of sending this data in a timely manner to a centralized data facility. Reporting data to the International Bone Marrow Transplant Registry is also desirable.

Standards for mobilizing, harvesting, enumeration of CD34⁺ cells, and cryopreservation of PBSC have to be in place. Currently, such facilities should meet standards for certification by the Foundation for the Accreditation of Hematopoietic Cell Transplantation (FAHCT), the American Association of Blood Banks, and, possibly in the future, the U.S. Food and Drug Administration.

Clinical capabilities include the development of standardized, coordinated approaches to supportive care, prophylaxis, and management of toxicities associated with HDC. A dedicated nursing staff familiar with the administration of HDC and the management of side effects is a necessity. In addition, ongoing training of nurses and support staff is an integral component of any HDC program. Recommended criteria for the performance of BM transplantation have been established by the American Society of Clinical Oncology and the American Society of Hematology, and, more recently, guidelines for accreditation of transplant centers have been established by FAHCT [16]. Guidelines and applications for accreditation from FAHCT are available from Phyllis Warkentin, M.D., University of Nebraska Medical Center, 600 S. 42nd Street, Omaha, Nebraska 68198.

Diseases Currently Treated with HDC and PBSC Support
Randomized prospective clinical trials, summarized in Table 1, have demonstrated superiority of HDC with stem cell support over conventional dose therapy for patients with: Hodgkin's disease who have relapsed [3], non-Hodgkin's lymphoma (NHL) with responding disease who have relapsed after achieving an initial remission [6], diffuse large-cell lymphoma as initial therapy [4], aggressive NHL for consolidation in first remission [5], breast cancer at diagnosis of metastatic disease [7], multiple myeloma as part of initial treatment strategy [9], and acute myeloid leukemia (AML) for consolidation in first remission [8].

Why Should HDC and PBSC Support Be Performed by Practicing Oncologists?

Peripheral blood stem cells can be harvested, cryopreserved, and infused safely in an outpatient setting.
Initially, PBSC were harvested after chemotherapy alone, usually high doses of cyclophosphamide, and infused after HDC [20, 21]. Following the availability of recombinant growth factors, G-CSF or GM-CSF were added to high doses of cyclophosphamide with or without other drugs such as etoposide and cisplatin [20]. With the use of chemotherapy and G-CSF or GM-CSF, adequate quantities of PBSC, as measured by the number of CD34⁺ cells, can be collected in one to three aphereses in the majority of patients [22-24]. With outpatient administration of chemotherapy and growth factors for mobilization of PBSC, 12%-30% of patients were admitted to the hospital for a median of five days [22, 23]. In a more recent study, only 9% of patients receiving cyclophosphamide, docetaxel, and G-CSF for mobilization of PBSC required hospitalization [25]. The administration of G-CSF or GM-CSF alone, without chemotherapy for mobilization of PBSC is not associated with any hospitalization and is usually the method of choice for blood banks [26-28]. However, the use of G-CSF alone results in the harvesting of fewer CD34⁺ cells/kg/apheresis than following chemotherapy plus G-CSF. Thus, when high doses of CD34⁺ cells are desired, the advantage is with chemotherapy plus a growth factor [28]. Currently, PBSC are thawed and infused following the administration of HDC in an outpatient setting with 24-h support, and patients are only admitted if and when they have clinical problems.

Resources for care of patients receiving HDC with PBSC support are available in community cancer centers.
The fundamental principle on which this approach is based is that, with an appropriate infrastructure, practicing oncologists who treat patients with intensive chemotherapy already have the skills necessary to manage patients receiving HDC with PBSC support. Most oncologists who received their training in the past 10 years have experience with managing patients who have received allogeneic or autologous transplants. Practicing oncologists have also referred patients to transplant centers for autologous or allogeneic BM transplantation and have been responsible for managing post-transplant complications, including: acute and chronic graft-versus-host disease, infections in immunocompromised patients, interstitial pneumonitis syndromes, veno-occlusive disease, complications of relapse, etc., once patients return to their care. Furthermore, the care of patients receiving well-tested HDC regimens with PBSC support is generally no more complex than that of patients with AML through multiple cycles of induction and consolidation. Oncologists who routinely manage patients with AML are caring for patients who receive very toxic regimens with resultant prolonged pancytopenia and severe and often fatal complications. Care of patients with AML requires sophisticated transfusion services and availability of consultants who can also be utilized for the care of patients receiving HDC. In contrast to intensive chemotherapy without stem cell support, patients receiving HDC with well-established regimens have well-defined and usually manageable nonhematologic toxicities associated with a relatively short period of pancytopenia following the infusion of PBSC.

HDC can be administered without prohibitive morbidity and mortality in an outpatient setting in community cancer centers.
A retrospective evaluation of the initial 1,000 consecutive patients with AML, NHL, Hodgkin's disease, multiple myeloma, sarcoma, ovarian cancer, or breast cancer who received one of five published HDC regimens followed by PBSC infusion over a five-year period in community cancer centers was performed to determine treatment-related mortality (TRM) [29]. Thirty-four patients (3.4%) died of TRM, 15 (1.5%) died from infection, and 19 (1.9%) from regimen-related toxicities. In a logistic model, increasing age (p = 0.001) and lower numbers of CD34⁺ cells/kg (p = 0.003) were associated with an increased risk of 100-day TRM. A regimen of high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) was associated with a lower risk of mortality than other high-dose regimens (p = 0.0001). Several disease-specific studies have now been completed documenting TRM of 0%-10%, and the results are summarized in Table 2. These results demonstrate that HDC and autologous PBPC support can be performed in community cancer centers with relative safety with TRM that is similar to that observed in patients treated in a similar manner in transplant centers [19].

Neutrophil and platelet recovery is rapid and complete following infusion of adequate quantities of PBSC as measured by CD34⁺ cells.
Autologous BM infusion after HDC resulted in three to four weeks of pancytopenia with a small but significant fraction of patients, depending on the quality of the marrow, having prolonged pancytopenia requiring extensive transfusion support and antibiotic therapy [38]. With the use of PBSC, larger quantities of stem cells and progenitors can be collected, resulting in more rapid recovery of neutrophils and platelets, with virtually all patients recovering blood counts within two weeks. An evaluation of over 600 patients has shown that the optimal cell dose for rapid and complete engraftment of all patients is 5 x 10⁶ CD34⁺ cells/kg [39]. Preliminary analyses have shown that the infusion of 5 x 10⁶/kg CD34⁺ cells is associated with less hospitalization and lower costs than infusion of lower CD34⁺ cell doses [40]. Patients will spend <7 days with neutrophils <0.5 and platelets <20 x 10⁹/l following infusion of 5.0 x 10⁶ CD34⁺ cells/kg. Figure 1 shows the mean neutrophil and platelet counts following high-dose CTCb and PBSC infusion of 5.0 x 10⁶ CD34⁺ cells/kg in patients with breast cancer. This short period of pancytopenia has significantly lowered the cost of performing HDC by allowing much of the treatment to take place in an outpatient setting where patients are carefully monitored and receive prophylactic antibiotics and platelet transfusions.

View larger version (23K): [in this window] [in a new window]   Figure 1. Mean neutrophil and platelet counts following the infusion of 5.0 x 106 CD34+ cells/kg in patients with breast cancer who have received high-dose cyclophosphamide, thiotepa, and carboplatin.

Outcomes of patients treated in community cancer centers are comparable to results reported in the literature from transplant centers.
Table 3 summarizes the results of clinical trials performed in community cancer centers by oncologists affiliated with ROI. These results are comparable to results published in peer-reviewed journals [19].

Patients most likely to benefit from HDC could be treated earlier in the natural history of their diseases if such therapy were available to the practicing oncologists.
Outcomes for patients receiving HDC are better if the therapy is applied early in the disease course before resistance develops. This has been well documented in patients with breast cancer, lymphoma, and multiple myeloma [41-43]. Women with newly diagnosed breast cancer treated in the adjuvant setting are more likely to benefit from HDC than patients with advanced disease who have received prior chemotherapy [41]. Community oncologists are more likely to participate in clinical trials of HDC in early disease settings if they are involved in the delivery of therapy than if they have to refer such patients to transplant centers. They also are more likely to become knowledgeable about the controversies surrounding the issues of HDC versus conventional therapies if they are directly involved in the delivery of both therapies.

Physicians directly involved in the administration of HDC may also be less likely to refer advanced and/or inappropriate patients to tertiary transplant referral centers as they become more familiar with the benefits and limitations of such therapy. The pattern of breast cancer referrals within the ROI network supports these arguments. The number of patients with metastatic breast cancer referred per ROI affiliate oncologist declined between 1995 and 1997, while the number of patients referred for adjuvant or neoadjuvant clinical trials increased.

What Are the Advantages To Patients of Performing HDC with PBSC Support In Community Cancer Centers?

Family and social support systems remain intact.
In addition to the fact that patients are accrued at a more favorable time in the natural history of their disease, there are other reasons for delivery of this treatment in community cancer centers. The ability to provide the continuity of care which is established with the treating oncologist, nurses, and personnel of the local hospital is a major advantage. When the patient is treated in the community where he or she lives, the support system remains intact. Patients treated at a tertiary transplant center are also required to have a full-time caregiver with them throughout treatment which can create hardships on family and friends. More inpatient hospitalization time can be incurred if family and/or friends are unable to provide this care.

Expense of living away from home can be avoided.
In addition to the social disruption of being treated away from home, the nonmedical economic costs can be great, especially when the primary caregiver is also the primary wage earner. In addition, the costs of living away from home while receiving therapy are not always reimbursed by third-party carriers.

Access to clinical trials is improved.
The social and economic problems described above frequently result in patients refusing clinical trials involving HDC with PBSC support in favor of lower-dose therapies which can be administered locally. Thus, for practical purposes, patients who cannot afford the social or economic dislocation that treatment in a transplant center entails are essentially denied access to clinical care of greater curative potential and clinical trials participation.

Patients treated in community cancer centers frequently have access to clinical trials sponsored by organizations such as ROI, which include pharmaceutical studies with access to new drugs. In addition, as mentioned below, patients treated in community cancer centers should but often do not, have access to NCI-sponsored clinical trials without leaving home.

What Are the Potential Advantages To Society of Performing HDC with PBSC Support In Community Cancer Centers?

Potential increased accrual to national trials.
There are several ongoing national trials in the U.S. comparing HDC to lower-dose therapy. Two prospective NCI-sponsored multicenter randomized trials in patients with stage II-III breast cancer with 10⁺ axillary lymph nodes have been under way for several years through the Eastern Cooperative Oncology Group (ECOG 9082), the Southwest Oncology Group (SWOG 9114), or through the Eastern Cooperative Oncology Group (ECOG 2190). There is also one prospective NCI-sponsored national randomized trial evaluating HDC in patients with breast cancer with 4-9+ axillary lymph nodes through a Cooperative Breast Cancer Inter-Group trial (SWOG 9623). There is also an Inter-Group Myeloma Trial which compares high-dose melphalan and total-body irradiation with PBSC to continued chemotherapy after induction with VAD (vincristine, doxorubicin, and dexamethasone). It is anticipated that 500 patients will be entered on each of these trials. Each of these studies will take five years or more to enroll the requisite number of patients and another two to three years of follow-up from the termination of study for the first preliminary analysis. When the time it takes to initiate such studies is added, it can be estimated that these studies will take at least 10 years from concept to meaningful analyses. Clearly, it would be advantageous to enter patients more rapidly to these types of trials in order to complete such studies in a timely fashion.

Currently, access to these NCI-sponsored randomized trials is restricted predominantly to patients treated at academic transplant centers or at institutions which are affiliated with academic institutions through cooperative groups. There is virtually no possibility for the majority of practicing oncologists to participate in these trials without referring their patients to another center. Allowing participation of patients treated with HDC with PBSC support in community cancer centers would increase the number of patients potentially available for such clinical trials. There is no doubt that the current ongoing national clinical trials outlined above could have been completed much more rapidly if the trials had included patients treated in the community. In the future, investigators designing clinical trials of HDC and PBSC supported by the NCI should consider a broader participation in these studies and encourage rather than discourage enrollment of patients treated in community cancer centers.

There are not enough transplant centers in the U.S. to perform indicated HDC treatments or necessary clinical trials.
Although still controversial in the minds of many investigators, HDC with PBSC support is emerging as the treatment of choice for newly diagnosed patients with low-burden chemosensitive metastatic breast cancer, for newly diagnosed patients with multiple myeloma under the age of 66, and for patients with malignant lymphoma who have relapsed or have high-risk features for failure of chemotherapy. In addition, ongoing phase II and III studies may define other populations of patients for whom HDC with PBSC support is a reasonable therapeutic option. Given the large numbers of patients with these diseases, tertiary transplant referral centers cannot treat the volume of patients in question. We estimate that only 10%-15% of patients under the age of 65 with NHL who fail chemotherapy receive HDC with its curative potential [6]. One reason for this is the current relative unavailability of this technology in the community. If patients cannot receive needed therapy at transplant centers, for whatever reasons, then attempts should be made to take this technology to the patients.

There is a potential cost savings in transferring of PBSC technology to the community.
Community cancer centers enjoy a lower fixed cost structure and should be able to deliver HDC with PBSC support at case rates lower than those required by academic centers who have the expense of research and education with a commensurately large overhead. Thus, higher case rates for academic centers involved in the development of innovative approaches to autologous transplantation are reasonable. However, at that point where a treatment has reached a level of standardization applicable to large numbers of patients, lower case rates in the community setting could represent a real savings. This point has been reached for the delivery of HDC with PBSC support for the diseases discussed in this manuscript. Savings to society of performing HDC and PBSC support may not only be associated with an absolute reduction in case rates but could, by providing earlier treatment, potentially avoid some of the costs associated with protracted palliative chemotherapy that follows the initial delivery of less effective therapy.

What Is the Future of HDC with PBSC Support?

Use of PBSC will expand as indicated therapy and in evaluating new therapies.
The use of PBSC for supportive care of patients receiving HDC and for patients with chemosensitive malignancies will undoubtedly continue to expand. If PBSC are collected early in the disease course, there is no reason not to incorporate their use into the management of selected patients with chemosensitive malignant disease. High-dose chemotherapy with PBSC support is best suited for diseases where intensive consolidation is an integral component of disease management. In this setting, it makes sense to assure hematopoietic and immunologic recovery by the infusion of PBSC that have not been extensively exposed to chemotherapy or radiotherapy. However, at the present time, HDC with PBSC support should only be carried out in the context of clinical trials generating meaningful outcome data.

Immune therapies will be evaluated after HDC with PBSC support.
HDC with PBSC support can provide further cytoreduction of patients already in remission but who have a high probability of relapse. This creates an ideal setting of minimal residual disease for the evaluation of biological modifiers (IL-2, IL-12), monoclonal antibodies (rituximab, HER-2/neu), and vaccines [44, 45]. Immunologic therapies could be enhanced by being carried out in patients who receive PBSC that have not been extensively exposed to chemotherapy and radiation. Such patients may be more immunocompetent than those who have been extensively treated with chemotherapy without cellular support.

Studies of immune therapies will require enrollment of large numbers of patients in clinical trials to document benefit. For example, one could envision evaluating an immune therapy where the cure rate is 50% with HDC and PBSC support. In order to detect a 20% decrease in relapses, one would have to enroll over 200 patients in each arm and even more if one wanted to detect a 10% decrease. These kinds of large numbers of patients can only be accrued by including patients being treated in community cancer centers.

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