Lowell E. Schnipper

Effect of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor on Chemotherapy-Induced Myelosuppression

An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.

GRANULOCYTE-MACROPHAGE COLONY STIMULATING FACTOR EXPANDS THE CIRCULATING HAEMOPOIETIC PROGENITOR CELL COMPARTMENT IN MAN

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on bone-marrow and peripheral-blood progenitor cells was investigated in a three-phase study in 13 patients with sarcoma. In the first phase patients were given GM-CSF alone. In phase II, which started a week after completion of phase I, patients received a course of cytotoxic chemotherapy, then a course of GM-CSF. Phase III consisted only of cytotoxic chemotherapy. GM-CSF (phase I) alone produced an 18-fold increase in peripheral blood granulocyte-macrophage colony-forming units (CFU-GM) and an 8-fold increase in erythroid burst-forming units (BFU-E) in the peripheral blood. GM-CSF had no effect on bone-marrow CFU-GM and BFU-E in the group as a whole. Three patients were investigated after phases II and III. GM-CSF increased the absolute number of peripheral blood CFU-GM by approximately 60-fold compared with the pretreatment baseline. These effects of GM-CSF may be of clinical importance with regard to facilitating the harvest of peripheral blood progenitor cells for autotransplantation.

A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy

PURPOSE The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

American Society of Clinical Oncology Statement: A Conceptual Framework to Assess the Value of Cancer Treatment Options

Health care costs in the United States present a major challenge to the national economic well being. The Centers for Medicare and Medicaid Services (CMS) has projected that US health care spending will reach

American Society of Clinical Oncology Guidance Statement: The Cost of Cancer Care

4.3 trillion and account for 19.3% of the national gross domestic product by 2019.1 This growth in spending—both in absolute terms and as a proportion of our gross domestic product—has not been accompanied by commensurate improvements in health outcomes, despite expenditures far exceeding those of other countries.2–4 One of the fastest growing components of US health care costs is cancer care, the cost of which is now estimated to increase from

American Society of Clinical Oncology Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology

125 billion in 2010 to

Nonlymphomatous malignant tumors complicating Hodgkin's disease. Possible association with intensive therapy.

158 billion in 2020.1 Although cancer care represents a small fraction of overall health care costs, its contribution to health care cost escalation is increasing faster than those of most other areas because of several factors: the increasing prevalence of cancer due to the overall aging of the population and better control of some causes of competing mortality; the introduction of costly new drugs and techniques in radiation therapy and surgery; and the adoption of more expensive diagnostic tests. In some cases, the adoption of newer, more expensive diagnostic and therapeutic interventions may not be well supported by medical evidence, thereby raising costs without improving outcomes.5 Coupled with, or even driving, some of these rising costs are sometimes unrealistic patient and family expectations that lead clinicians to offer or recommend some of these services, despite the lack of supporting evidence of utility or benefit.6 Historically, most individuals in the United States were shielded from the acute economic impact of expensive care because they had health insurance. However, current trends suggest that patients will find themselves increasingly responsible for a greater proportion of the cost of their health care. Cost shifting or sharing can occur through the increased use of high-deductible policies and larger copayments. These increased costs are already commonplace and may not be affordable for many families. Indeed, health care expenditures are cited as a major cause of personal bankruptcy,7 and the term financial toxicity has entered the vernacular as a means of describing the financial distress that now often accompanies cancer treatment.8 Like other toxicities of cancer treatment, financial toxicity resulting from out-of-pocket treatment expenses can reduce quality of life and impede delivery of high-quality care.9,10 Patients experiencing high out-of-pocket costs have reported reducing their spending on food and clothing, reducing the frequency with which they take prescribed medications, avoiding recommended procedures, and skipping physician appointments to save money.10,11 These unintended consequences risk an increase in health disparities, which runs counter to some of the key goals of health care reform. In many communities, the high costs associated with cancer care have created a difficult situation for patients and the oncologists who care for them. Addressing this situation will require greater understanding of all the risks and benefits of various treatment options as well as the consequences of specific choices. In this regard, studies have shown that patients specifically want financial information about treatment alternatives along with information about medical effectiveness and treatment toxicity. However, they often do not receive it. Closing this knowledge gap will require educated providers who are able to sensitively initiate a dialogue about the cost of care with their patients when appropriate.12,13 Patients with cancer are often surprised by and unprepared for the high out-of-pocket costs of treatments. They also overestimate the benefits of treatments that sometimes extend life by only weeks or months or not at all. Oncologists are generally aware of this conundrum but uncertain about whether and how the cost of care should affect their recommendations.14 Although raising awareness of costs and providing tools to assess value may help to manage costs while maintaining high-quality care, some oncologists see this as being in conflict with their duty to individual patients.15 Recent American Society of Clinical Oncology Efforts Motivated by our responsibility to help oncologists deliver the highest-quality care to patients everywhere, the American Society of Clinical Oncology (ASCO) formed the Task Force on the Cost of Cancer Care in 2007. Its mission includes educating oncologists about the importance of discussing costs associated with recommended treatments, empowering patients to ask questions pertaining to the anticipated costs of their treatment options, identifying the drivers of the rising costs of cancer care, and ultimately developing policy positions that will help Americans move toward more equal access to the highest-quality care at the lowest cost.16 In 2012, through the work of the Task Force, ASCO responded to the Choosing Wisely Campaign of the American Board of Internal Medicine Foundation and identified specific instances of overuse in the delivery of cancer care. ASCO used a deliberative consensus process to identify five common clinical practices that are not supported by high-level evidence. A second list of five was developed using the same process and submitted to the Choosing Wisely Campaign in 2013. ASCO amplified the evidence basis for both top-five lists in two publications17,18 and is now developing measures to evaluate the use of these practices as part of its Quality Oncology Practice Initiative. These exercises have provided opportunities to develop a rigorous but flexible approach to assessing efficacy across diagnostic and treatment domains.

Attitudes and Practices Among Pediatric Oncologists Regarding End-of-Life Care: Results of the 1998 American Society of Clinical Oncology Survey

Advances in early detection, prevention, and treatment have resulted in consistently falling cancer death rates in the United States. In parallel with these advances have come significant increases in the cost of cancer care. It is well established that the cost of health care (including cancer care) in the United States is growing more rapidly than the overall economy. In part, this is a result of the prices and rapid uptake of new agents and other technologies, including advances in imaging and therapeutic radiology. Conventional understanding suggests that high prices may reflect the costs and risks associated with the development, production, and marketing of new drugs and technologies, many of which are valued highly by physicians, patients, and payers. The increasing cost of cancer care impacts many stakeholders who play a role in a complex health care system. Our patients are the most vulnerable because they often experience uneven insurance coverage, leading to financial strain or even ruin. Other key groups include pharmaceutical manufacturers that pass along research, development, and marketing costs to the consumer; providers of cancer care who dispense increasingly expensive drugs and technologies; and the insurance industry, which ultimately passes costs to consumers. Increasingly, the economic burden of health care in general, and high-quality cancer care in particular, will be less and less affordable for an increasing number of Americans unless steps are taken to curb current trends. The American Society of Clinical Oncology (ASCO) is committed to improving cancer prevention, diagnosis, and treatment and eliminating disparities in cancer care through support of evidence-based and cost-effective practices. To address this goal, ASCO established a Cost of Care Task Force, which has developed this Guidance Statement on the Cost of Cancer Care. This Guidance Statement provides a concise overview of the economic issues facing stakeholders in the cancer community. It also recommends that the following steps be taken to address immediate needs: recognition that patient-physician discussions regarding the cost of care are an important component of high-quality care; the design of educational and support tools for oncology providers to promote effective communication about costs with patients; and the development of resources to help educate patients about the high cost of cancer care to help guide their decision making regarding treatment options. Looking to the future, this Guidance Statement also recommends that ASCO develop policy positions to address the underlying factors contributing to the increased cost of cancer care. Doing so will require a clear understanding of the factors that drive these costs, as well as potential modifications to the current cancer care system to ensure that all Americans have access to high-quality, cost-effective care.

Resistance to Antiviral Drugs of Herpes Simplex Virus Isolated from a Patient Treated with Acyclovir

Lowell E. Schnipper, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Thomas J. Smith, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD; Derek Raghavan, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; Douglas W. Blayney, Stanford Cancer Institute, Stanford University School of Medicine, Stanford; Patricia A. Ganz, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA; Therese Marie Mulvey, Southcoast Center for Cancer Care, Southcoast Health System, New Bedford, MA; Dana S. Wollins, American Society of Clinical Oncology, Alexandria, VA.

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

Abstract Case records of 425 patients with Hodgkins disease treated at the NIH were reviewed. Note of all biopsy-proved malignant tumors other than Hodgkins disease was made. Cases were divided into subgroups on the basis of treatment received, and expected incidences of malignant tumors were calculated for each subgroup on the basis of age, sex, and mean follow-up period from the time of diagnosis of Hodgkins disease. Significantly increased risks of development of second malignant tumors were found in the entire 425 patients (ratio of observed to expected, 3.5) and in the subgroups treated with both radiotherapy and chemotherapy (ratio, 3.3) and with intensive radiotherapy without intensive chemotherapy (ratio, 3.8). The greatest increase in risk was observed in 35 patients who received both intensive radiotherapy and intensive chemotherapy (ratio, 29).