J. Sybil Biermann

American Society of Clinical Oncology Clinical Practice Guidelines: The Role of Bisphosphonates in Multiple Myeloma

PURPOSE To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of lytic bone disease in multiple myeloma and to determine their respective role relative to other conventional therapies for this condition. METHODS An expert multidisciplinary Panel reviewed pertinent information from the published literature through January 2002. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the Panel. Expert consensus was used if there were insufficient published data. The Panel addressed which patients to treat and when to treat them in the course of their disease. Additionally, specific drug delivery issues, duration of therapy, initiation of treatment and management of treatment of lytic bone disease was reviewed and compared with other forms of therapy for lytic bone lesions. Finally, the Panel discussed patient and physician expectations associated with this therapy for bony metastases, as well as public policy implications related to the use of bisphosphonates. The guidelines underwent external review by selected physicians, by the Health Services Research Committee members, and by the ASCO Board of Directors. RESULTS The available evidence involving randomized controlled trials is modest but supports that oral clodronate, intravenous pamidronate, and intravenous zoledronic acid are superior to placebo in reducing skeletal complications. A reduction in vertebral fractures has consistently been seen across all studies. No agent has shown a definitive survival benefit. Intravenous zoledronic acid has recently been shown to be as effective as intravenous pamidronate. Because there are no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent cannot be definitively established. However, the panel recommends only intravenous pamidronate or zoledronic acid in light of the use of the time to first skeletal event as the primary end point and more complete assessment of bony complications in studies evaluating it. Additionally, clodronate is not available in the United States. The choice between pamidronate and zoledronic acid will depend on choosing between the higher drug cost of zoledronic acid, with its shorter, more convenient infusion time (15 minutes), versus the less expensive drug, pamidronate, with its longer infusion time (2 hours). CONCLUSION Bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. However, further research on bisphosphonates is warranted, including the following: (1) when to start and stop therapy, (2) how to integrate their use with other treatments for lytic bone disease, (3) how to evaluate their role in myeloma patients without lytic bone involvement, (4) how to distinguish between symptomatic and asymptomatic bony events, and (5) how to better determine their cost-benefit consequence.

American Society of Clinical Oncology Guideline on the Role of Bisphosphonates in Breast Cancer

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected p...

American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer

PURPOSE To update the recommendations on the role of bone-modifying agents in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases. METHODS A literature search using MEDLINE and the Cochrane Collaboration Library identified relevant studies published between January 2003 and November 2010. The primary outcomes of interest were SREs and time to SRE. Secondary outcomes included adverse events and pain. An Update Committee reviewed the literature and re-evaluated previous recommendations. RESULTS Recommendations were modified to include a new agent. A recommendation regarding osteonecrosis of the jaw was added. RECOMMENDATIONS Bone-modifying agent therapy is only recommended for patients with breast cancer with evidence of bone metastases; denosumab 120 mg subcutaneously every 4 weeks, intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence to demonstrate greater efficacy of one bone-modifying agent over another. In patients with a calculated serum creatinine clearance of more than 60 mg/min, no change in dosage, infusion time, or interval of bisphosphonate administration is required. Serum creatinine should be monitored before each dose. All patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health. Current standards of care for cancer bone pain management should be applied at the onset of pain, in concert with the initiation of bone-modifying agent therapy. The use of biochemical markers to monitor bone-modifying agent use is not recommended.

Evaluation of cancer information on the Internet

The Internet is a massively expanding body of information, with an estimated 320 million Web pages available. In 1997 an estimated 24 million North Americans used the Internet, and Internet use has been estimated to double each year. Even prior to the advent of the Internet as a source of medical information, patients have become more informed regarding their care, seeking increased amounts of information regarding their diagnoses and primarily wanting more information regarding their treatment options. In the past, these patients would rely heavily on health professionals for this information, through conversations or from pamphlets, videos, or books available to physicians for office distribution. Some resourceful patients may have ventured into medical libraries and some may have navigated through Index Medicus. Even the accessibility of MEDLINE searches in libraries and public institutions provided patients chiefly with peer-reviewed medical articles. We are living in a time of exponential expansion in accessibility to medical information. Data that previously would have required hours of research in a medical library now can be found easily by anyone with access to the Internet. This has enhanced the medical professional’s ability to gain extensive knowledge of research findings from many different medical specialties. However, medical professionals are not the only ones searching the Internet for such information. Our patients have the same capability that we have to research a medical topic thoroughly via the Internet. However, of concern is the quality of this newly gained knowledge. The free flow of information on the Internet permits anyone with good computer skills and a modem to establish a Web site with whatever information they wish to share. In this respect, the Internet becomes the great equalizer: experts, specialists, authorities, professionals, alternative therapy promoters, interested lay people, charlatans, and hucksters all may set up sites containing information regarding specific topics of interest. As physicians, we are concerned whether medical information 381

Diagnostic Accuracy and Charge-Savings of Outpatient Core Needle Biopsy Compared with Open Biopsy of Musculoskeletal Tumors*

We performed a prospective study of sixty-two patients who were managed with a closed core needle biopsy in an outpatient clinic for a soft-tissue mass or a bone tumor with soft-tissue extension between August 1, 1992, and June 1, 1994. Eight (13 per cent) of the closed core needle biopsies yielded no neoplastic tissue. Two needle biopsies (3 per cent), which were of myxomatous masses, did not allow distinction between a benign and a malignant neoplasm; both masses were extraskeletal myxoid chondrosarcomas. Additionally, the histological grade of four resected specimens (6 per cent) differed from that determined with the closed needle biopsy. The diagnostic accuracy of the closed needle biopsies was 84 per cent (fifty-two of sixty-two). All ten diagnostic errors involved soft-tissue tumors. A retrospective study of a similar cohort of patients, who had open biopsy in an outpatient operating room by the same surgeon in a contemporary period in the same institution and with analysis by the same pathologist, revealed a diagnostic accuracy of 96 per cent (forty-eight of fifty). The hospital charges for the closed core needle biopsy were

Response of extraabdominal desmoid tumors to therapy with imatinib mesylate

1106, compared with

Laboratory and Clinical Evidence of Synergistic Cytotoxicity of Sequential Treament With Gemcitabine Followed by Docetaxel in the Treatment of Sarcoma

7234 for the open biopsy. We concluded that core needle biopsy can be performed in an outpatient clinic with use of local anesthesia and that it is substantially less expensive and more convenient than open biopsy. This technique has an acceptable but definitely lower rate of accuracy compared with open biopsy, especially for soft-tissue tumors, and it should be used only in a small subset of patients (those who have a large soft-tissue mass or a bone tumor with palpable soft-tissue extension). However, given the small size of the tissue sample, the clinician must recognize possible disadvantages, including a non-diagnostic biopsy, an indeterminate biopsy, or a potential error in the histological grade. These problems are much more likely to occur after core needle biopsy of soft-tissue masses. Because of the potential for errors in diagnosis when core needle biopsy is used, the musculoskeletal oncologist must rely on his or her clinical acumen. When a diagnostic is in reasonable doubt, there is no radiographic confirmation, the biopsy shows no tumor cells, or there is a combination of these findings, operative decisions should be made as if no biopsy had been performed. The management of patients who, after core needle biopsy, have a diagnosis of a bone or soft-tissue tumor, is best carried out by an experienced musculoskeletal oncologist working in close collaboration with an experienced musculoskeletal pathologist.

The Musculoskeletal Effects of Cigarette Smoking

Desmoid tumor represents a rare monoclonal neoplasm arising from deep musculoaponeurotic structures and may occur sporadically or in association with the familial adenomatous polyposis and Gardner syndromes. Desmoid tumors do not appear to demonstrate metastatic potential; however, local infiltrative growth results in significant morbidity and potential mortality. Although the delineation of optimal therapy for desmoid tumors has been confounded by several factors, surgical resection with adjuvant radiotherapy for a positive surgical margin remains the standard approach. Responses have been demonstrated to nonsteroidal antiinflammatory agents, antiestrogen compounds, and a variety of other agents in small series. Imatinib mesylate appears to demonstrate inhibitory activity against multiple class 3 receptor tyrosine kinases, including platelet‐derived growth factor receptor (PDGFR)‐α and PDGFR‐β, as well as c‐kit.

Women in surgical residency training programs.

PURPOSE A recent report of the combination of gemcitabine and docetaxel described favorable results in patients with uterine leiomyosarcoma. The objective of this report is to describe experience with this combination in a variety of histologic subtypes of sarcoma. Additionally, cell-culture studies were performed to assess the effect of the sequence of drug administration on colony formation. PATIENTS AND METHODS A medical record review of 35 patients receiving the gemcitabine/docetaxel combination was undertaken. Gemcitabine 675 mg/m(2) intravenously was administered over 90 minutes on days 1 and 8, and docetaxel 100 mg/m(2) intravenously was administered over 60 minutes on day 8 of a 21-day cycle. Cell culture studies using the SAOS-2 osteosarcoma cell line and MCF-7 breast cancer cell line were also performed. Gemcitabine and docetaxel were added to cells either simultaneously for 24 hours, gemcitabine for 24 hours followed by docetaxel for 24 hours, or the reverse sequence. RESULTS Thirty-five patients were treated. Five complete responses and 10 partial responses were observed for an overall response rate of 43%. Responses occurred in uterine, extremity, and retroperitoneal leiomyosarcoma, osteosarcomas, angiosarcomas, malignant fibrous histiocytomas, malignant peripheral-nerve sheath tumors, and Ewings sarcoma. In the cell culture studies, gemcitabine followed by docetaxel provided synergy. In contrast, the administration of drugs simultaneously resulted in antagonism, and docetaxel followed by gemcitabine provided mixed results. CONCLUSION The combination of gemcitabine and docetaxel seems to be active in a variety of sarcomas. A multicenter, randomized clinical trial in soft tissue sarcoma comparing gemcitabine alone with this combination, is ongoing.

Common benign lesions of bone in children and adolescents.

➤ Cigarette smoking decreases bone mineral density and increases the risk of sustaining a fracture or tendon injury, with partial reversibility of these risks with long-term cessation of smoking. ➤ Cigarette smoking increases the risk for perioperative complications, nonunion and delayed union of fractures, infection, and soft-tissue and wound-healing complications. ➤ Brief preoperative cessation of smoking may mitigate these perioperative risks. ➤ Informed-consent discussions should include notification of the higher risk of perioperative complications with cigarette smoking and the benefits of temporary cessation of smoking.