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Osteolytic disease is a major complication of multiple myeloma that may lead to devastating skeletal-related events (SREs). Conventional radiography remains the gold standard for the evaluation of bone disease in patients with myeloma. However, whole-body magnetic resonance imaging (MRI) is recommended in patients with normal conventional radiography and should be performed as part of staging in all patients with a solitary plasmacytoma of bone. Urgent MRI is also the diagnostic procedure of choice to assess suspected cord compression, whereas computed tomography can guide tissue biopsy. Positron emission tomography with computed tomography can provide complementary information to MRI, but its use in multiple myeloma must be better defined by further studies. The incorporation of abnormal MRI findings into the definition of symptomatic myeloma also needs to be clarified. Bisphosphonates remain the cornerstone for the management of myeloma bone disease. Intravenous pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future.

Purpose: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases., Patients and Methods: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis., Results: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures., Conclusion: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.

Purpose: To compare the efficacy of two different schedules of epirubicin and paclitaxel, as first-line chemotherapy, in patients with advanced breast cancer (ABC)., Patients and Methods: From October 1997 until May 1999, 183 eligible patients with ABC entered the study. Chemotherapy in group A (93 patients) consisted of four cycles of epirubicin at a dose of 110 mg/m(2) followed by four cycles of paclitaxel at a dose of 225 mg/m(2) in a 3-hour infusion. All cycles were repeated every 2 weeks with granulocyte colony-stimulating factor support. The therapeutic regimen in group B (90 patients) consisted of epirubicin (80 mg/m(2)) immediately followed by paclitaxel (175 mg/m(2) in a 3-hour infusion) every 3 weeks for six cycles., Results: In total, 79 patients (85%) in group A and 72 patients (80%) in group B completed treatment. The median relative dose-intensity of epirubicin was 0.96 in both groups, and that of paclitaxel was 0.96 and 0.97 in groups A and B, respectively. The complete response rate was higher in group A (21.5% v 9% P =.02). Nevertheless, there was no significant difference in the overall response rate between the two groups (55% v 42%, P =.10). Severe neutropenia was more frequently observed with concurrent treatment. After a median follow-up of 16.5 months, median time to progression was 10 months in group A and 8.5 months in group B (P =.27), and median survival was 21.5 and 20 months, respectively (P =.17)., Conclusion: The present study failed to demonstrate a significant difference in overall response rate between dose-dense sequential administration of epirubicin and paclitaxel compared with the combination of the two drugs given on the same day, even though the sequential treatment resulted in a significantly higher complete response rate.

Purpose: To review the clinical features, complications, and treatment of Waldenström's macroglobulinemia, a low-grade lymphoproliferative disorder that produces monoclonal immunoglobulin (Ig) M., Methods: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus., Results: The clinical manifestations associated with Waldenström's macroglobulinemia can be classified according to those related to direct tumor infiltration, to the amount and specific properties of circulating IgM, and to the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. For symptomatic patients, standard treatment consists primarily of oral chlorambucil; nucleoside analogs, such as fludarabine and cladribine, are effective in one third of previously treated patients and in up to 80% of previously untreated patients. Preliminary evidence suggests that anti-CD20 monoclonal antibody may be active in about 30% of previously treated patients and that high-dose therapy with autologous stem-cell rescue is effective in most patients, including some with resistance to nucleoside analogs., Conclusion: Waldenström's macroglobulinemia has a wide clinical spectrum that practicing physicians need to recognize early to reach the correct diagnosis. When therapy is indicated, oral chlorambucil is the standard primary treatment, but cladribine or fludarabine can be used when a rapid cytoreduction is desirable. Prospective randomized trials are required to elucidate the impact of nucleoside analogs on patients' survival. A nucleoside analog is the treatment of choice for patients who have been previously treated with an alkylating agent.

Purpose: Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent cancer of the cervix, and the combination of these two agents has shown activity and possible synergism in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent cervical cancer to evaluate its activity., Patients and Methods: Thirty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m2 administered intravenously over a 3-hour period followed by cisplatin 75 mg/m2 administered intravenously with granulocyte colony-stimulating factor support. The chemotherapy was administered every 3 weeks for a maximum of six courses., Results: Sixteen patients (47%; 95% confidence interval, 30% to 65%) achieved an objective response, including five complete responses and 11 partial responses. Responses occurred in 28% of patients with disease within the radiation field only and in 57% of patients with disease involving other sites. The median duration of response was 5.5 months, and the median times to progression and survival for all patients were 5 and 9 months, respectively. Grade 3 or 4 toxicities included anemia in 18% of patients and granulocytopenia in 15% of patients. Fifty-three percent of patients developed some degree of neurotoxicity; 21% of cases were grade 2 or worse., Conclusion: The combination of paclitaxel with cisplatin seems relatively well tolerated and moderately active in patients with metastatic or recurrent cervical cancer. The significant incidence of neurotoxicity is of concern, and alternative methods of administration of the two agents could be evaluated. Then, further study of this combination, alone or with the addition of other active agents, is warranted.

Purpose: The standard treatment for patients with muscle-invasive carcinoma of the urinary bladder is radical cystectomy. While radical cystectomy cures many patients with this tumor, almost 50% of them will develop metastatic disease. Adjuvant chemotherapy has been proposed for these patients in an attempt to reduce the probability of relapse and to improve survival. To assess whether adjuvant chemotherapy does benefit patients with muscle-invasive bladder cancer, we reviewed all phase II and III studies published in the English literature over the last 20 years., Methods: A review of all published reports was facilitated by the use of Medline computer search and by manual search of the Index Medicus., Results: Several comparative, nonrandomized studies have indicated that adjuvant chemotherapy may prolong disease-free survival. Four randomized studies have been conducted and all had a suboptimal patient accrual. Three studies used a cisplatin-containing combination chemotherapy and included primarily patients with non-organ-confined transitional-cell carcinoma (TCC) of the bladder. All three studies indicated that adjuvant chemotherapy improved disease-free survival and two of them also showed improvement in event-free survival and overall survival, respectively., Conclusion: Published series have been unable to establish an undisputed benefit of adjuvant chemotherapy over radical cystectomy alone for muscle-invasive bladder cancer. The interpretation of the available data is compromised by several methodologic and statistical problems. Thus, adjuvant chemotherapy cannot be considered as a standard treatment for all patients with muscle-invasive carcinoma of the bladder. Well-designed prospective randomized studies are needed to clarify the role of adjuvant chemotherapy in this disease. However, outside a protocol setting, there is some evidence that patients with extravesical disease or with lymph node involvement may benefit from adjuvant treatment with cisplatin-based combination chemotherapy. No data support such an approach for patients with muscle-invasive but organ-confined bladder cancer.

Purpose: To assess the prognostic significance of magnetic resonance (MR) imaging in patients with newly diagnosed asymptomatic multiple myeloma., Patients and Methods: Thirty-eight consecutive patients with asymptomatic myeloma of low tumor mass and negative skeletal surveys underwent MR imaging of the thoracic and lumbosacral spine. The presence and patterns of marrow involvement were correlated with standard laboratory parameters and time to disease progression., Results: Nineteen patients (50%) had evidence of marrow involvement at spinal MR imaging. MR patterns of marrow involvement were classified as diffuse (five patients), variegated (nine), and focal (five). Patients with abnormal MR imaging studies required therapy after a median of 16 months, versus 43 months for those with normal MR studies (P < .01)., Conclusion: Abnormal marrow patterns were present in half of patients with asymptomatic myeloma. An abnormal MR study of the spine identified asymptomatic patients who were likely to require treatment earlier than those with a normal MR study. A normal MR pattern provided additional justification to defer institution of chemotherapy. However, MR imaging remains an investigational tool to stage patients with multiple myeloma until more data are accumulated.

Purpose: To assess prospectively the role of magnetic resonance (MR) imaging in the staging of patients with a solitary bone plasmacytoma (SBP)., Patients and Methods: Twelve consecutive patients with an apparent SBP underwent MR imaging of both the primary tumor and the thoracic and lumbosacral spine to seek additional foci of marrow involvement that might have been undetected by standard skeletal survey. All patients received megavoltage irradiation (total dose, 40 Gy) to the primary lesion., Results: MR imaging of the thoracic and lumbosacral spine showed additional foci of marrow replacement in four of 12 patients, with signal characteristics identical to those of the primary tumor. In all four patients, the abnormal protein persisted at greater than 50% of the pretreatment value following radiation treatment. In contrast, the myeloma protein disappeared or was reduced by greater than 50% in five of the six patients with secretory disease and without additional marrow abnormalities. One of four patients progressed to multiple myeloma 10 months after diagnosis with new lesions on conventional radiographs in the same areas as detected previously by MR imaging., Conclusion: Four of 12 patients considered to have a SBP by standard criteria may have been understaged, because MR imaging showed additional marrow abnormalities consistent with myeloma. MR imaging of the spine may contribute to the initial staging of SBP, especially since some patients may be cured with radiotherapy.