Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics.

BACKGROUND: Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. PATIENTS AND METHODS: Patients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. RESULTS: Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types. CONCLUSION: Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.

Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid.

BACKGROUND: Patients with metastatic bone disease are living longer in the metastatic stage due to improvements in cancer therapy, making strategies to prevent the aggravation of bone disease and its complications, such as skeletal-related events (SREs) and pain, increasingly important. PATIENTS AND RESULTS: In this phase 3 trial in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma, denosumab reduced the risk of radiation to bone by 22% relative to zoledronic acid (P = 0.026), prevented worsening of pain and pain interference (2-point increase in Brief Pain Inventory score; P < 0.05 versus zoledronic acid), and reduced the frequency of a shift from no/weak opioid analgesic use to strong opioids (P < 0.05 versus zoledronic acid at months 3-5). Denosumab delayed the time to moderate-to-severe pain compared with zoledronic acid in patients with mild or no pain at the baseline (P = 0.04), supporting early treatment. Health-related quality-of-life scores were similar in both groups. The number needed to treat to avoid one SRE for denosumab was 3 patient-years versus placebo and 10 patient-years versus zoledronic acid. CONCLUSION: The use of denosumab was associated with better prevention of the complications of metastatic bone disease secondary to solid tumors or multiple myeloma versus zoledronic acid.

Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.

BACKGROUND: Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies. PATIENTS AND METHODS: Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts. RESULTS: Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab). CONCLUSIONS: In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.

Neoadjuvant chemotherapy, radical resection with intraoperative radiation therapy (IORT): improved treatment for gastric adenocarcinoma.

BACKGROUND: Adenocarcinoma of the stomach and gastroesophageal junction results in substantial morbidity, locoregional recurrence, and death. Surgical procedures, even with adjuvant therapy, have not significantly improved survival. This study evaluated the toxicity, response rate, locoregional control, and survival of patients with locally advanced gastric cancer that was treated with neoadjuvant multimodality therapy. METHODS: Patients with stage IIIA or early stage IV gastric adenocarcinoma received neoadjuvant 5-fluorouracil, Leucovorin, Adriamycin, and Cisplatin and underwent gastrectomy or esophagogastrectomy with intraoperative radiotherapy (IORT; 1000 cGY) to the gastric bed and postoperative radiation therapy. RESULTS: Nine of 15 patients (60%) with transmural extension and/or nodal metastases received IORT. There were 2 pathologically complete responses at the primary site. Eleven of 15 patients (73%) had tumor in perigastric lymph nodes; however, 9 of 15 patients (60%) had mucin-filled nodes without tumor cells. Neoadjuvant treatment did not increase operative morbidity rates. Ten of 15 patients (67%) remain free of disease (median, 27 months; range, 6-60 months). Five patients died 13 to 41 months (median, 17 months) after diagnosis. CONCLUSIONS: Neoadjuvant multimodality therapy with neoadjuvant 5-fluorouracil, Leucovorin, Adriamycin, and Cisplatin, radical resection with IORT, and postoperative radiation therapy is safe, can downstage tumors, provides improved locoregional control, and appears to cause significant tumor regression that may result in long-term survival or cure.

Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-hodgkin lymphoma.

BACKGROUND: Central nervous system involvement is a common manifestation of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected individuals. The purpose of this study was to review the frequency and pattern of neurologic manifestation of lymphoma in a cohort of HIV-infected individuals with systemic NHL. METHODS: Sixty-two patients with HIV-associated systemic NHL received infusional cyclophosphamide, doxorubicin, and etoposide. Five patients with lymphomatous meningitis at presentation received whole brain radiation therapy plus intrathecal chemotherapy (ITC). Of the remaining 57 patients, prophylactic ITC was recommended only for those patients with lymphomatous bone marrow involvement and/or high grade histology (N = 31). RESULTS: Thirteen patients (21%) had histologically documented (N = 6) or presumed (N = 7) central nervous system involvement, including 7 patients (11%) with meningeal lymphoma discovered either at presentation (N = 5) or soon after diagnosis (N = 2), and 6 patients (10%) with cerebral mass lesions at the time of disease recurrence consistent with parenchymal brain involvement. Five of six parenchymal brain recurrences occurred in the setting of progressive systemic disease. Four of 7 patients (57%) with meningeal lymphoma detected at presentation (N = 5) or within 3 months of presentation (N = 2) responded to therapy and survived >1 year. Of the 26 patients assigned to receive no prophylactic ITC, no patient developed an isolated meningeal recurrence and 1 patient developed an isolated parenchymal brain recurrence. CONCLUSIONS: The findings of the current study suggest that in patients with HIV-associated systemic lymphoma, meningeal lymphoma is potentially curable, parenchymal brain recurrence usually occurs in the setting of uncontrolled systemic disease, and prophylactic ITC may not be necessary for patients with intermediate grade histology and uninvolved bone marrow.

A retrospective review of blood transfusions in cancer patients with anemia.

BACKGROUND: The factors contributing to blood transfusions in patients with anemia of chronic disease are not well documented in the literature. We analyzed all blood transfusion events within a single oncology practice to determine if certain chemotherapy drugs, cancer types, or other factors necessitated more frequent transfusions. PATIENTS AND METHODS: Out of 331 patients receiving chemotherapy, 103 (31%) patients received a blood transfusion in 1995. Each of these charts was reviewed and sorted by diagnosis, treatment medications, and past transfusion and/or treatment history. Hemoglobin levels were obtained for each transfusion received in 1995. RESULTS: The average hemoglobin at time of transfusion was 7.9 g/dl. Higher hemoglobin levels at transfusion were observed for patients over the age of 60 and patients who received prior chemotherapy. Lower hemoglobin levels at transfusion were observed for patients receiving Epoetin Alfa and sarcoma patients. The average number of red blood cell (RBC) units transfused in 1995 was 5.1 per patient. More units were given to patients receiving etoposide, while fewer units were given to those receiving ifosfamide. We created a transfusion severity index (TSI) to jointly measure these two variables. CONCLUSION: The results of this study identify transfusion needs associated with certain groups of cancer patients and with certain types of chemotherapy drugs.

Epoetin alfa and high-dose chemotherapy.

High-dose chemotherapy (HDCT) with bone marrow transplantation (BMT) is associated with the development of significant anemia. The anemia is caused mainly by myelosuppression, although gastrointestinal-, genitourinary-, and phlebotomy-induced blood loss may also contribute. The number of red blood cell units transfused during the first 30 days following HDCT depends on the chemotherapy used, the underlying disease, and whether BMT was allogeneic, autologous, and used either peripheral blood stem cell or bone marrow support. Epoetin alfa has been used to treat the anemia that develops in the HDCT setting. Controlled studies in patients with both hematologic malignancies and solid tumors who were given epoetin alfa following HDCT have shown that red blood cell transfusion requirements decrease in patients receiving allogeneic BMT. Results using epoetin alfa in patients receiving autologous BMT have been disappointing. Alternatively, combination therapy with granulocyte colony-stimulating factor and epoetin alfa has been effective in mobilizing stem cell and committed myeloid/erythroid precursors before HDCT, but has not resulted in a lower red blood cell transfusion requirement after HDCT. Administration of epoetin alfa before HDCT while the bone marrow is still responsive to growth factors may be a new strategy with which to decrease the anemia in this setting.

Experience with epoetin alfa and acquired immunodeficiency syndrome anemia.

Anemia is common in patients infected with the human immunodeficiency virus (HIV). The etiology is often multifactorial and may include the HIV infection itself, opportunistic infections, cancer, medications (particularly zidovudine and sulfa-containing drugs), or anemia of chronic disease. Epoetin alfa therapy may play a supportive role in some HIV-infected patients by increasing hemoglobin, decreasing fatigue, and reducing the need for exposure to red blood cell transfusions. A large, placebo-controlled trial in the United States for anemic patients with the acquired immunodeficiency syndrome taking zidovudine demonstrated a statistically significant improvement in hematocrit in patients treated with epoetin alfa compared with placebo. Transfusion requirements decreased in epoetin alfa-treated patients over a 3-month period compared with placebo with a trend toward improvement in quality of life. Epoetin alfa was effective, however, only in patients whose pretreatment erythropoietin levels were less than 500 mU/mL. These advantages of epoetin alfa treatment may become especially important as HIV becomes more of a chronic disease, with the concern that red blood cell transfusion may accelerate progression of HIV.

Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial.

PURPOSE: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS). PATIENTS AND METHODS: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes. RESULTS: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin. CONCLUSION: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma.

Protease inhibitors are an important new class of agents for the treatment of human immunodeficiency virus (HIV) infection. The purpose of our trial was to determine the feasibility of combining the protease inhibitor saquinavir with a 96-hour continuous intravenous infusion of cyclophosphamide (800 mg/M2), doxorubicin (50 mg/M2, and etoposide (240 mg/M2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma associated with HIV infection. The effect of saquinavir on CDE-induced myelosuppression, CD4 lymphopenia, and non-hematologic toxicity was also sought. Twelve patients with HIV-related lymphoma received CDE every 28 or more days. All patients received saquinavir (600mg PO TID), filgrastim and Pneumocystis carinii and fungal prophylaxis. Patients also received either stavudine (n = 2) or both stavudine and didanosine (n = 10). Toxicity was analyzed using the NCI Common Toxicity Criteria for each cycle and the data were compared with the data from our prior study of CDE plus didanosine. An interim analysis was performed after accrual of the first 12 patients in order to assess toxicity. Severe (grade 3 or 4) mucositis occurred in eight of 12 patients (67%) treated with CDE plus saquinavir compared with three of 25 patients (12%) in our prior study treated with CDE without saquinavir (P < 0.001). In logistic regression analysis, saquinavir use was the only factor associated with a significantly greater risk of severe mucositis (relative risk 7.9; P = 0.03). Saquinavir use was not associated with a significant difference in the incidence of febrile neutropenia, prolonged neutropenia, chemotherapy dose reduction, or in the degree of myelosuppression. The decrease in CD4 lymphocytes for patients treated with saquinavir (absolute decrease of 23/microL, or a 26% decrease from baseline) was significantly less than for patients treated without saquinavir in the prior study (absolute decrease of 91/microL, or 42% decrease from baseline; P = 0.05). Four of 10 patients (40%) treated with saquinavir had an increase in CD4 lymphocytes of > or = 10/microL compared with none of 25 patients (0%) treated without saquinavir (P < 0.001). Combination of the protease inhibitor saquinavir with infusional CDE in patients with HIV-associated lymphoma was associated with a significant increase in the incidence of severe mucositis. This finding suggests that saquinavir may alter the metabolism of one of more of the cytotoxic agents in the CDE regimen, and underscores the need for careful investigation regarding the use of the protease inhibitors in patients receiving chemotherapy.

Opportunistic infection and immunologic function in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma treated with chemotherapy.

BACKGROUND: The incidence of systemic non-Hodgkin's lymphoma (NHL) is higher in the population infected with human immunodeficiency virus (HIV) than in the uninfected population. Standard treatment for this cancer involves the administration of systemic chemotherapy. PURPOSE: Our objective was to determine the relative risk (RR) of opportunistic infection and the relative change in immunologic function in a cohort of patients who had HIV-associated NHL and who were treated with combination chemotherapy and to compare them with those in a matched cohort of control subjects who had advanced HIV infection but no signs of NHL. METHODS: We performed a case-control study in which the clinical course of each patient with HIV-associated NHL (n = 43; case subjects) treated with infusional cyclophosphamide, doxorubicin, and etoposide was compared with that of two patients with HIV infection but without lymphoma who were matched for CD4 lymphocyte count and prior opportunistic infection (n = 86; control subjects). The patients' medical records were reviewed for all information related to acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections, survival, cause of death, and lymphocyte subset analyses. Univariate and multivariate analyses were performed to determine whether any of a number of confounding factors (e.g., age, sex, CD4 count, prior opportunistic infection, and prior antiretroviral therapy) could have influenced the risk of developing a first infectious event (defined as opportunistic infection or nonlymphoma death). All P values resulted from two-sided statistical tests. RESULTS: In the univariate analysis, a significantly greater risk for a first event was associated with being a case subject (RR = 1.8; 95% confidence intervals [CI] = 1.1-3.0; P < .05), having a low CD4 count (< 100/microL) (RR = 3.1; 95% CI = 1.8-5.4; P < .0001), being female (RR = 1.7; 95% CI = 1.1-3.3; P < .05), having prior Pneumocystis carinii pneumonia (RR = 3.5; 95% CI = 1.9-6.3; P < .0001), having any prior opportunistic infection (RR = 3.6; 95% CI = 2.1-6.4; P < .0001), and having prior antiretroviral therapy (RR = 1.9; 95% CI = 1.1-3.3; P < .05). In the multivariate analysis, however, being a case subject (RR = 2.1; 95% CI = 1.2-3.6; P < .01), having a low CD4 count (RR = 2.1; 95% CI = 1.2-3.9; P < .05), and being female (RR = 3.0; 95% CI = 1.8-5.6; P < .001) were the only characteristics associated with an increased risk of a first event. When the mean CD4 lymphocyte count at approximately 1 year was compared with that at baseline, there was a significantly greater decrease in the CD4 count among case subjects than among control subjects (mean decrease +/- standard deviation [SD] = 99/microL +/- 138/microL versus 29/microL +/- 100/microL; P = .03). CONCLUSIONS: Treatment of patients who have HIV-associated NHL with a non-steroid-containing chemotherapy regimen was associated with a significant and sustained reduction in the CD4 lymphocyte count and a twofold increase in the risk of developing opportunistic infection. IMPLICATIONS: Oncologists and other physicians who treat patients with HIV-associated NHL should be familiar with the prophylaxis, recognition, and management of opportunistic infection. In addition, there is a need to identify effective strategies for the amelioration of chemotherapy-induced immunosuppression in this population.

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma.

PURPOSE: To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS: Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS: ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION: Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.

Recombinant human erythropoietin treatment of anemic cancer patients.

PURPOSE: This article describes the mechanism of anemia in patients with cancer and the potential role of recombinant human erythropoietin in its treatment. Dosing, safety, prediction of response, and reimbursement issues also are discussed. OVERVIEW: Patients with advanced cancer frequently experience significant, chronic anemia that can contribute to overall morbidity. The causes of this anemia are multifactorial, including blood loss, nutritional deficiencies, hemolysis, bone marrow infiltration by tumors, and the anemia of chronic disease. In addition, myelosuppressive chemotherapy can cause or exacerbate this anemia. CLINICAL IMPLICATIONS: Several clinical studies have demonstrated that the use of recombinant human erythropoietin may prevent or ameliorate anemia by significantly increasing the hematocrit in patients who receive chemotherapy. This can reduce the proportion of patients who require erythrocyte transfusions. In addition, responding patients experience an improvement in quality of life.

Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy.

PURPOSE: To assess whether the administration of recombinant human erythropoietin (r-HuEPO) would increase the hematocrit, reduce the requirement for transfusion, and improve the quality of life in anemic cancer patients receiving myelosuppressive, cisplatin-based chemotherapy. PATIENTS AND METHODS: One hundred thirty-two anemic cancer patients receiving cyclic, cisplatin-containing, myelosuppressive chemotherapy were evaluated. Patients received either r-HuEPO (150 U/kg) or placebo, subcutaneously, three times a week for 3 months. Responses were assessed by measuring changes in hemoglobin/hematocrit, transfusion requirement, and quality of life. RESULTS: The mean hematocrit increased by 6.0 percentage points in the r-HuEPO group versus 1.3 in the placebo group. A decrease in transfusion requirement did not reach significance over all 3 months, but there was a significant reduction in the percentage of patients transfused in the second and third months (27% r-HuEPO vs. 56% placebo) and a trend toward reduction in the mean total number of units transfused (1.20 units r-HuEPO vs. 2.02 units placebo), suggesting a lag of 1 month before r-HuEPO can affect the transfusion requirement. Pretreatment serum erythropoietin levels were lower in responders than in nonresponders (73.5 IU/L and 86.3 IU/L means, respectively). However, the magnitude of this difference was not helpful in defining which patients were likely to respond. There was a significant improvement in overall quality of life between the two treatment arms in favor of the r-HuEPO-treated group. There were no significant adverse effects associated with r-HuEPO. CONCLUSIONS: r-HuEPO is safe and can cause a significant improvement in the hematocrit and quality of life of anemic cancer patients receiving myelosuppressive, cisplatin-based chemotherapy. After 1 month of r-HuEPO, there is also a reduction in transfusion requirement.

Clinical use of erythropoietin.

Recombinant human erythropoietin has been available for clinical use since 1985. It was an immediate success in treating the anemia of chronic renal failure and has also enjoyed some objective success in the treatment of other anemias in either a therapeutic or prophylactic setting, but the issues of appropriate patient selection and cost-benefit ratios are still unresolved. This review discusses the most recent literature concerning the use of recombinant human erythropoietin for the anemia associated with cancer, HIV infection, myelodysplasia, prematurity, autologous blood transfusion, bone marrow transplantation, and chronic renal failure.

The management of cancer anemia.

Anemia is common in patients with cancer and is often exacerbated by myelosuppressive chemotherapy. If severe enough, the anemia may require red blood cell transfusion for symptomatic palliation. However, blood transfusion will never be completely safe. Inconvenience and acute transfusion reactions are a problem and there is still a small risk of hepatitis. In selected patients with cancer-related anemia, recombinant human erythropoietin is another option to consider for the symptomatic patient.