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.

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.

Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.

BACKGROUND: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. PURPOSE: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). METHODS: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. RESULTS: The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group. CONCLUSIONS: We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.

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.

Protein A immunoadsorption in the treatment of malignant disease.

Circulating immune complexes (CIC) are known to be present in cancer patients and are responsible for much of the cancer-associated immunosuppression. Removal or modulation of these "blocking factors" can reverse the immunosuppression. Protein A from Staphylococcus aureus has the unusual property of binding to CIC with high avidity. Use of protein A as an immunoadsorbent in extracorporeal immunotherapy affinity columns has resulted in antitumor and antiviral responses in animals. Our group developed a multicenter trial to assess toxicity and antitumor response with this biologic response modifier alone. Overall, 24% (21 of 87 patients) had objective tumor regressions including both partial responses (PR) and less than PR. No complete responses (CR) were observed. Responses were observed in acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (six of 17 PR; two of 17 less than PR; overall, 47%), breast adenocarcinoma (five of 22 PR; three of 22 less than PR; overall response, 36%), colon adenocarcinoma, (one PR, one less than PR; overall response, 11%), and non-oat cell lung carcinoma (two of seven less than PR). The procedure was well tolerated and could be performed on an outpatient basis. No adverse reaction was observed in 735 of 1,113 treatments (66%). The most common adverse effect was an "influenza-like" syndrome consisting of fever and chills. Pain was present in 12% of the patients. There were no study-related deaths. Serum IgG and CIC levels did not statistically change due to therapy in responding or nonresponding patients. Complement levels remained within the normal range. Liver and renal tests remained stable throughout the study. In summary, protein A immunoadsorption of plasma is well tolerated in the outpatient clinic, has demonstrated antitumor activity in resistant solid tumors, and functions as a biologic response modifier.

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.

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.

Use of protein A immunoadsorption as a treatment for thrombocytopenia in HIV-infected homosexual men: a retrospective evaluation of 37 cases.

Thirty-seven HIV-infected homosexual men with thrombocytopenia (less than 100 x 10(9)/l) received protein A immunoadsorption treatments to remove platelet-sensitizing immunoglobulin (Ig) G and circulating immune complexes (CIC) from plasma. Patients received an average of six treatments each, consisting of 250 ml plasma over a 3-week period. Clinical improvement in hemorrhagic symptoms associated with substantial increase in platelet counts was achieved in 18 patients. These responses were maintained over a median follow-up period of more than 7 months in 14 evaluable patients who were not lost to follow-up (three patients relapsed in 2 weeks and one received another therapy). Generally, moderate transient treatment-related side-effects included fever, musculoskeletal pain, chills and nausea. A transient serum sickness-like reaction was observed in seven patients, leading to termination of treatment in two. Clinical responses were associated with significant decreases in levels of platelet-sensitizing Ig, including CIC. Stimulation of broadly cross-reactive anti-antigen-binding fragment [F(ab)2], antibodies contributed to these responses. Protein A immunoadsorption is an effective alternative treatment for HIV-associated thrombocytopenia.

Recombinant human erythropoietin for the treatment of anemia in patients with advanced cancer.

The results of the multicenter trials demonstrate that r-HuEPO therapy can increase the hematocrits of anemic patients with advanced cancer. The multicenter trials were undertaken because, in previous smaller trials without placebo controls, patients with cancer and anemia had been shown to be likely responders to r-HuEPO therapy. To varying degrees in these trials, RBC transfusion requirements were eliminated or decreased in comparison to those of placebo-treated patients, and anemia was lessened or corrected in the r-HuEPO groups. The side effects of r-HuEPO treatment were minor; anemic patients with advanced cancer receiving r-HuEPO therapy did not develop significant hypertension, seizures, or thrombotic events, and progression of tumor was not observed. Moreover, patients in the multicenter trials whose hematocrits increased to 38% or greater, or increased 6 percentage points or more, experienced significant improvement in all aspects of the quality of their lives. On the basis of these trials, r-HuEPO therapy appears to treat effectively the anemia of cancer. The importance of eliminating the need for transfusions and preventing sensitization to human leukocyte antigens will be major factors affecting the clinical future of r-HuEPO.

Treatment of patients with HIV thrombocytopenia and hemolytic uremic syndrome with protein A (Prosorba column) immunoadsorption.

Both antibodies and circulating immune complexes (CIC), which bind to platelets and induce the destruction and clearance of platelets by the reticuloendothelial system, are found in patients with human immunodeficiency virus (HIV) and immune thrombocytopenic purpura (ITP). IgG and CIC were removed from patients' plasma by extracorporeal immunoadsorption using protein A-silica columns (PROSORBA columns). Of the 36 HIV-positive ITP patients treated, 29 received more than one treatment and were evaluated for response. Sixteen patients showed more than a 50% increase in their platelet counts. Platelet-associated IgG (PAIgG) and/or platelet-directed IgG and CIC were elevated in all patients. After four to eight treatments, 16 of 29 patients showed a 170% to 430% increase in platelet counts. A decrease in CIC and PAIgG was noted in responding patients. The median duration of response to date was 8 to 12 months. This treatment was associated with immune modulation and the development of an anti-F (ab')2 antibody response. The antibody functions by complexing with both platelet-binding IgG and CIC, neutralizing their binding capacity for platelets and enhancing their clearance from the circulation. Nine patients with mitomycin-C-induced hemolytic uremic syndrome (HUS) were also treated with PROSORBA columns. Pretreatment platelet counts were markedly reduced while a definite increase in platelet counts was observed upon completion of therapy. There was a decrease of hemolysis and stabilization of renal function in three patients. PROSORBA column treatment has demonstrated marked activity against both HIV-ITP and HUS, and has successfully freed patients from the bleeding diathesis associated with these syndromes.

Protein A immunotherapy in the treatment of cancer: an update.

Protein A, a naturally occurring Staphylococcus aureus cell surface protein, has the unusual property of binding circulating immune complexes and immunoglobulin G with high avidity. CIC have played a major role in cancer-associated immunosuppression. Thus, removal of the immunosuppressive agents, ie, the CIC, may lead to a modulation of the immunosuppression and a liberation of the immune system to perform an antitumor effect. In animal studies, protein A has been used in extracorporeal immunoadsorption columns and treatments have resulted in tumor shrinkage and antiviral responses. Our group developed a multicenter clinical trial to assess toxicity and antitumor responses with this biologic response modifier alone. This is an update of our original trial. We have now treated 142 patients for a total of 1,306 treatments. The patients consisted of 74 males and 68 females. Their age ranged from 7 to 83 years, with a mean of 50 years. The Karnofsky performance index values ranged from 40 to 95, with a mean of 80. Patients who received seven or more treatments were considered eligible for tumor response assessment, and all patients with one or more treatments were eligible for toxicity assessment. Thus, there were 101 patients eligible for tumor response and 142 eligible for toxicity response. The total response rate was 22 patients or 21.8% (partial remission [PR], 12 patients, 12%; less than PR, 10 patients, 10%). Response rates were similar in the 13 treatment centers. Toxicity was assessed in 142 patients. One thousand three hundred six treatments were assessed for treatment toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human erythropoietin and health-related quality of life of AIDS patients with anemia.

To evaluate the effect of recombinant human erythropoietin on anemia and health-related quality of life in patients with acquired immunodeficiency syndrome (AIDS), we initiated an observational study with an open-label multicenter treatment protocol that involved multiple academic and community physicians in the United States. Our subjects comprised 251 anemic (i.e., hematocrit < 30%) patients with a clinical diagnosis of AIDS using 1987 CDC criteria, age > or = 12 years, and serum erythropoietin level < or = 500 IU/L. The initial dosage of recombinant human erythropoietin was 4,000 units subcutaneously for 6 days each week. Based on the patient's response to therapy, the dosage was increased sequentially to 8,000 units subcutaneously for 6 days per week. Our measurements included changes in mean hematocrit and health-related quality of life. The interview included measures of energy/fatigue; physical, social, role and cognitive function; depression; health perceptions; and life satisfaction. Adverse experiences were also documented to assess safety. Changes in mean hematocrit level from a baseline of 27.9% to 33.6% at week 12 (p < .0001) and 34.5% at week 24 (p < .0001) were observed in patients treated with recombinant human erythropoietin. Adverse experiences, not clearly associated with AIDS, were reported by 10% of patients. Increases in energy (p < .05) were observed after 12 and 24 weeks of drug therapy, and increases in health perceptions were seen after 24 weeks (p < .05). No statistically significant increases or decreases were observed on measures of physical functioning, cognitive functioning, depression, social functioning, or home management activities over the 24-week follow-up. Anemia correctors (defined as hematocrit > or = 38%) showed greater improvement in energy, health perceptions, home management, and role function than noncorrectors. Study dropouts and those who died had significantly worse scores for health-related quality of life at baseline compared to study completers. Thus, the AIDS patients with anemia and serum erythropoietin levels < or = 500 IU/L treated with recombinant human erythropoietin showed increased mean hematocrit and improved health perceptions and energy levels. The drug therapy was associated with increased feelings of energy, but it was not associated with other changes in health status and well-being in the AIDS patients completing the study. These observations need to be confirmed in randomized clinical trials.

Changing patterns of care in the management of anemia.

There exists a potential for change in the approach to the management of the patient with chronic disease, specifically, the anemia of chronic disease (ACD). One of the components in the pathophysiology of ACD is inadequate erythropoietin response. Normally, as anemia develops, the erythropoietin level does not begin to increase until the hematocrit level decreases below 35%. However, the increase in the erythropoietin level is blunted in ACD. Increasing the hematocrit level by transfusion or recombinant human erythropoietin (r-HuEPO) treatment can subjectively and objectively improve the ACD patient's symptoms and performance. Although objective data in support of blood transfusions do exist, this treatment can carry risks of acute and chronic reactions, infection, and possibly immunosuppression. Treatment with r-HuEPO is a safer, nontransfusion means of increasing the hematocrit level of the patient with ACD symptoms.

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.

Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies.

Anemia associated with advanced cancer is common. Contributing factors include the anemia of chronic disease, chemotherapy, radiation therapy, and bone marrow invasion with tumor. Based on the observation that endogenous erythropoietin (EPO) levels in anemic patients with cancer are inadequate for the degree of anemia, three randomized double-blind, placebo-controlled trials of recombinant human erythropoietin (rHuEPO) treatment in anemic patients with cancer were performed in patients (1) not receiving concomitant chemotherapy (NO CTX), (2) receiving myelosuppressive chemotherapy that did not include cisplatin (CTX-NO PLAT), and (3) receiving myelosuppressive cisplatin-containing chemotherapy (CTX-PLAT). In the NO CTX trial, patients were treated with rHuEPO 100 U/kg or placebo subcutaneously (SQ) three times per week for up to 8 weeks. In the CTX trials, patients were treated with rHuEPO 150 U/kg or placebo SQ three times per week for 12 weeks. Four hundred thirteen patients were enrolled (124, NO CTX; 157, CTX-NO PLAT; and 132, CTX-PLAT). In all three trials, patients receiving rHuEPO had a significantly (P < .004) greater increase in hematocrit (HCT) than placebo-treated patients. In the two CTX trials combined, rHuEPO-treated patients also had a significantly (P < or = .009) lower transfusion requirement than placebo-treated patients after the first month of therapy. Quality of life improved significantly (P < .05) in responding (> or = 6%-point HCT increase without transfusion) rHuEPO-treated patients compared with placebo-treated patients. Overall, no adverse events occurred more frequently in rHuEPO-treated patients compared with placebo-treated patients. Following completion of the double-blind phase, patients received rHuEPO on an open-label basis as needed for correction of anemia with the dose titrated to a maximum of 900 U/kg/wk. During total rHuEPO exposure (either started at the beginning of double-blind therapy for patients initially randomized to rHuEPO or at the beginning of open-label therapy for patients initially randomized to placebo; 363 treated/347 evaluable for efficacy), 40.0%, 56.1%, and 58.3% of the NO-CTX, CTX-NO PLAT, and CTX-PLAT patients, respectively, responded to rHuEPO therapy with an increase of HCT > or = 6% unrelated to transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Clinical application of recombinant erythropoietin in anemic cancer patients.

Anemia is common in cancer patients and may require treatment for symptomatic palliation. Transfusion has been the mainstay of therapy, but is not without risk. Because erythropoietin levels in cancer-related anemia are inadequate for the degree of anemia, recombinant human erythropoietin has been studied to treat the anemia. Results from these studies are encouraging.

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.