Changes in plasma iron levels following Carboplatin administration

Carboplatin-induced changes in plasma iron levels and the related erythropoiesis impairment were investigated in 32 neoplastic patients for a total of 64 courses of chemotherapy. Iron showed a significant increase over pretreatment levels starting from day 1 after carboplatin administration (p< 0.001). Return to pre-treatment levels was achieved on day 14. Hemoglobin decreased significantly on day 7 (p< 0.05) and further on days 14 and 21 (p< 0.001). In patients undergoing 3 consecutive cycles of chemotherapy, basal hemoglobin before the 2nd cycle was significantly lower than before the 1st (p< 0.05), whereas before the 3rd cycle the levels were similar to those before the 2nd. Hemoglobin time-course did not differ among the three cycles. No relationship was observed between maximum iron levels and hemoglobin at minimum levels, nor between pre-treatment hemoglobin levels and severity of chemotherapy-induced subacute anemia. These results suggest that neither pre-treatment hemoglobin nor the entity of iron increase are predictive of the need of blood transfusion. Moreover, the absence of correlation between iron increase and hemoglobin decrease suggests that the toxic block on erythroid maturation is not the only mechanism with which platinum compounds interfere with iron metabolism. It is possible that the bivalent platinum ion may displace competitively iron from its binding sites, either on proteins or on cells.     

Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy

This randomised controlled multicentre trial evaluated the effectiveness of recombinant human erythropoietin (rhEPO) in preventing anaemia and reducing the need for blood or erythrocyte transfusion in 122 ovarian cancer patients receiving platinum-based chemotherapy. The patients were randomly allocated to receive rhEPO 150 U/kg or 300 U/kg subcutaneously, three times a week, or open control. Patients also received up to 6 cycles of carboplatin or cisplatin, alone or in combination with other cytotoxic agents. Intention-to-treat analysis showed that 39.4% of patients in the control group received at least one blood transfusion, compared with 9.2% of patients treated with rhEPO. Patients treated with rhEPO experienced a significantly longer time to first erythrocyte transfusion than the control group and were less likely to experience nadir haemoglobin levels <10 g/dl (P<0.001 and <0.05, respectively). A haemoglobin decrease <1 g/dl during the first chemotherapy cycle, as well as a low baseline serum erythropoietin concentration, predicted a low transfusion need in rhEPO-treated patients but not in controls. During the study, 103 patients suffered at least one adverse event, but no serious, and only nine non-serious adverse events were considered possibly related to rhEPO therapy. These results indicate that treatment with rhEPO prevents anaemia, it reduces the need for blood or rhEPO erythrocyte transfusion in patients with ovarian cancer receiving platinum-based chemotherapy, and it is well tolerated. A starting dose of 150 U/kg of rhEPO, three times a week, may be recommended.     

Treatment-induced anaemia and its potential clinical impact in patients receiving sequential high dose chemotherapy for metastatic testicular cancer

First-line sequential high dose chemotherapy is under investigation in patients with "poor prognosis" metastatic germ cell tumours in order to improve survival. Despite the use of autologous peripheral blood stem cell transplantation and granulocyte colony stimulating factor chemotherapy dose intensification is associated with severe haematotoxicity including anaemia, which may significantly affect quality of life and tolerability of chemotherapy. This study investigates the frequency and degree of anaemia in patients receiving first-line sequential high dose chemotherapy for metastatic testicular cancer and the impact of anaemia on treatment outcome. A total of 101 newly diagnosed patients with "poor prognosis" metastatic nonseminomatous germ cell tumours were treated with one cycle of standard VIP followed by three cycles of HD-VIP-chemotherapy (etoposide, ifosfamide, cisplatin) within a large phase I/II study. Differential blood cell counts were taken prior, during and after every cycle of chemotherapy. Additionally, the numbers of red blood cell and platelet transfusions were recorded. Kaplan-Meier analyses were performed to correlate pre-treatment and post-treatment haemoglobin values to response and overall survival. Forty-eight per cent of the patients were classified anaemic (haemoglobin <12 g dl(-1)) prior to the start of chemotherapy. The application of sequential HD-VIP resulted in median haemoglobin nadirs between 7.8 g dl(-1) (range 5.5-11.1 g dl(-1)) in the first cycle and 7.6 g dl(-1) (range 6.0-11.4 g dl(-1)) in the third cycle despite the frequent use of red blood cell transfusions. Almost all patients (99%) had haemoglobin levels <10 g dl(-1) at some timepoint during first-line sequential high dose chemotherapy. Overall, 97 patients received red blood cell transfusions with a median of 10 units (range 2-25) per patient during the four consecutive cycles of therapy. The time to first transfusion was shortest in patients with the lowest initial haemoglobin values. While there was no prediction of response or outcome by baseline haemoglobin-levels, a significant survival difference in favour of patients with a haemoglobin value >10.5 g dl(-1) after completion of four cycles of therapy (at leukocyte recovery after the last cycle) compared to those with haemoglobin values <10.5 g dl(-1) was found with 3-year overall survival rates of 87% vs 68%, respectively (P<0.05). Severe anaemia is a very frequent side effect of sequential dose intensive therapy in patients with germ cell cancer, with almost all patients becoming transfusion dependent. Despite the frequent use of red blood cell transfusions, median haemoglobin nadirs remained about 7.5-8 g dl(-1) during therapy. A correlation of haemoglobin-values after completion of therapy to overall treatment outcome was found.     

Anemia in oncology practice: relation to diseases and their therapies

Anemia is common in patients with cancer and is a frequent complication of myelosuppressive chemotherapy. In this study, we investigated the incidence and severity of chemotherapy-induced anemia caused by the most common chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults. Five hundred fifty-two patients with histologically proven carcinoma originating from breast (n = 165), lung (n = 128), colon (n = 75), ovary (n = 84), and malignant lymphoma (n = 100) were included in this study. Hemoglobin levels for each patient were measured with an automatic counter during both pretreatment and before each chemotherapy cycle during therapy. To document the incidence of anemia, the National Cancer Institute grading system was used. Before chemotherapy, 44% of patients with breast carcinoma had anemia. There was a 16% increase in the incidence of anemia after chemotherapy. Severe anemia was observed in less than 1% of patients. No difference was found in the incidence of anemia between the fluorouracil, doxorubicin, cyclophosphamide (FAC) and cyclophosphamide, methotrexate, fluorouracil (CMF) regimens used in the adjuvant setting. However, single-agent chemotherapy with newer generation caused more anemia when compared with the FAC regimen (p < 0.005). Chemotherapy resulted in a significant decrease in hemoglobin levels when compared with pretreatment values in patients with lung cancer (p < 0.001). During treatment, the increase in the incidence of grade II anemia was associated with a parallel decrease in the incidence of grade I anemia. The incidence of severe anemia did not exceed 15%. The incidence of anemia was equivalent in both patients with small-cell lung cancer and those with non-small-cell lung cancer treated with the etoposide and cisplatin (EP) combination. Seventy-one percent of patients with colon cancer had anemia before initiation of chemotherapy. No difference was observed in posttreatment hemoglobin values compared with pretreatment values. Patients treated with irinotecan and fluorouracil and leucovorin (FUFA) combination showed similar rates of anemia. Incidence of anemia in patients with ovarian cancer at admission was 68%. Chemotherapy resulted in a prominent increase in incidence of anemia, which increased to 91.5%. There was an increase in grade II anemia, which corresponded to the decrease in grade I anemia. Less than 10% of patients developed severe anemia. No difference in the incidence of anemia was observed in patients with ovarian cancer treated with either cisplatin and cyclophosphamide or cisplatin combination. Showing a high incidence of anemia (82%) at presentation, hemoglobin levels in patients with malignant lymphoma were unaltered with chemotherapy. Severe anemia occurred in less than 3% of patients. There was a higher incidence of anemia in patients with non-Hodgkin's lymphoma receiving the cyclophosphamide, epirubicin, vincristine, prednisone (CEOP) regimen in contrast to patients with Hodgkin's lymphoma treated with the doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) combination. There was a prominent decline in the hemoglobin levels with cisplatin-based combinations in contrast to combinations including noncisplatin agents (p < 0.001). In this study, we have observed equivalent rates of treatment-related anemia when compared with previous data in patients with specific tumor types. The incidence of pretreatment anemia was high in various malignancies. The mechanisms underlying the propensity for a higher risk of pretreatment anemia in patients with malignant disorders and its influence on the outcome has to be elucidated by further population-based and molecular studies.     

Bone marrow suppression in gynecological patients with malignant tumor treated with combination chemotherapy cyclophosphamide, pirarubicin and cisplatin

We treated 14 patients with cyclophosphamide, adriamycin and cisplatin (CAP), and 16 patients with cyclophosphamide, Pirarubicin and cisplatin (CTP). Hematological changes in the peripheral blood were compared in the two groups to determine whether there was any difference in bone marrow suppression. 1) The lowest leukocyte counts were similar in the two groups. The leukocyte count reached its nadir at 11.6 +/- 2.1 days in the CTP group and at 15.1 +/- 2.8 days in the CAP group, a significant difference (p less than 0.01). 2) The leukocyte count recovered rapidly in the CTP group and was significantly higher (p less than 0.01) at 3 to 4 weeks than in the CAP group, and it returned to the pretreatment level in the CTP group in the fourth week. 3) The platelet count reached its lowest level in the second week in both groups. In the CTP group, it was significantly higher (p less than 0.01) than in the CAP group. 4) Reticulocyte count reached its lowest level in the first week in both groups, and then started increasing. 5) In the CTP group, a course of treatment was 28.0 +/- 2.3 days and it was 29.5 +/- 2.3 days in the CAP group. In 28% of the CPA group, it took 30 days or more for the leukocyte count to return to normal after one course, while none of the CTP group did the leukocyte count remain low for 30 days. These results show that CTP causes more rapid bone marrow suppression (particularly leukocytopenia) than CAP, does but that a recovery is more rapid with CTP. These CTP may be a better form of treatment than CAP.     

Dose and schedule effects of cisplatin on the related acute iron changes

To investigate the relationships between cisplatin and the related erythropoiesis impairment, 14 patients receiving very-high-dose cisplatin (40 mg/m2/day for 5 days) and 17 patients receiving standard-high-dose cisplatin (either a single dose of 100 or 20 mg/m2/day for 5 days) entered this study. Iron, ferritin, hemoglobin, and reticulocyte levels were evaluated before, 4 and 6 days after each course of cisplatin. A complete blood count was obtained weekly. During the 1st week after chemotherapy, iron and ferritin levels significantly increased, and the reticulocyte count decreased. Iron changes depend on the cisplatin dose, but are not related to the different schedules employed. The severity of subacute anemia was found to be dependent on the cisplatin dose administered and on hemoglobin pretreatment levels. Some relationships between cisplatin, iron changes, and the subacute hemoglobin decrease are described.     

Prognostic factors in metastatic nasopharyngeal carcinoma

BACKGROUND: The current retrospective study aimed to identify some determinants of survival in metastatic NPC. METHODS: The study concerned 95 patients with metastatic nasopharyngeal carcinoma treated between 1993 and 2001. Statistical comparison between patients subgroups survival was carried out employing the log-Rank test (statistical significance was defined as p45 years and25 years), gender, performance status at diagnosis of metastatic disease (PS 0-1 or 2-3), time of metastasis diagnosis(at presentation or later), number of metastatic sites (single or multiple), specific metastatic sites(bone, liver, lung, distant nodes), number of bone metastasis (single or multiple), disease free survival (DFI) (6 months), prior chemotherapy, radiotherapy of metastatic sites. RESULTS: Negative prognostic factors in univariate analysis were: poor PS (>or=1), multiple metastatic sites, multiple bone metastasis, previous chemotherapy, visceral or node metastasis and non irradiated metastasis. Poor PS, multiple metastatic sites, and prior chemotherapy were independently significant negative prognostic factors in multivariable analysis. CONCLUSIONS: In this study we identified new prognostic factors in univariate and multivariate analysis. A regular and careful follow-up of patients treated for NPC is then recommended in order to detect early metastatic dissemination (with minimal localizations) while patients have still a good PS.     

Relationship between prostate volume, prostate-specific antigen nadir, and biochemical control

PURPOSE: In patients treated with definitive three-dimensional conformal radiotherapy (3D-CRT) for localized prostatic adenocarcinoma, we sought to evaluate the relationship between pretreatment prostate gland volume and posttreatment prostate-specific antigen (PSA) nadir, as well as the relationship of prostate volume and PSA nadir with biochemical control (bNED). Two subgroups were studied: favorable (PSA <10 ng/mL, Gleason score 2-6, and T1-T2A) and unfavorable (one or more: PSA >/=10 ng/mL, Gleason score 7-10, T2B-T3). MATERIALS AND METHODS: A total of 655 men (n = 271 favorable and 384 unfavorable) were treated with 3D-CRT alone between May 1989 and November 1997. All patients had information on prostate volume and a minimum follow-up of 24 months (median 56, range 24-126). Of the 655 men, 481 (n = 230 favorable and 251 unfavorable) remained bNED at time of analysis, with biochemical failure defined in accordance with the American Society for Therapeutic Radiology and Oncology consensus definition. Factors analyzed for predictors of bNED included pretreatment prostate volume, posttreatment PSA nadir, pretreatment PSA, palpation T stage, Gleason score, center of the prostate dose, and perineural invasion (PNI). We also analyzed pretreatment prostate volume and its correlation to prognostic factors. For bNED patients, the relationship between PSA nadir and prostate volume was evaluated. RESULTS: On multivariate analysis, prostate volume (p = 0.04) and palpation T stage (p = 0.02) were the only predictors of biochemical failure in the favorable group. On multivariate analysis of the unfavorable group, pretreatment PSA (p <0.0001), Gleason score (p = 0.02), palpation T stage (p = 0.009), and radiation dose (p <0.0001) correlated with biochemical failure, and prostate volume and PNI did not. For all 481 bNED patients, a positive correlation between pretreatment volume and PSA nadir was demonstrated (p <0.0001). Subgroup analysis of the favorable and unfavorable patients also demonstrated a positive correlation between prostate volume and PSA nadir (p = 0.003 and p = 0.0002, respectively). Using multiple regression analysis, the following were found to be predictive of PSA nadir in all bNED patients: prostate volume (p <0.0001), pretreatment PSA (p <0.0001), palpation T stage (p = 0.0002), and radiation dose (p = 0.0034). Gleason score and PNI were not predictive. For the favorable group, palpation T stage (p = 0.0006), pretreatment PSA (p = 0.0083), prostate volume (p = 0.0186), and Gleason score (p = 0.0592) were predictive of PSA nadir, and PNI and radiation dose were not predictive. In the unfavorable group, prostate volume (p = 0.0024), radiation dose (p = 0.0039), pretreatment PSA (p = 0.0182), and palpation T stage (p = 0.0296) were predictive of PSA nadir, and Gleason score and PNI were not predictive. CONCLUSION: This report is the first demonstration that prostate volume is predictive of PSA nadir for patients who are bNED in both favorable and unfavorable subgroups. PSA nadir did not correlate with bNED status in the favorable patients, but it was strongly predictive in the unfavorable patients. Prostate gland volume was also predictive of bNED failure in the favorable but not the unfavorable group.     

ERCC1 Expression in Metastatic Triple Negative Breast Cancer Patients Treated with Platinum-Based Chemotherapy

Background: Possible targeted therapies for metastatic triple negative breast cancer (TNBC) include cytotoxic chemotherapy that causes interstrand breaks (platinum-based drugs). The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway, removing platinum-induced DNA adducts and contributing to cisplatin resistance. Detecting ERCC1 overexpression is important in considering treatment options for metastatic TNBC, including individualized approaches to therapy, and may facilitate improved responses or reduction of unnecessary toxicity. We hypothesized that assigning cisplatin based on pretreatment ERCC1 expression would improve response and survival. This study was conducted to assess the impact of ERCC1 expression on PFS, OS and response rates in metastatic triple negative breast cancer patients treated with platinum-based chemotherapy. Methods: From June 2012 to November 2013, 52 metastatic triple negative breast cancer patients were enrolled. ERCC1 protein expression was detected from pretreatment biopsies by Immunohistochemistry. All patients received cisplatin plus paclitaxel. The primary end point was the impact of ERCC1 expression on PFS and OS. Results: 34 patients (65.4%) showed positive ERCC1 expression while 18 (34.6%) proved negative. Positive ERCC1 expression was associated with short PFS (median, 5 months vs. 7 months; P = 0.043), short OS (median, 9 months vs. 11 months; P = 0.033) and poor response to cisplatin based chemotherapy (P = 0.046). Conclusions: This prospective study further validated ERCC1 as a reliable biomarker for customized chemotherapy in metastatic triple negative breast cancer patients. High expression of ERCC1 was thereby fond to be significantly associated with poor outcome in patients treated with platinum based chemotherapy.     

Serum hyaluronan (hyaluronic acid) in breast cancer patients

Eighty-three women with breast cancer (57 with systemic metastasis, 26 without) were investigated for serum hyaluronan (HA) and compared to 50 patients with benign diseases of the breast. Hyaluronan was significantly increased in sera of metastatic patients compared to sera of non-metastatic patients (p less than 0.0001) and also in sera of non-metastatic patients when compared to control sera (p less than 0.01). The difference was not related to the number of metastatic sites involved. Three months after starting cytotoxic chemotherapy in metastatic patients, lower HA concentrations were observed in patients responding to chemotherapy. The initial level of serum HA had no predictive value concerning response to chemotherapy.     

Metastatic pattern in non-resectable non-small cell lung cancer

This study describes the metastatic pattern at autopsy in patients with non-resectable non-small cell lung cancer (NSCLC) and evaluates the impact of various pretreatment variables and treatment outcomes on the metastatic spread. In eight phase II chemotherapy trials from 1985 through 1993, 337 patients were treated and 51 autopsies were performed (autopsy rate 15%). The male/female ratio was 31/20, median age 56 years (range 36-71), response rate to chemotherapy 8%, and median survival 88 days (range 3-899). Histologic types included adenocarcinoma, 31 cases (60%), squamous cell carcinoma, 9 cases (18%), large cell carcinoma, 9 cases (18%), and unclassified NSCLC, 2 cases (4%). Patients who were autopsied had a shorter median survival than patients without autopsy (p = 0.002, log-rank test). Most commonly involved metastatic sites found at autopsy were mediastinal lymph nodes (84%), pleura (51%), liver (47%), bone (34%), brain (32%), pericardium (29%), adrenals (29%). The median number of involved organs was 5 (range 1-16), with a median of 3 intrathoracic sites (range 1-8) and 2 extrathoracic sites (range 0-11). Patients who initially had metastatic NSCLC also had significantly more metastatic sites at autopsy both extrathoracic (p = 0.004) and totally (p = 0.03) compared to patients with locally advanced disease. No other relation to pretreatment variables was found.     

Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide

Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients (n = 28) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide. No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.     

Severity, risk factors, and physician practices in the management of anemia during concurrent chemoradiation for head and neck carcinoma

BACKGROUND: Anemia is a well-recognized complication of concurrent chemoradiation therapy for head and neck carcinoma. It impairs quality of life and many studies also have reported an association between anemia and increased tumor recurrence and decreased long-term survival. In the current study, the authors attempted to identify the severity, risk factors, and physician practices in the management of anemia. METHODS: Medical records of those patients receiving concurrent chemoradiation for head and neck carcinoma between 1999-2003 were reviewed. The average weekly nadir hemoglobin level (AWNH) was defined as the mean value of the lowest hemoglobin concentration in each week. Independent predictors for an AWNH < 11 g/dL were identified using multivariable logistic regression analyses. RESULTS: Seventy-two patients were included in the current study, 66.7% of whom had unresectable disease. The overall median survival was 402 days. At baseline, 76.4% (95% confidence interval [95% CI], 66.3-86.4%) of patients already had a hemoglobin level < 13.5 g/dL. The hemoglobin level dropped 2.5 +/- 1.9 g/dL during concurrent chemoradiation, resulting in 95.8% of patients having a hemoglobin level < 13.5 g/dL at the end of the observation period. Blood was transfused to 24 patients (33.3%); erythropoietin or darbepoietin was administered to 2 patients (2.7%). The mean lowest hemoglobin threshold of transfusion was 7.3 +/- 1.0 g/dL. The cumulative percentage of patients who received a transfusion reached 50% when the mean nadir hemoglobin level was 7.4 g/dL. Independent predictors of an AWNH < 11.0 g/dL were low baseline hemoglobin and receiving multiple concurrent chemotherapeutic agents, with relative risks of 13.6 and 1.8, respectively (95% CI,1.9-93.9 and 1.1-3.1, respectively). CONCLUSIONS: Anemia is prevalent in patients undergoing treatment for head and neck carcinoma and can be severe with concurrent chemoradiation therapy. However, the intensity of anemia management is low. A low baseline hemoglobin level and the reception of multiple concurrent chemotherapeutic agents are considered to be the main risk factors of anemia. Cancer 2006.     

Posttreatment M-protein nadir level is a significant prognostic factor associated with survival in multiple myeloma. Nagoya Myeloma Cooperative Study Group.

In the present study 142 patients with myeloma (102 with IgG M-protein and 40 with IgA) treated with either VMCP (65 patients) or MMCP (77 patients) as remission induction therapy were retrospectively analyzed. Response to treatment was evaluated in terms of a more-than-50% fall of pretreatment M-protein and the posttreatment M-protein nadir. Though significantly more patients treated with MMCP achieved partial response (PR) as compared with those treated with VMCP (P=0.019) and though patients achieving PR showed a significantly longer survival than those with less responsiveness (P=0.0091), the difference in survival curves between the two treatment groups was not significant (P=0.1871). The difference in response between the treatment groups evaluated in terms of posttreatment nadir was not significant (P=0.507). Multivariate analysis identified posttreatment M-protein nadir as a significant prognostic factor associated with survival, along with 3 other factors: sex, performance status, and hemoglobin. The lack of difference between the survival curves for patients treated with the 2 regimens despite the significantly different response rates evaluated in terms of percent fall of pretreatment M-protein levels was considered to be due to the lack of a difference in the ability to induce a deep posttreatment nadir between the regimens. Posttreatment M-protein nadir is an important prognostic factor associated with survival and should be included in the evaluation of the efficacy of chemotherapy.     

Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: Results of a multicenter randomised controlled trial

This work was conducted to evaluate the effect of early intervention with epoetin alfa (EPO) on transfusion requirements, hemoglobin level (Hb), quality of life (QOL) and to explore a possible relationship between the use of EPO and survival, in patients with solid tumors receiving platinum-based chemotherapy. Three hundred and sixteen patients with Hb12.1g/dL were randomised 2:1 to EPO 10000 IU thrice weekly subcutaneously (n = 211) or best supportive care (BSC) (n = 105). The primary end point was proportion of patients transfused while secondary end points were changes in Hb and QOL. The protocol was amended before the first patient was recruited to also prospectively collect survival data. EPO therapy significantly decreased transfusion requirements (P < 0.001) and increased Hb (P < 0.005). EPO-treated patients had significantly improved QOL compared with BSC patients (P < 0.05). Kaplan-Meier estimates showed no differences in 12-month survival (P = 0.39), despite a significantly greater number of patients with metastatic disease in the EPO group (78% vs. 61%, P = 0.001). EPO was well tolerated. This study has shown that early intervention with EPO can result in a significant reduction of transfusion requirements and increases in Hb and QOL in patients with mild anemia during platinum-based chemotherapy.     

Efficacy of epoetin alfa in a retrospective non-stratified subgroup analysis of a breast cancer cohort receiving non-platinum chemotherapy

AIMS AND BACKGROUND: More than 60% of patients with metastatic breast cancer receiving non-platinum-based chemotherapy experience anemia, which is associated with fatigue and impaired quality of life. Epoetin alfa treatment in patients with a variety of malignancies has been shown to decrease transfusion requirements and improve hemoglobin levels and quality-of-life efficacy parameters. PATIENTS: Retrospective subgroup analyses were performed in patients with breast cancer who were part of a multinational, randomized (2:1), double-blind, placebo-controlled trial of anemic cancer patients (n = 375) undergoing non-platinum-based chemotherapy. RESULTS: In the breast cancer subpopulation (n = 114, 48% with stage IV disease at baseline), the hemoglobin increase was greater for epoetin alfa patients than placebo patients (2.3 versus 0.9 g/dL). Epoetin alfa patients had lower transfusion requirements (28.2% versus 33.3%), improvement or preservation versus deterioration of quality of life, and a higher proportion of responders (patients achieving a > or = 2 g/dL increase in hemoglobin levels unrelated to transfusion) (68.0% versus 22.9% for placebo). The results were similar to those observed in the full study cohort, where statistical analyses showed the differences to be significant (P <0.05 for all). Epoetin alfa treatment was well tolerated. Although the study was not designed or powered for survival as an endpoint, Kaplan-Meier estimates for the full cohort showed a trend in overall survival favoring epoetin alfa treatment (P = 0.13, log rank test); a similar benefit was seen in the breast cancer subpopulation. CONCLUSIONS: In the full study cohort and the breast cancer subpopulation, epoetin alfa effectively treated anemia (increased hemoglobin levels and decreased transfusion requirements) and improved or preserved quality of life. Results concerning potential survival benefits support further study of epoetin alfa in anemic cancer patients.     

A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.

This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.     

Serial measurement of sister chromatid exchanges in the peripheral lymphocytes of patients with lung cancer receiving chemotherapy in relation to bone marrow toxicity

The frequencies of sister chromatid exchanges (SCE) in the peripheral lymphocytes of patients with lung cancer before and after initial chemotherapy were serially measured and the correlation between SCE frequencies and bone marrow toxicity was evaluated. The addition of mitomycin C to vindesine plus cisplatin increased SCE frequencies significantly in patients with non-small cell lung cancer. A significant increase in frequencies of SCE was observed in patients treated with cyclophosphamide plus adriamycin plus vincristine as compared with those treated with cisplatin plus etoposide in small cell lung cancer. A significant inverse correlation was observed between SCE frequencies in the peripheral lymphocytes 7 days after treatment (x) and the nadir value/pretreatment value of platelets (y)(r = -0.685, P = 0.0007, y = 0.842-0.022x). The relation between SCE frequency and leukopenia showed the same trend as thrombocytopenia, but the correlation was not statistically significant (r = -0.444, P = 0.057). SCE assay may have potential clinical use for the prediction of chemotherapy-induced thrombocytopenia.     

Serial Measurement of Sister Chromatid Exchanges in the Peripheral Lymphocytes of Patients with Lung Cancer Receiving Chemotherapy in Relation to Bone Marrow Toxicity

The frequencies of sister chromatid exchanges (SCE) in the peripheral lymphocytes of patients with lung cancer before and after initial chemotherapy were serially measured and the correlation between SCE frequencies and bone marrow toxicity was evaluated. The addition of mitomycin C to vindesine plus cisplatin increased SCE frequencies significantly in patients with non-small cell lung cancer. A significant increase in frequencies of SCE was observed in patients treated with cyclophosphamide plus adriamycin plus vincristine as compared with those treated with cisplatin plus etoposide in small cell lung cancer. A significant inverse correlation was observed between SCE frequencies in the peripheral lymphocytes 7 days after treatment ( x ) and the nadir value/pretreatment value of platelets ( y )( r = -0.685, P = 0.0007, y = 0.842–0.022 x ). The relation between SCE frequency and leukopenia showed the same trend as thrombocytopenia, but the correlation was not statistically significant ( r = - 0.444, P = 0.057). SCE assay may have potential clinical use for the prediction of chemotherapyinduced thrombocytopenia.     

Prognostic Significance of Serum Lactate Dehydrogenase in Patients with Osteosarcoma of the Extremities

Summary

Six hundred and fifty-six patients with osteosarcoma of the extremities (107 metastatic and 549 with localized disease) were followed from 2.5 to 20 years (average: 10 years) to evaluate whether their pretreatment serum lactate dehydrogenase (LDH) enzyme levels had a clinical value in predicting the course of the disease. The percentage of patients who had an elevated serum LDH at the time of diagnosis was significantly higher in those patients with metastatic disease than those who had localized disease (64% versus 33%, p < 0.0001), For those who presented with localized disease and had an increased serum LDH level, far more ultimately developed a relapse of disease (60% versus 38%, p < 0.0001) than those patients with a normal pre-treatment value. The prognostic significance of the serum LDH was more pronounced for the 247 patients treated with adjuvant chemotherapy (relapse rate of 72% versus 48%: p < 0.0002) than the 271 patients treated with neoadjuvant chemotherapy (relapse rate: 46% versus 28%, p < 0.005). Following treatment, serum LDH levels almost uniformly returned to normal and no correlation between postoperative levels and relapse of disease could be identified.

We have demonstrated that in patients with osteosarcoma of the extremities, pretreatment serum LDH levels have a definite prognostic value which should be considered when comparing the results achieved with different therapeutic protocols and in planning new randomized clinical trials.