Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer.

Patients with cervical cancer frequently suffer from anemia. This two-stage, adaptive-design study investigated the effect of anemia correction with epoetin beta on treatment outcomes. Patients with stage IIB-IVA cervical cancer received radiochemotherapy (RCT) and were randomized to epoetin 150 IU/kg three times weekly (n = 34) or standard care (control; n = 40) for up to 12 weeks. Primary end point for stage 1 aimed to establish a correlation between anemia correction and treatment failure (no complete response or relapsing within 6 months after RCT initiation) as a proof of concept before moving into stage 2. Secondary end points included progression/relapse-free survival, overall survival, response to RCT, hemoglobin (Hb) response, and safety. Median baseline Hb was 11.4 and 11.6 g/dL in epoetin and control groups, respectively. At treatment end point, median Hb increased by 1.3 g/dL with epoetin, but decreased by 0.7 g/dL in the control group (P < 0.0001). No significant correlation between Hb increase and treatment failure was demonstrated. There were no significant differences between epoetin and control groups in progression/relapse-free survival (29.4% vs 32.5% patients with events; P = 0.96), overall survival (23.5% vs 12.5% patients with events; P = 0.22) or overall complete response (53% vs 58%; P = 0.86). Adverse events were well matched between groups. This study shows that epoetin beta rapidly, effectively, and safely increases Hb levels in patients with cervical cancer receiving RCT. No positive correlation of Hb increase and improvement in clinical outcomes could be demonstrated.

Tumor hypoxia and systemic levels of vascular endothelial growth factor (VEGF) in head and neck cancers.

BACKGROUND: Hypoxia is the most important stimulus for the up-regulation of vascular endothelial growth factor (VEGF), one of the key cytokines for angiogenesis. We have investigated the possible relationship between tumor hypoxia and systemic levels of VEGF. PATIENTS AND METHODS: 56 patients with head and neck cancers underwent measurement of tumor volume (pretreatment CT scans), tumor oxygenation (pO2 histography) and serum levels of VEGF. The hemoglobin level ranged from 9.1 to 16 g/dl. The absolute amount of hypoxic tumor (hypoxic tumor volume) was determined as the product of the absolute tumor volume and the relative frequency of hypoxic (< 5 mm Hg) measurements in the pO2 histography. RESULTS: The serum VEGF levels in the 56 head and neck cancer patients ranged from 102 to 1699 pg/ml (median 405 pg/ml, mean 527 +/- 396 pg/ml). Elevated serum-VEGF levels (> 700 pg/ml) were found in 14/56 patients (25%). Serum-levels of VEGF were significantly and independently correlated with hypoxic tumor volume (R2 = 0.63, p < 0.001), but also with total tumor volume, hemoglobin levels, platelet counts and tumor hypoxia. There was no correlation with T and N category, histological grading, and age. CONCLUSIONS: The strong and independent impact of the hypoxic tumor volume on systemic VEGF levels suggests that the absolute amount of hypoxia within a tumor represents the most important stimulus for up-regulation of angiogenesis. Anemia acts as a co-factor via worsening of tumor tissue oxygenation.

Tumor hypoxia, p53, and prognosis in cervical cancers.

BACKGROUND: The p53 protein is involved in the regulation of initiation of apoptosis. In vitro, p53-deficient cells do not respond to hypoxia with apoptosis as do p53-normal cells, and this may lead to a relative growth advantage of cells without a functioning p53 under hypoxia. On the basis of this hypothesis, a selection of cells with a functionally inactive p53 may occur in hypoxic tumors. The development of uterine cervical carcinomas is closely associated with infections of human papilloma viruses, which may cause a degradation of the tumor suppressor gene p53, resulting in a restriction of apoptosis. Thus, cervical cancers have often a functionally inactive p53. The purpose of our clinical study was therefore to investigate the association between p53, hypoxia, and prognosis in cervical cancers in which the oxygenation status can be determined by clinical methods. MATERIAL AND METHODS: Seventy patients with locally advanced squamous cell cervical cancer Stages IIB (n = 14), IIIB (n = 49), and IVA (n = 7) were investigated in the period from 1996 through 1999. All were treated with definitive radiotherapy with curative intent by a combination of external radiotherapy plus high-dose-rate afterloading. Before therapy, tumor oxygenation was measured with a needle probe polarographically using the Eppendorf histograph. Hypoxic tumors were defined as those with pO(2) measurements below 5 mm Hg (HF5). Pretreatment biopsies were taken and analyzed immunohistologically for p53 protein expression with the DO-7 antibody. The DNA index was measured by flow cytometry. The statistical data analysis was done with SPSS 9.0 for Windows. RESULTS: The 3-year overall survival was 55% for the whole group of patients. Clinical prognostic factors in a multivariate analysis were pretreatment hemoglobin level (3-year survival 62% for patients with a pretreatment hemoglobin > or =11 g/dl vs. 27% for hemoglobin <11 g/dl, p = 0.006) and FIGO stage (Stage IIB: 65%; Stage IIIB: 60%; Stage IVA: 29%, p = 0.01). Sixty of the 70 tumors showed positive immunohistologic staining for p53 protein (transformed p53 = tp53), and 10/70 were negative (wild-type p53 = wtp53); p53 expression had no significant impact on survival (50% for tp53 vs. 79% for wtp53, p = 0.11). FIGO stage and anemia had no impact on p53 expression. Forty-nine of 70 tumors were hypoxic (HF5+), and 21 showed no hypoxia (HF5-). Hypoxic carcinomas were more frequently positive for p53 as compared to nonhypoxic tumors (27% vs. 13%, p = 0.011) and showed a trend toward a lower survival (48% vs. 70%, p = 0.07). In a further multivariate analysis, the impact of a combination of p53 expression and hypoxia on survival was examined. After adjusting for FIGO stage and pretreatment anemia, patients with wtp53 tumors had the best prognosis (3-year survival 79%) followed by tp53-HF5(-) patients (57%), and the most unfavorable prognosis was observed for tp53-HF5(+) patients (47%). The DNA index was higher in tp53 carcinomas compared to wtp53 tumors, 1.97 +/- 0.4 vs. 1.67 +/- 0.1, p = 0.05. The highest DNA index was found in hypoxic tumors with transformed p53 (2.2 +/- 3.1). CONCLUSIONS: Advanced stage and pretreatment hemoglobin level are independent prognostic factors in cervical carcinomas. The immunohistologic detection of (a functionally inactive) p53 and the presence of hypoxia had no prognostic impact, if analyzed as single parameters. However, the combination of both parameters was able to discriminate different prognostic subgroups. Moreover, hypoxic cancers were more often immunohistologically positive for tp53 protein and had a higher DNA index with the highest DNA index in tumors with both hypoxia and tp53 protein expression. These findings in summary support the theory that the tumor's microenvironment may influence the biologic behavior via hypoxia.

Simultaneous radiochemotherapy in cervical cancer: recommendations for chemotherapy.

BACKGROUND: Simultaneous radiochemotherapy has recently been demonstrated to be superior to radiation alone in the treatment of cervical cancer. The objective of this article is to summarize the data of major randomized trials and to derive recommendations for daily clinical practice. MATERIALS AND METHODS: We have analyzed the data from seven randomized trials in the recent literature in which radiotherapy alone as standard treatment has been compared to simultaneous radiochemotherapy. Four trials used cisplatin-based chemotherapy regimens, 5-FU, mitomycin C and epirubicin were used each in one trial. RESULTS: All trials demonstrated some improvement in survival which was significant in the studies with cisplatin-based chemotherapy regimens. The survival benefit resulted mainly from an improvement in local control whereas chemotherapy had only a small and insignificant effect on distant metastases. Thus, the main action of chemotherapy is "radiosensitization". Cisplatin as single drug yielded comparable results as compared to combined regimens although the cisplatin dose was lower in the studies with combination chemotherapy. For the definitive treatment of locally advanced cancers, monotherapy with cisplatin can be recommended. Mitomycin C offers an attractive alternative to cisplatin in patients with contraindications for cisplatin. For postoperative radiochemotherapy, a combination of cisplatin/5-FU should be used because data with cisplatin alone are lacking so far. Simultaneous radiochemotherapy should also be considered for the curative treatment of local recurrences. CONCLUSIONS: The addition of simultaneous chemotherapy to radiotherapy is indicated in the vast majority of patients with cervical cancers who are treated with curative intent.

[Clinical experience with short-term afterloading therapy in comparison with conventional brachytherapy in the treatment of gynecologic tumors]. / Klinische Erfahrungen bei der Afterloading-Kurzzeittherapie im Vergleich zur konventionellen Brachytherapie bei der Behandlung gynäkologischer Tumoren.

The short-term afterloading therapy (AL-ST) with high dose rates (DR) and remote control prevents the risk of a radiation exposure of the staff, facilitates the optimization of the dose distribution in space, makes the treatment easier for patients and hospital, and allows a considerable increase of the treatment capacity without additional need of staff or capital. AL-ST works with another dose distribution in time than the conventional brachytherapy, so a higher fractionation of high-dose-rate afterloading is substituted for the classical protraction of low-dose-rate brachytherapy. 2072 patients with gynecologic tumors were treated by AL-ST between 1974 and 1983. 1762 out of them (964 carcinomas of the cervix, 677 carcinomas of the body, and 121 vaginal tumors, metastases and urethral carcinomas) could be checked up for at least twelve months up to more than five years, which allowed an evaluation with regard to recurrence-free survival rate, local absence of tumors, and side effects. The five-year survival rates obtained by primary and post-operative AL-ST are compared to historical control groups of our own hospital and to the international results. The results, related to the stages, are at least equivalent; several groups show a statistically significant improvement compared to conventional brachytherapy. The incidence of early and late reactions in bladder and rectum showed a statistically significant decrease after AL-ST and was dependent on the dose in a statistically highly significant manner (p = 0.001). In addition to the well-known advantages of AL-ST, the following may be mentioned: 1. The intracavitary application was made without general anaesthesia, only with sedation by drugs, which prevented the primary treatment mortality. 2. An ambulatory treatment was possible in about 40% of the cases due to the time-sparing and patient-sparing method--the advantages are evident. 3. The therapeutic efficacy is increased and the risk of side effects in bladder and rectum is decreased by the better radiobiologic (same DR) and dosimetric adaption of AL-ST and percutaneous high-voltage therapy.