The effects of knockdown of wild-type survivin, survivin-2B or survivin-delta3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions.

The inhibitor of apoptosis wild-type survivin is a multifunctional protein that suppresses apoptosis and regulates cell cycle progression. An association between wild-type survivin expression and radiosensitivity has been described in different tumor cells. The effects of siRNA-induced knockdown of wild-type survivin and survivin-splice variants survivin-2B and survivin-Delta3 were investigated under normoxic and hypoxic conditions in the human sarcoma cell line US 8-93 (mutant p53). Inhibition of the survivin isoforms by siRNA resulted in a decrease of target mRNA down to 14-70% compared to cells treated with control siRNA independent of the oxygen level. The mRNA expression of survivin isoforms was decreased by the factor of 1-12 when the cells were cultivated under hypoxic conditions. Moreover, the knockdown of wild-type survivin reduced colony formation independent of oxygen concentration down to 70% and induced formation of polyploid cells. Less reduction of plating efficiency was observed after specific knockdown of survivin-2B and survivin-Delta3 under hypoxic or normoxic conditions. A knockdown of wild-type survivin, survivin-Delta3 and survivin-2B isoforms in combination with irradiation caused no radiosensitization in cell line US 8-93, neither under hypoxic nor under normoxic conditions tested in the colony-forming assay. However, knockdown of wild-type survivin caused radiosensitization in the megacolony assay.

[Adjuvant radio- and chemotherapy in cervix carcinoma]. / Adjuvante Radio- und Chemotherapie beim Zervixkarzinom.

The screening for cervical cancer has been reduced both the incidence of and mortality from invasive cervical cancer in the western world. Radical pelvic surgery is an effective treatment for early invasive cervical cancer (FIGO-stage IB and IIA), but for woman with more advanced disease radiotherapy is the standard treatment. However, the survival of the cervical cancer patients has not been improved over the last decade. Previous studies have suggested that chemotherapy and radiotherapy are synergistic. The results of five large studies have shown that cisplatin-based chemotherapy when given at the same time a radiation therapy, prolongs survival in woman with cervical cancer. This was also observed in primary treatment schedule as in adjuvant situation. The side effects were temporary and manageable. The results suggest that chemoradiation is the favorable therapy for cervical cancer in advanced stage and in high-risk-situation.

[Association between elevated serum VEGF and polarographically measured tumor hypoxia in head and neck carcinomas]. / Assoziation zwischen erhöhten Serum-VEGF-Werten und polarographisch gemessener Tumorhypoxie bei Patienten mit Kopf-Hals-Karzinomen.

PURPOSE: Clinical investigation of a potential relationship between VEGF concentration in serum (sVEGF) and polarographically measured tumor oxygenation in patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: In 56 patients with SCCHN we estimated the classical tumor parameters, the sVEGF concentration (immunoassay) and the tumor oxygenation (Eppendorf pO2 histograph). The platelet count and the tumor volume were evaluated simultaneously. RESULTS: In a unifactorial analysis the total volume (132 cm3 vs. 38 cm3), the hypoxic subvolume (HSV = total volume multiplied with the relative frequency of values < or = 5 mm Hg/63 cm3 vs. 10 cm3) and the platelet count (380 10(9)/l vs. 271 10(9)/l) were significantly higher in the patient group with a sVEGF level > 707 pg/ml compared to the group with a sVEGF below this threshold. The multifactorial analysis confirmed significant effects for the hypoxic subvolume and the platelet count. Regarding hypoxic subvolume and sVEGF as continuous parameters a significantly positive correlation was found. This correlation remained somewhat weaker but significant after inclusion of the platelet count as covariate. CONCLUSION: On base of our data a clinical association between elevated sVEGF and polarographically measured tumor hypoxia could be confirmed. This was possible considering not only the relative grade of hypoxia but also the absolute amount of hypoxic regions. The VEGF released from platelets during blood clotting influences the sVEGF level essentially, however, the hypoxia effect was not completely deleted. Due to the platelet effect an estimation of sVEGF is not able to substitute polarographical measurement of tumor pO2. Therefore in an ongoing study we investigate whether VEGF values estimated in plasma are better correlated with the polarographically measured tumor pO2 than serum VEGF levels.

[No association between p53 overexpression and polarographically measured tumor oxygenation in patients with head and neck carcinomas]. / Keine Assoziation zwischen p53-Uberexpression und polarographisch gemessener Tumoroxygenierung bei Patienten mit Kopf-Hals-Karzinomen.

PURPOSE: Clinical investigation of a potential relationship between the polarographically measured tumor oxygenation and the p53 status in patients with squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: In 99 patients with mostly advanced, histologically proven squamous cell carcinoma of the head and neck we estimated the classical tumor parameters (TNM stage, histological grading) the immunohistochemical p53-overexpression (DO-7) and the tumor oxygenation status (Eppendorf pO2 Histograph). The tumor volume and the hemoglobin concentration were evaluated simultaneously. RESULTS: No statistically significant difference could be detected between immunohistological p53-positive (p53 > or = 10% stained cells) and p53-negative tumors (p53 < 10% stained cells) regarding both the median pO2 and the relative frequency of values < or = 5 mm Hg. Moreover, no statistically relevant differences could be seen between both p53-groups considering the hemoglobin concentration, the TNM stage, the histological grading and the tumor volume. CONCLUSION: Our data imply that there is no association between p53-overexpression and tumor hypoxia in head and neck carcinomas. However, this is not necessarily in contradiction to experimental or clinical data that confirmed a relationship between hypoxia and p53-mediated increased malignancy of tumor cells in other tumor entities. The comparable oxygenation status of p53-positive and p53-negative tumors in our study is associated with an analogous clinical tumor aggressiveness of both groups. That could be caused by a hypoxia related but p53-independent selection of tumor cells with a more malignant phenotype in head and neck carcinomas. However, further research is needed to prove this possible relationship.

Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas.

PURPOSE: To investigate the relationship between tumor oxygenation and the blood hemoglobin (Hb) concentration in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: A total of 133 patients with SCCHN underwent pretreatment polarographic pO2 measurements of their tumors. In 66 patients measurements were also made in sternocleidomastoid muscles. The patients were divided into three groups according to their Hb concentration-severe anemia (Hb < 11.0 g/dl), mild anemia (female: Hb 11.0-11.9 g/dl; male: Hb 11.0-12.9 g/dl), and normal Hb concentration (female: Hb > or =12.0 g/dl; male: > or =13.0 g/dl). RESULTS: No significant difference in tumor oxygenation could be detected between mildly anemic patients and patients with a normal Hb level. However, the tumor oxygenation in the severely anemic group was significantly below that of each of the other two groups (p < 0.0001). There was no significant difference between the Hb groups in oxygenation of sternocleidomastoid muscles. In a multivariate analysis including Hb group, tumor volume, smoking habits, gender, T-stage, N-stage, and histologic grade a Hb level < 11 g/dl was found to be the strongest predictor for a poor tumor oxygenation. Smoking also had a marginal influence on median pO2. CONCLUSION: Our data suggest that a low Hb concentration and cigarette smoking contribute to inadequate oxygenation of SCCHN and thus for increased radioresistance. Consequently, Hb correction and abstinence from smoking may significantly improve tumor oxygenation.

[Postoperative radiotherapy in endometrial carcinoma. A retrospective analysis of 541 cases]. / Die postoperative Strahlentherapie beim Endometriumkarzinom. Eine retrospektive Analyse von 541 Patienten.

PURPOSE: This retrospective study was designed to evaluate the role of adjuvant radiotherapy for surgically treated endometrial carcinoma. PATIENTS AND METHODS: From 1980 through 1988, 541 patients were treated with either intravaginal cuff irradiation with a high-dose-rate (HDR) Iridium-192 remote afterloading technique (n = 294) or with combined HDR-brachytherapy and additional external pelvic irradiation to 54 Gy (n = 247) after surgery for endometrial cancer. Afterloading irradiation was administered in 4 fractions 4 to 6 weeks after surgery. A dose of 30 Gy was delivered at a depth of 0.5 cm from the vaginal mucosa. RESULTS: Patients with HDR-brachytherapy alone showed a 5-year survival of 94.3% for Stage I and 73.6% for Stage II (p = 0.0007). Patients who received both brachytherapy and additional external pelvic irradiation had a 5-year survival of 94.1% for Stage I, 81.1% for Stage II, 70.4% for Stage III and 46.9% for Stage IV (p = 0.0001). The main predictors for survival in a multivariate analysis were stage and grading. Patients with combined radiotherapy had a local recurrence rate of 3.2%, whereas patients with brachytherapy alone who were better selected and had more favorable prognostic factors showed a recurrence rate of 2%. Low-risk patients (Stage I, Grade 1, low infiltration) in the HDR-brachytherapy group had 6 relapses, mainly caused by insufficient treatment on the basis of papillary histology. High-risk patients with poorly differentiated tumors, which infiltrate more than half the myometrial wall might benefit from additional external radiotherapy in terms of reduction of local recurrence and better survival. Five-year actuarial survival rate was 93.6% after combined radiotherapy vs 86.7% after brachytherapy alone. Complications were graded according to the RTOG scoring system. Severe late complications were fistulas of bladder and/or bowel, which occurred in 2.8% in the combined radiotherapy group, and 0.7% in the HDR brachytherapy group. CONCLUSIONS: Low-risk patients should be generally treated postoperative with HDR-brachytherapy alone. Combined radiotherapy decreased pelvic relapses for high-risk patients with overall low complication rates. We conclude that an individually adjusted postoperative radiotherapy allows a well tolerated treatment with excellent results.

Influence of the hypoxic subvolume on the survival of patients with head and neck cancer.

PURPOSE: Tumor hypoxia is regarded as an important factor influencing radiation response, disease-free, and overall survival of patients with squamous cell carcinoma of the head and neck (SCCHN). This study was performed to reevaluate the prognostic significance of the "classical oxygenation parameters" hypoxic fraction (percentage of pO2 values < 5 mmHg or < 2.5 mmHg, respectively) and median pO2, and to determine the influence of a new radiobiological factor. This factor was termed the "hypoxic subvolume" (HSV) and was defined as percentage of pO2-values below 5 mmHg multiplied by the total tumor volume. The rationale of this parameter was to quantify approximately the amount of hypoxic tissue which should be correlated to the number of hypoxic cells in the tumor. It is obvious that a tumor of 100 cm3 with a hypoxic fraction of 20% (HSV = 20 cm3) contains more hypoxic cells than a tumor of 1 cm3 with a hypoxic fraction of 50% (HSV = 0.5 cm3). METHODS AND MATERIALS: Pretreatment pO2 was assessed in 59 patients with SCCHN with the Eppendorf histograph, and pretreatment volume was determined by ultrasonography (lymphnode metastases) and computer tomography (primaries). All patients were referred to our departments for radiotherapy (n = 27, median dose 70 Gy) or radiochemotherapy (n = 32; 5-FU, mitomycin C, median dose 70 Gy), respectively. All parameters were evaluated using the Kaplan-Meier analysis, and significance was assumed at a p-value of < 0.05 (log-rank test, Cox-Mantel). A multivariate analysis was performed to control for confounding factors. The median follow-up was 233 days. At the time of the evaluation, 34 of the 59 patients were dead. RESULTS: In univariate analyses, the hypoxic fraction (pO2 < 5 mmHg, PO2 < 2.5 mmHg [p < 0.05]), the hemoglobin concentration (p < 0.05), and the hypoxic subvolume (p < 0.01) were of prognostic significance for overall survival. In multivariate analysis, the hemoglobin concentration and the hypoxic subvolume (p = 0.01) were significant prognosticators. We found no significant correlation between tumor volume or median pO2 and overall survival. No clear correlation was found between tumor volume and hypoxic fraction. CONCLUSION: These data suggest that the total amount of hypoxic tissue, as determined by the hypoxic subvolume, influences the prognosis of patients suffering from SCCHN. In addition, our data confirm the statements of previous studies that low pretherapy pO2-values indicate a worse prognosis.

Low hemoglobin is associated with increased serum levels of vascular endothelial growth factor (VEGF) in cancer patients. Does anemia stimulate angiogenesis?

BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell specific mitogen with strong angiogenic activity. Expression of VEGF may therefore be an indicator for the angiogenic potential and biological aggressiveness of a tumor. Recently, measurement of the VEGF-protein in sera has become available. We report results of serum-VEGF in an unselected group of patients with cancer with special emphasis on a possible role of anemia. PATIENTS AND METHODS: Between August 1997 and January 1998, serum-levels of VEGF were determined in a total number of 54 consecutive patients with previously untreated, non-metastatic carcinomas at the Department of Radiotherapy at the Martin-Luther University Halle-Wittenberg. The age ranged from 35 through 89 years with a median age of 67 years. All patients had locoregional confined disease without evidence of hematogenous metastases. Tumor sites were gynecological cancers in 22, head and neck in 14, gastrointestinal in 13, lung in 4 and prostate in 1 case. Forty-four patients had squamous carcinomas and 10 adenocarcinomas. Prior to treatment, routine laboratory work-up was done including measurement of serum-vascular endothelial growth factor (VEGF). The pretreatment hemoglobin ranged from 8.9 through 15.6 g/dl with a median of 13 g/dl. VEGF was measured with a quantitative sandwich enzyme immunoassay technique. RESULTS: The serum levels of VEGF in 40 patients with benign diseases ranged from 57 through 891 pg/ml with a mean of 267 +/- 170 pg/ml. In the investigated 54 cancer patients, VEGF ranged from 62 through 2,609 pg/ml with a mean of 614 +/- 551 pg/ml. Age, UICC/FIGO-stage, T- or N-category, primary tumor site, grade and histologic type had no significant impact on VEGF-serum levels. There was, however, an association between hemoglobin level and serum-VEGF with an increased mean serum-VEGF in 26 patients with a low hemoglobin (< 13 g/dl) as compared to 28 patients with a hemoglobin > 13 g/dl (805 +/- 656 vs 438 +/- 360, p = 0.016, 2-sided t-test). CONCLUSIONS: With regard to the recently established correlation between anemia and intratumoral hypoxia, the increased serum-VEGF levels in patients with low hemoglobin may be explained via hypoxia-induced VEGF secretion. This would suggest that anemia may stimulate angiogenesis via hypoxia. The hypothesis, however, requires further investigation and might have important therapeutical impact.

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon.

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6x10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3x10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p<0.01. The increase in the median pO2 was more pronounced in patients with radiotherapy plus additional cRA/IFN treatment as compared to patients treated with irradiation alone (median pO2 raised from 7.0+/-3.5 mm Hg to 40.9+/-21.3 mm Hg versus 5.7+/-3.1 mm Hg to 14.7+/-17.9 mm Hg). In a multivariate analysis, both the effect of radiation dose (pretreatment versus 19.8 Gy) and the type of treatment (XRT alone versus XRT plus cRA/IFN) had significant impact on the pO2 (P = 0.003 and p = 0.04). In patients with well-oxygenated tumors (pretreatment median pO2>10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated.

A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers.

BACKGROUND: We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy. PATIENTS AND METHODS: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph. RESULTS: In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = 0.012, t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. CONCLUSIONS: Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended.

[Oxygenation status of squamous cell carcinoma of the head and neck: comparison of primary tumors, their neck node metastases and normal tissue]. / Oxygenierungsstatus von Plattenepithelkarzinomen der Kopf-Hals-Region. Vergleich von Primärtumoren, ihren Halslymphknotenmetastasen und Normalgewebe.

AIM: Investigation of the relationship between the pO2-status of primary tumors, their cervical neck node metastases and normal tissues in squamous cell carcinomas of the head and neck. PATIENTS AND METHODS: Pretreatment oxygenation of primary tumors, their neck node metastases and of the contralateral sternocleidomastoid muscle was assessed in 16 patients with histologically proven advanced squamous cell carcinomas of head and neck. Oxygenation was measured with a polarographic microelectrode system (Eppendorf-pO-Histograph). Using CT/MRT additionally the volume of the tumors was estimated. RESULTS: A highly significant correlation existed between the median pO2 of primary tumors and their neck node metastases and between the relative proportion of hypoxic values (< 5 mm Hg) of both anatomic sites (both p = 0.0001) (Figure 1). Primary tumors were not different from their neck node metastases, neither regarding the pO2 median values nor in view of the relative frequency of hypoxic values (Table 1). No correlation was found between the volume of primary tumors and the one of their neck node metastases. For volume of tumors and the oxygenation status no relationship was found as well. Significantly different was the median pO2 in the muscles from the one of the malignant tissues (p = 0.0004). CONCLUSION: The results suggest that for to estimate the oxygenation status of squanious cell carcinomas of the head and neck pO2 measurements of primary tumors and neck node metastases are equally sufficient.

Oxygenation of squamous cell carcinoma of the head and neck: comparison of primary tumors, neck node metastases, and normal tissue.

BACKGROUND: Most previous oxygenation measurements of head and neck tumors have mainly been performed in neck nodes. We investigated, therefore, the relationship between the pO2 status of primary tumors, cervical neck node metastases and normal tissues. PATIENTS AND METHODS: 30 patients with histologically proven advanced stage III-IV squamous cell carcinoma of head and neck underwent pretreatment polarographic pO2 measurements with a pO2 histograph (Eppendorf, Hamburg, Germany). We obtained data on oxygenation of 23 primary tumors, of 22 neck node metastases, and of 30 contralateral sternocleidomastoid muscles. In 15 cases, we were able to perform measurements in all three regions in the same individual. results: A highly significant correlation existed between the median pO2 of primary tumors and their neck node metastases (p=0.0001), as well as between the proportion of pO2 values < or =2.5 mmHg and +/-5.0 mmHg (p=0.0001, p=0.001) in both anatomic sites. The average pretreatment median PO2 was 14.7 mmHg (range 0.2-58.5 mmHg) in primary tumors, 13.7 mmHg (range 1.9-50.3 mmHg) in neck node metastases, and 43.8 mmHg (range 20.8-67.7 mmHg) in sternocleidomastoid muscles. In all cases, the oxygenation of malignant tissue was below that of the corresponding muscle. There was also a weak, but significant, correlation between hemoglobin level and the median pO2 of the primary tumors, as well as between hemoglobin concentration and the proportion of values below 5 mmHg at the primary site (p=0.017, p=0.003). CONCLUSIONS: Primary tumors and their regional lymph node metastases in advanced squamous cell carcinoma of the head and neck show comparable patterns of oxygenation in terms of the median pO2 and the proportion of hypoxic measurements. This report suggests that, in patients with such carcinomas, the oxygenation data obtained at one site are related to tumor oxygenation at other sites, so that measurements in any anatomic site would be sufficient to estimate a tumor's oxygenation status. The weak correlation between pO2 and hemoglobin level requires further investigation.

[Intratumor pO2, S-phase fraction and p53 status in cervix carcinomas]. / Intratumoraler pO2, S-Phase-Anteil und p53-Status bei Zervixkarzinomen.

PURPOSE: Investigation whether tumor tissue oxygenation is influenced by proliferation or p53-status in cervical cancers. MATERIAL AND METHODS: From April 1995 through December 1996, 28 patients with locally advanced cervical cancers (age 36 to 78 years; FIGO stages: 10 patients IIB, 16 patients IIIB, 2 patients IVA) underwent intratumoral measurement of pO2 prior to definitive radiotherapy. The histological specimens were examined for grading and quantitative immunohistological expression of the MIB-antigen and p53-protein. Proliferation was estimated by measuring the S-phase fraction with flow cytometry. RESULTS: The median pO2-values showed a broad variation from 2.2 through 60.4 mm Hg, median 19.7 mm Hg. The S-phase fraction varied from 4.2 through 34.2% (median 11.6%), MIB-positive cells from 20 through 100% (median 74%), and immunohistologically p53-positive cells from 0 through 95% (median 2%). The patients were divided in 2 groups according to the pretreatment pO2. Tumors with a pO2 above the median had a lower S-phase fraction than tumors with a pO2 below the median, 10.4 +/- 3.8% versus 16.3 +/- 5.5%, p < 0.02. MIB and p53 were not different in both groups (MIB: 68.1 +/- 27.7% versus 75.0 +/- 18.4%, p = 0.1; p53: 26.4 +/- 38.5% versus 18.1 +/- 19.8%, n. s.). Grade of differentiation and FIGO stage had no impact on pO2. CONCLUSION: Locally advanced cervical cancers with a poor oxygenation have a higher proliferative activity. Tumor proliferation may play a causative role for the development of hypoxia as suspected from radiobiological theories.

[Treatment of ovarian cancer with combined operative, radiologic and cytostatic therapy]. / Die Behandlung des Ovarialkarzinoms mit einer kombinierten operativen, radiologischen und zytostatischen Therapie.

It is reported about significant superior results of two years of the combined ovarian cancer treatment in contrast to operation and chemotherapy. Our therapy is the combination of operation, great field radiation technique, chemotherapy and second-look-operation. The remission of two years: Stage I: 64%, stage II: 50%, stage III: 45% and stage IV: -Only in stage IV no improvement can be achieved by addition of the radiation therapy.