Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix

Höckel, Michael; Knoop, Claudia; Schlenger, Karlheinz; Vorndran, Birgit; Bauβnann, Evmarie; Mitze, M.; Knapstein, P.; Vaupel, Peter

doi:10.1016/0167-8140(93)90025-4

Cited by 745 publications

(417 citation statements)

References 16 publications

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“…The present study showed that the outcome of treatment was associated with FIGO stage, tumour volume and tumour oxygenation status prior to treatment, consistent with previous studies of advanced cervix carcinoma (Höckel et al, 1993;Fyles et al, 1998a;1998b). In the study reported here, tumour oxygenation status, measured as HSV (pO 2 < 5 mmHg), showed a higher prognostic value than both FIGO stage and tumour volume.…”

Section: Discussionsupporting

confidence: 92%

“…The present study confirmed the results of previous studies suggesting that tumour oxygenation status is an important prognostic factor in advanced cervix carcinoma (Höckel et al, 1993;Fyles et al, 1998a;1998b). Median pO 2 and HF (pO 2 < 5 mmHg) were used as parameters for tumour oxygenation status in these previous studies.…”

Section: Discussionsupporting

confidence: 91%

“…Hypoxia may cause resistance to radiation therapy (Stone et al, 1993) and increased metastatic propensity (Hill, 1990). Several studies of advanced cervix carcinoma have demonstrated a positive association between poor outcome of radiation therapy and poor oxygenation of the primary tumour, measured with the Eppendorf pO 2 histograph prior to treatment (Höckel et al, 1993;Fyles et al, 1998a;1998b). The worse treatment outcome of the patients with the most hypoxic tumours could be related to the classical oxygen effect (Bush, 1986;Overgaard et al, 1989) or to the development of metastases associated with hypoxia (Höckel et al, 1996;Sundfør et al, 1998).…”

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confidence: 99%

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Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

et al. 2000

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Summary Poor outcome of treatment in advanced cervix carcinoma has been shown to be associated with poor oxygenation of the primary tumour. Hypoxia may cause radiation resistance and promote lymph-node metastasis. The purpose of the study reported here was to investigate whether hypoxia-induced treatment failure in advanced cervix carcinoma is primarily a result of hypoxia-induced radiation resistance or the presence of hypoxia-induced lymph-node metastases at the start of treatment. Thirty-two patients with squamous cell carcinoma of the uterine cervix were included in the study. Radiation therapy was given with curative intent as combined external irradiation and endocavitary brachytherapy. The oxygenation status of the primary tumour was measured prior to treatment using the Eppendorf pO 2 Histograph. Pelvic and para-aortal lymph-node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. The primary tumours of the patients with metastases (n = 18) were significantly more poorly oxygenated than those of the patients without metastases (n = 14). Multivariate Cox regression analyses involving biological and clinical parameters identified the tumour subvolume having pO 2 values below 5mmHg (HSV (pO 2 < 5mmHg) as the only significant, independent prognostic factor for locoregional control, disease-free survival and overall survival. The probabillities of locoregional control, disease-free survival and overall survival were significantly lower for the patients with HSV (pO 2 < 5 mmHg) above the median value than for those with HSV (pO 2 < 5 mmHg) below the median value. On the other hand, the outcome of treatment was not significantly different for the patients with metastases and the patients without metastases at the start of treatment, irrespective of clinical end-point. Consequently, treatment failure was primarily a result of hypoxia-induced radiation resistance rather than hypoxia-induced lymph-node metastasis, suggesting that novel treatment strategies aiming at improving tumour oxygenation or enhancing the radiation sensitivity of hypoxic tumour cells may prove beneficial in attempts to improve the radiation therapy of advanced cervix carcinoma.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

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Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

et al. 2000

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“…Measurements of oxygen tension in human tumours using polarographic microelectrodes have demonstrated the existence of large hypoxic fractions (Höckel et al, 1993;Brizel et al, 1996;Nordsmark et al, 1996;Collingridge et al, 1999), and other studies have shown that human tumour pO 2 can be modified to improve therapeutic response (Saunders and Dische, 1996;Hoskin et al, 1997). The use of polarographic electrodes is restricted however by their invasive nature, and their limited accessibility to superficial tumours or sites exposed during surgery.…”

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confidence: 99%

Proportion of infiltrating IgG-binding immune cells predict for tumour hypoxia

Collingridge

Hill

Dj³

2001

Br J Cancer

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Summary Macrophages can account for up to 50% of tumour mass and secrete many angiogenic factors. Furthermore, tumour hypoxia is thought to play a major role in the activation of macrophages and the regulation of angiogenesis. In this paper, we demonstrate a strong correlation between hypoxia and the recruitment of immune cells binding to IgG in 8 experimental tumours. We provide evidence that IgG binding immune cells in 3 tumour lines are predominately composed of macrophages. Reduced oxygenation may act as a stimulus for recruitment of immune cells to the tumour mass, and the detection of either IgG-positive host cells or macrophages may offer an alternative method for monitoring tumour hypoxia.

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“…These hypoxic cells, which can present a problem in the radiotherapy of solid tumours (Bush et al, 1978;Gatenby et al, 1988;Hockel et al, 1993), are probably also resistant to many chemotherapeutic agents (Tannock, 1978;Hughes et al, 1989;Wilson and Denny, 1992). It has recently been proposed that with the use of bioreductive drugs, which are selectively activated to a cytotoxic species under hypoxic conditions, it may be possible to exploit hypoxic tumour cells so that their presence in solid tumours is an advantage rather than a disadvantage (Brown and Koong, 1991;Denny and Wilson, 1993;Brown and Giaccia, 1994).…”

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confidence: 99%

Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro

Siim

Zijl²,

Brown³

1996

Br J Cancer

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Summary Tirapazamine (SR 4233), a bioreductive drug selectively toxic towards hypoxic cells, is presently in phase II clinical trials. Since it would not be expected that all tumours would respond equally to the drug, we are exploring ways of predicting the response of individual tumours. In this study we have tested whether the comet assay, which measures DNA damage in individual cells, can provide a simple, surrogate end point for cell killing by tirapazamine. We examined the relationship between the cytotoxicity of tirapazamine under hypoxic conditions and tirapazamine-induced DNA strand breaks in murine (SCCVII, EMT6, RIF-1) and human (HT1080, A549, HT29) tumour cell lines. These results were compared with the relationship between tirapazamine cytotoxicity and another measure of the ability of cells to metabolise tirapazamine; highperformance liquid chromatography (HPLC) analysis of tirapazamine loss or formation of the two electron reduction product SR 4317. The correlation between the hypoxic cytotoxic potency of tirapazamine and DNA damage was highly significant (r=0.905, P=0.013). A similar correlation was observed for hypoxic potency and tirapazamine loss (r=0.812, P=0.050), while the correlation between hypoxic potency and SR 4317 formation was not significant (r=0.634, P=0.171). The hypoxic cytotoxicity of tirapazamine in vitro can therefore be predicted by measuring tirapazamine-induced DNA damage using the comet assay. This approach holds promise for predicting the response of individual tumours to tirapazamine in the clinic.

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Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix

Cited by 745 publications

References 16 publications

Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

Proportion of infiltrating IgG-binding immune cells predict for tumour hypoxia

Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro

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