Blood flow and associated pathophysiology of uterine cervix cancers: Characterisation and relevance for localised hyperthermia

Figures & data

Figure 1. Tumour blood flow (TBF) as a function of volume of cancers of the uterine cervix. Graph based on data published by Lyng et al. [7]. Values are means and ranges.

Table I.  Blood flow in normal uterus and in cancers of the uterine cervix.

	Blood flow (ml/g/min)^1	Method	References
Normal	0.10-0.25	Review of data	[6]
uterus	0.13	Review of data	[4]
Cervical	0.11 ± 0.03^2	Thermal washout	[7]
cancer	(0.05–0.18)^3
	0.08 [II/III]^4	CE–MRI	[8]
	(0.02–0.29)^3
	0.87 ± 0.38 [I]^4	DCE–CT	[9]
	0.99 ± 0.17 [II–IV]^4
	0.62 ± 0.36	H2^15O–PET	[11]
	0.72 (0.47–1.32)^3	CT (maximum slope)	[10]
	1.03 (0.59–1.43)^3	CT (1-compartment model)

¹Or (mL/mL/min).

²Recurrent cervical cancers.

³Range.

⁴Tumour stage.

Table II.  Oxygenation status of the uterine cervix.

Median pO2 (mmHg) [range]	n	HF 2.5 (%)	HF 5 (%)	HF 10 (%)	References
40[4–79]^a					[21], [22]
42[1–100]	7 ^b	8	13	20	[26]

^aEstimated from measurements in superficial tissue regions.

^b432 pO₂ measurements in the normal cervix of nullipara.

n, number of patients.

Table III.  Pre-therapeutic oxygenation status of primary, locally advanced cancer of the uterine cervix and prognostic significance of tumour hypoxia (n = number of patients; updated from Vaupel et al. [27]).

						Prognostic significance of tumour hypoxia
Centre	n	Median pO2 (mmHg) (range)	HF 2.5 (%)	HF 5 (%)	HF 10 (%)	Endpoint	Oxygenation parameter
Mainz/Leipzig	150	9 (2–34)	23	37	51	DFS, OS	pO2 < 10 mmHg
Toronto	156 ^a	5 (0–94)		50		DFS, PFS, DS^b	pO2 < 5 mmHg
Halle	87	17 (0–81)	16	26
Leipzig	86	5 (1–57)
Vienna	51	10 (0–60)	22	28	50	DFS, (LC)	pO2 < 10 mmHg
Oslo	49	4 (1–25)	47	64	76	DFS, OS, LC, DS	HSV^c
							pO2 < 5 mmHg
							pO2 < 10 mmHg
Manchester	43	3 (0–42)	39	58	75
	30	6 (0–41)
Paris	37	12	15	17	21
Aarhus	24	3 (0–19)	49	61	73
Vancouver	19	3 (0–34)	38	66	76
Vienna	10	17 (3–54)		42
Durham	9	5		61
Overall	751	9	28	44	59

^aData of Lim et al. [28] added.

^bIn node-negative patients.

^cHypoxic subvolume calculated as the product of the total tumour volume and the relative frequency of hypoxic pO₂ readings <5 mmHg.

There may be some overlaps in patients reported from the same institution. Empty boxes indicate lack of suitable information. Data of Nakamo et al. [29] and Sakata et al. [30] are not included (measurements in tumour periphery only). DFS, disease-free survival; OS, overall survival; PFS, progression-free survival; DS, distant spread; LC, local control.

Table IV.  Interstitial fluid pressure (IFP) in normal tissues and in cervical cancer.

Type of tissue	IFP (mmHg) (range)	References
Subcutis	−3	[43]
Fibrous tissue	−3	[44]
Submucosa (paravaginal)	1	[45]
Cervical cancers	16 (10 to 26)	[46]
	19 (−6 to 76)	[45]
	19 (3 to 48)	[47]
	15 (6 to 40)	[9]
	19 (−3 to 48)	[48]
	29 (4 to 94)	[49]

Figure 2. Frequency distribution (histogram) of oxygen partial pressures (pO₂) in squamous cell carcinomas (SCC) of the uterine cervix. N = number of patients, n = number of pO₂ values measured (modified from [64]).

Figure 3. Histogram of measured glucose concentrations in a cancer of the cervix (modified from [64]).

Figure 4. Histogram of measured lactate concentrations in a cancer of the cervix (modified from [64]).

Figure 5. Histogram of measured ATP concentrations in a cancer of the cervix (modified from [64]).

Lewis BV. Uterine blood flow. Review. Obstet Gyn Survey 1969; 24: 1211–1233

 PubMedGoogle Scholar

Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res 1989; 49: 6449–6465

 PubMed Web of Science ®Google Scholar

Molls M, Feldmann HJ. Clinical investigations of blood flow in malignant tumors of the pelvis and the abdomen in patients undergoing thermoradiotherapy. Funktionsanalyse biolog Systeme 1991; 20: 143–153

 Google Scholar

Lyng H, Vorren AO, Sundfor K, Taksdal I, Lien HH, Kaalhus O, et al. Intra- and intertumor heterogeneity in blood perfusion of human cervical cancer before treatment and after radiotherapy. Int J Cancer 2001; 96: 182–190

 PubMed Web of Science ®Google Scholar

Haider MA, Milosevic M, Fyles A, Sitartchouk I, Yeung I, Henderson E, et al. Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements. Int J Radiat Oncol Biol Phys 2005; 62: 1100–1107

 PubMed Web of Science ®Google Scholar

Lüdemann L, Sreenivasa G, Amthauer H, Michel R, Gellermann J, Wust P. Use of H215O-PET for investigating perfusion changes in pelvic tumors due to regional hyperthermia. Int J Hyperthermia 2009; 25: 299–308

 PubMed Web of Science ®Google Scholar

Shibuya K, Tsushima Y, Horisoko E, Noda S, Taketomi-Takahashi A, Ohno T, et al. Blood flow change quantification in cervical cancer before and during radiation therapy using perfusion CT. J Radiat Res 2011; 52: 804–811

 PubMed Web of Science ®Google Scholar

Kolstad P, Vascularization, Oxygen Tension, and Radiocurability in Cancer of the Cervix. Oslo: Universitetsvorlaget, 1964

 Google Scholar

Kolstad P. Intercapillary distance, oxygen tension and local recurrence in cervix cancer. Scand J Clin Lab Invest Suppl 1968; 106: 145–157

 PubMedGoogle Scholar

Höckel M, Schlenger K, Knoop C, Vaupel P. Oxygenation of carcinomas of the uterine cervix: Evaluation of computerized O2 tension measurements. Cancer Res 1991; 51: 6098–6102

 PubMed Web of Science ®Google Scholar

Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007; 9: 1221–1235

 PubMed Web of Science ®Google Scholar

Lim K, Chan P, Dinniwell R, Fyles A, Haider M, Cho Y-B, et al. Cervical cancer regression measured using weekly magnetic resonance imaging during fractionated radiotherapy: Radiobiologic modeling and correlation with tumor hypoxia. Int J Radiat Oncol Biol Phys 2008; 70: 126–133

 PubMed Web of Science ®Google Scholar

Nakano T, Suzuki Y, Ohno T, Kato S, Suzuki M, Morita S, et al. Carbon beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia. Clin Cancer Res 2006; 12: 2185–2190

 PubMed Web of Science ®Google Scholar

Sakata K, Someya M, Nagakura H, Nakata K, Oouchi A, Hareyama M, et al. A clinical study of hypoxia using endogenous hypoxic markers and polarographic oxygen electrodes. Strahlenther Onkol 2006; 182: 511–517

 PubMed Web of Science ®Google Scholar

Guyton AC, Hall JE. Textbook of Medical Physiology11th. Elsevier, Philadelphia 2006

 Google Scholar

Gutmann R, Leunig M, Feyh J, Goetz AE, Messmer K, Kastenbauer E, et al. Interstitial hypertension in head and neck tumors in patients: Correlation with tumor size. Cancer Res 1992; 52: 1993–1995

 PubMed Web of Science ®Google Scholar

Milosevic MF, Fyles AW, Wong R, Pintilie M, Kavanagh M-C, Levin W, et al. Interstitial fluid pressure in cervical carcinoma: Within tumor heterogeneity, and relation to oxygen tension. Cancer 1998; 82: 2418–2426

 PubMed Web of Science ®Google Scholar

Roh HD, Boucher Y, Kalnicki S, Buchsbaum R, Bloomer WD, Jain RK. Interstitial hypertension in carcinoma of uterine cervix in patients: Possible correlation with tumor oxygenation and radiation response. Cancer Res 1991; 51: 6695–6698

 PubMed Web of Science ®Google Scholar

Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, et al. Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 2001; 61: 6400–6405

 PubMed Web of Science ®Google Scholar

Fyles A, Milosevic M, Pintilie M, Syed A, Levin W, Manchul L, et al. Long-term performance of interstitial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006; 80: 132–137

 PubMed Web of Science ®Google Scholar

Yeo S-G, Kim J-S, Cho M-J, Kim K-H, Kim J-S. Interstitial fluid pressure as a prognostic factor in cervical cancer following radiation therapy. Clin Cancer Res 2009; 15: 6201–6207

 PubMed Web of Science ®Google Scholar