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

Becker, Axel; Stadler, Peter F.; Lavey, Robert S.; Hänsgen, Gabriele; Kuhnt, Thomas; Lautenschläger, Christine; Feldmann, Horst Jürgen; Molls, M.; Dunst, Jürgen

doi:10.1016/s0360-3016(99)00384-3

Cited by 208 publications

(162 citation statements)

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“…These experimental data are endorsed by more recent clinical findings in patients with cancer of the uterine cervix, and head and neck tumours undergoing radiotherapy (Hoeckel et al, 1996;Nordsmark et al, 1996). The intratumoral oxygen tension depends at least partly on the haemoglobin level of the blood (Vaupel and Hoeckel, 1998;Becker et al, 2000).…”

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confidence: 78%

Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro

et al. 2003

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Platinum-based chemotherapy is the main treatment element to achieve cure for patients with metastatic germ cell tumours. Drug resistance in testicular germ cell tumours (TGCTs) is rare and the reasons are not fully understood. While recent investigations have indicated decreased efficacy of chemotherapy in several tumour types under hypoxic conditions, this aspect has not been investigated in TGCTs so far. Furthermore, for cisplatin -the most active drug in this disease -controversial effects of hypoxia on cytotoxic efficacy have been reported. The relative efficacy of cytotoxic agents for the treatment of TGCT patients was studied in three different cell lines derived from human embryonal carcinomas (EC) in an in vitro hypoxia model. NT2, 2102 EP, and NCCIT were tested for their sensitivity towards cisplatin, etoposide, bleomycin, 4-OOH-ifosfamide, carboplatin, paclitaxel, gemcitabine, oxaliplatin, irinotecan, and mitomycin C under normoxic and hypoxic conditions using the MTT assay. Inhibitory concentrations IC 50 of the tested agents under both conditions were compared. Selected results were confirmed by flow-cytometric assessment of the apoptotic index. In all cells, doubling times were prolonged in hypoxia (NT2oNCCITo2102 EP). All drugs were less effective under hypoxic conditions, including mitomycin C (eg, 1.6-fold increase of IC 50 in hypoxia compared to normoxia for NT2) and cisplatin (eg, NT2: two-fold increase). The relative effect of hypoxia on the IC 50 depended mainly on the cell line, and to a lesser extent on the drug. The results indicate that the reduced cell proliferation in hypoxia might be an important factor, but not the only determinant of a reduced cytotoxicity. In view of the broad spectrum of drugs with different modes of action tested, the relative resistance cannot be mediated by substance-specific resistance mechanisms like hypoxia-induced upregulation of P-glycoprotein or increased DNA-repair capacity, since many unrelated drugs were affected to a comparable extent in their efficacy by hypoxia. This study also provides the rationale to test the hypothesis whether improving tumour oxygenation by raising haemoglobin concentrations, for example, with erythropoietin in patients with TGCTs receiving chemotherapy may improve the outcome.

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confidence: 78%

Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro

et al. 2003

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“…A Cochrane review based on 5 randomized Time since randomization ( controlled trials found strong indications that for patients with head and neck cancer, the addition of erythropoietin to radiotherapy negatively affects patient outcome in terms of loco-regional progression-free survival and OS (7). Suggested explanations for the lack of benefit of erythropoietin include presence of erythropoietin receptors on the tumor cell membranes stimulating tumor growth, and a decrease of tissue oxygenation because of increased viscosity when hemoglobin concentrations become too high (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

“…It is generally assumed that this is primarily a consequence of the impaired tumor oxygenation resulting in a more aggressive and treatment resistant tumor phenotype (15,27). Indeed, clinical and preclinical studies do provide evidence for a correlation between hemoglobin level and tumor hypoxia measured by polarographic pO 2 electrodes (15,16,28,29). In particular, this association is present in patients with severe anemia [hemoglobin < 11.0 g/dL (<6.9 mmol/L)], whereas it is much weaker in patients with mild anemia or low normal hemoglobin levels.…”

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confidence: 99%

Improved Recurrence-Free Survival with ARCON for Anemic Patients with Laryngeal Cancer

Janssens

Rademakers

Terhaard

et al. 2014

Clinical Cancer Research

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Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial.Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient.Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P ¼ 0.44) and disease-free survival (DFS, 75% vs. 70%; P ¼ 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P ¼ 0.03) and DFS (68% vs. 45%; P ¼ 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed.Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345-54. Ó2014 AACR.

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“…There appears to be a correlation between anemia and increased hypoxia in patients with solid tumors. Becker et al 28 examined the tumor oxygenation status in 133 patients with head and neck carcinomas. Pretreatment Hb level Ͻ 11 g/dL was found to be a stronger predictor of poor tumor oxygenation than was tumor stage, tumor volume, or smoking status.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of hemoglobin levels on treatment outcome in patients with nasopharyngeal carcinoma treated with sequential chemoradiotherapy or radiotherapy alone

Chua

Sham

Choy

2004

Cancer

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BACKGROUNDThe goal of the current study was to investigate the impact of hemoglobin (Hb) levels on treatment outcome in a randomized Phase III trial of patients with nasopharyngeal carcinoma (NPC) treated with induction chemotherapy followed by radiotherapy or with radiotherapy alone.METHODSBetween September 1989 and August 1993, 334 patients with advanced NPC were entered into a randomized trial comparing 3 cycles of induction chemotherapy (cisplatin and epirubicin) followed by radiotherapy with radiotherapy alone. Only evaluable patients who completed radiation were included in the analysis (n = 286). Patients were stratified into normal and low Hb groups according to baseline, preradiation, and midradiation Hb levels. Local recurrence–free, distant metastasis–free, and disease‐specific survival rates were estimated using the Kaplan–Meier method. Multivariate analysis was performed using the Cox model.RESULTSIn the chemotherapy arm, the mean baseline, preradiation, and midradiation Hb levels were 13.6, 11.0, and 11.8 g/dL, respectively. In the radiotherapy arm, the mean baseline/preradiation and midradiation Hb levels were 13.7 and 12.9 g/dL, respectively. A midradiation Hb level ≤ 11 g/dL was associated with significantly poorer 5‐year local recurrence–free (60% vs. 80%; P = 0.0059) and disease‐specific survival rates (51% vs. 68%; P = 0.001), with no difference in distant metastasis–free rates (69% vs. 67%; P = 0.83). No significant difference in treatment outcome according to baseline or preradiation Hb levels was noted. Multivariate analysis showed that a low midradiation Hb level, but not a low baseline or preradiation Hb level, was an independent predictor of local disease recurrence and malignancy‐related death.CONCLUSIONSThe current study showed that midradiation Hb level was an important prognostic factor with respect to local control and survival in patients with NPC. The high incidence of anemia after chemotherapy has a negative impact on treatment outcome, and this condition may reduce the benefit of induction chemotherapy. Attempts to correct anemia during radiation and the impact of anemia on treatment outcome requires further study. Cancer 2004. © 2004 American Cancer Society.

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

Cited by 208 publications

References 34 publications

Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro

Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro

Improved Recurrence-Free Survival with ARCON for Anemic Patients with Laryngeal Cancer

Prognostic impact of hemoglobin levels on treatment outcome in patients with nasopharyngeal carcinoma treated with sequential chemoradiotherapy or radiotherapy alone

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