Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx

doi:10.1016/S0360-3016(01)01488-2

International Journal of Radiation OncologyBiologyPhysics

Volume 50, Issue 3, 1 July 2001, Pages 705-715

Presented at the 41st Annual Meeting of the American Society for Therapeutic Radiology and Oncology, San Antonio, TX, October 31–November 4, 1999.

https://doi.org/10.1016/S0360-3016(01)01488-2 Get rights and content

Abstract

Purpose: We assessed the influence of hemoglobin level and r-HuEPO administration on response to chemoradiotherapy, locoregional tumor control, and overall survival in patients treated with neoadjuvant chemoradiotherapy and surgery for a squamous cell carcinoma of the oral cavity or oropharynx.

Methods and Materials: The 191 study patients were treated with mitomycin C (15 mg/m² day 1), 5-fluorouracil (750 mg/m²/day, days 1–5), and radiotherapy (50 Gy in 25 fractions weeks 1–5), followed by resection of the primary tumor bed and neck dissection at the General Hospital Vienna, Austria, between November 1989 and October 1998 for a T2–4, N0–3, M0 SCC of the oral cavity or oropharynx. Starting in May 1996, patients with a low hemoglobin (Hgb) before or during chemoradiotherapy received r-HuEPO 10,000 IU/kg s.c. 3–6 times/week until the week of surgery.

Results: On multivariate analysis, Hgb level and use of r-HuEPO were independent prognostic factors for response to chemoradiotherapy and locoregional tumor control (p < 0.01). Pathologic response to neoadjuvant therapy was also predictive of locoregional control (p < 0.001). Patients with a pretreatment Hgb ≥ 14.5 g/dL had significantly higher complete response, locoregional control, and survival rates than the patients with a pretreatment Hgb < 14.5 g/dL who did not receive r-HuEPO (p < 0.05). The response, control, and survival rates in patients with a pretreatment Hgb < 14.5 g/dL given r-HuEPO were significantly higher than in low Hgb patients not given r-HuEPO (p ≤ 0.001) and equivalent to patients with a pretreatment Hgb > 14.5 g/dL (p ≥ 0.3).

Conclusion: Low pretreatment Hgb is a negative prognostic factor for oral cavity and oropharyngeal SCCA patients, but was completely abrogated by r-HuEpo administration during neoadjuvant chemoradiotherapy. Randomized trials of radiation and/or chemotherapy with or without r-HuEPO for patients whose Hgb level is either low at the start of therapy or is anticipated to become low during therapy are indicated.

Introduction

Oral cavity and oropharynx malignancies can arise from the lip, tongue, floor of mouth, gingiva, buccal mucosa, palate, retromolar trigone, or tonsillar area. The vast majority of these malignancies are squamous cell carcinomas (SCC). They have traditionally been treated using surgery, radiation therapy, or resection with postoperative irradiation. Chemotherapy or combined radiation and chemotherapy (chemoradiotherapy) is increasingly being used before surgery for locally advanced SCC of the head and neck 1, 2, 3. By diminishing primary tumor size and infiltration, neoadjuvant therapy may permit less radical surgical procedures and improve tumor control.

The efficacy of radiation therapy in patients with SCC of the oral cavity, oropharynx, and larynx has been associated with their systemic hemoglobin (Hgb) concentration in several multivariate as well as univariate analyses 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. Hgb concentration was strongly associated with local tumor control (p = 0.004) in a multivariate analysis of 181 patients treated in Denmark for SCC of the oropharynx (12). A multivariate analysis of patients treated for oral cavity SCC in Norway found Hgb level to be a strong independent prognostic factor for survival (p = 0.01). The 5-year overall survival was approximately 66% for patients presenting with a Hgb concentration > 14 g/dL, 50% for patients with a Hgb between 11–14 g/dL, and 22% for patients with a Hgb < 11 g/dL (13).

Anemia is common among patients with SCC of the oral cavity and oropharynx at presentation 9, 10, 11, 12, 13. Chemotherapy generally causes a further decrease in Hgb level during treatment. Recombinant human erythropoietin (r-HuEPO) has been demonstrated to prevent and/or reverse chemotherapy-induced anemia 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. r-HuEPO has also been shown to increase Hgb levels during radiation therapy 28, 29, 30, 31.

Eligible patients with locally advanced SSC of the oral cavity and oropharynx at the General Hospital Vienna in Vienna, Austria, have been treated according to a single protocol involving neoadjuvant chemoradiotherapy followed by resection of the primary tumor and regional lymphatics since 1989. Starting in May 1996, r-HuEPO was added to the protocol treatment for patients whose Hgb was < 12.5 g/dL at the start of or during neoadjuvant chemoradiotherapy.

This study examines the effect of pretreatment hemoglobin level and the use of r-HuEPO in low hemoglobin patients on tumor response, locoregional control, and overall survival in 191 patients treated on the General Hospital Vienna chemoradiotherapy protocol for a T2 –T4 N0–N3 M0 squamous cell carcinoma of the oral cavity or oropharynx at the General Hospital Vienna between 1989 and 1998.

Section snippets

Patients

This retrospective review includes all 191 patients who were treated at the General Hospital Vienna, Austria, between November 1989 and December 1998 using the neoadjuvant chemoradiotherapy regimen described below for a histologically confirmed Union Internationale Contre Le Cancer (UICC) stage T2–4, N0–3, M0 SCC of the oral cavity or oropharynx (32). The primary tumor was located in the floor of mouth in 121 patients, tonsillar region in 41 patients, tongue in 20 patients, and palate in 5

Patient characteristics

Patients were separated into groups for this data analysis according to whether their pretreatment Hgb was less than 14.5 g/dL and whether they received r-HuEPO during neoadjuvant chemoradiotherapy. Characteristics of the 191 patients in each of the other three groups are listed in Table 1. Group 1 patients, who had a pretreatment Hgb ≥ 14.5 g/dL and did not receive r-HuEPO, did not differ significantly from Group 2 patients, who had a pretreatment Hgb < 14.5 g/dL and did not receive r-HuEPO,

Discussion

The systemic Hgb level at the start of radiation therapy has been found to be significantly associated with tumor control in over 40 published studies 6, 7, 9, 16, 36, 37, 38, including multiple studies of patients with squamous cell carcinoma of the head and neck 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. A retrospective analysis of 1,112 patients treated with radiation therapy for squamous cell carcinoma of the larynx or pharynx revealed a positive correlation between pretreatment Hgb

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We investigated the influence of change in hemoglobin (Hgb) levels during concurrent chemoradiotherapy (C-CRT) on outcomes of non-anemic patients with stage IIIA/B non-small cell lung cancer (NSCLC).
We identified 722 patients with stage IIIA/B NSCLC without anemia at baseline [hemoglobin (Hgb) <12 g/dL for women or <13 g/dL for men], either nonsmokers or ex-smokers, who received C-CRT between 2007 and 2012. All patients had received 1−3 cycles of platinum-based doublet chemotherapy during radiotherapy to 60−66 Gy and had documented Hgb measurements before treatment and at weekly intervals for 6 weeks during the C-CRT. Potential associations were assessed between baseline, nadir, extent of change in Hgb level, and anemia and overall survival (OS), locoregional progression-free survival (LRPFS), and PFS.
The median baseline Hgb level was 13.9 g/dL (range 12.0–16.8) and declined to a median 12.4 g/dL (range 7.9–16.1) during treatment. Anemia appeared in 237 patients (32.8%) and was more common among women (44.8% vs. 26.5%, P < 0.001). Neither baseline Hgb level nor change during treatment nor anemia emergence influenced any survival endpoint. Receiver operating curve analysis revealed an Hgb nadir of 11.1 g/dL to be associated with outcomes, in that a nadir Hgb <11.1 g/dL (in 156 patients) was linked with shorter median OS time (P < 0.001), LRPFS time (P < 0.001), and PFS time (P < 0.001); retained significance for all three endpoints in multivariate analyses; and was more strongly associated with OS in squamous cell carcinoma (P < 0.001) than in adenocarcinoma (P = 0.009).
Nadir Hgb <11.1 g/dL levels during C-CRT were associated with significantly poorer survival times in initially non-anemic patients presenting with locally advanced NSCLC.
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Preoperative radiotherapy followed by surgery is an effective treatment option for solid tumors including locally advanced squamous cell cancers of the head and neck region. Histopathologic response to radiation has been shown to be associated with survival. However, the relative prognostic importance of regression grade compared to other potential biomarkers has not been established yet.
One-hundred forty-four oral squamous cell carcinoma patients with stage III/IV disease were included in this analysis. Patients had received preoperative radiotherapy (RT) up to 50 Gy total dose in combination with 5-Fluorouracil (5-FU)/Mitomycin C (MMC) or with Cetuximab, followed by radical surgery six to eight weeks later. Outcome data were obtained from the patient’s files. Survival rates were estimated by the Kaplan-Meyer method. Cox-proportional-hazard regression models were used to compare the risk of death among patients stratified according to risk factors.
Five-year overall survival (OS) was 58% in the presented collective. Regression grade 4 (HR 3.58; p < 0.001) was most significantly associated with reduced survival, followed by elevated neutrophils (HR 2.22; p = 0.01), the combination of elevated neutrophils plus elevated CRP (HR 2.40; p = 0.01), and elevated CRP alone (HR 1.74; p = 0.03). In a multivariate analysis, the regression grade remained the most influential predictor of outcome (HR 4.23; p < 0.001).
In a comparative analysis, tumor response to pre-operative radiotherapy remains the strongest prognostic factor for treatment outcome, while elevated CRP, as well as neutrophils, were also found to be of significance.
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Recurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging.
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Les cancers des voies aérodigestives supérieures sont un modèle pour l’étude de la radiosensibilité tumorale. De très nombreux facteurs influencent cette radiosensibilité. Certains sont liés à la tumeur. La taille, l’infiltration et la localisation, comme la cavité buccale ou les adénopathies, sont des paramètres de mauvaise réponse. D’autres sont liés au patient. L’intoxication tabagique en cours de radiothérapie et une concentration d’hémoglobine basse sont des facteurs de radiorésistance. Plus récemment, l’infection par les papillomavirus humains a été montrée comme pouvant influencer positivement la radiosensibilité. Enfin, d’autres paramètres sont liés à la biologie tumorale. L’oxygénation tumorale, la radiosensibilité intrinsèque des cellules tumorales, la différenciation tumorale et la repopulation tumorale en cours de radiothérapie (reflétée par le Ki-67 et la concentration d’epidermal growth factor receptor [EGFR]) sont des facteurs de radiosensibilité des cancers des voies aérodigestives supérieures. Les stratégies de radiosensibilisation, comme la chimioradiothérapie concomitante ou la chimiothérapie d’induction à base de taxanes, ont permis d’améliorer les résultats cliniques chez les patients atteints d’un cancer des voies aérodigestives supérieures localement évolué avec une amélioration des taux de contrôle locorégional et de la survie par rapport à la radiothérapie exclusive. L’association de la radiothérapie et du cétuximab (anti-EGFR) est une autre approche validée mais avec une seule étude randomisée. Des modifications de fractionnement comme l’hyperfractionnement augmentent les taux de contrôle local et de survie. Les modifications de l’hypoxie améliorent le taux de contrôle locorégional mais avec un impact clinique faible.
Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact.
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Clinical investigation: head and neckImpact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx

Abstract

Introduction

Section snippets

Patients

Patient characteristics

Discussion

Oral Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

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Blood

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

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Preoperative simultaneous chemoradiotherapy in locally advanced cancer of the oral cavity and oropharynx

Am J Clin Oncol

Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx

J Clin Oncol

Does initial hemoglobin level modify the efficacy of radiosensitizers? An analysis of the MRC misonidazole studies in head and neck cancer and cervix cancer

Int J Radiat Biol

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Int J Radiat Oncol Biol Phys

A multivariate study of the prognosis of oral squamous cell carcinomas

Cancer

Clinical investigation: head and neck
Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx