Clinical Investigation
Anemia During Sequential Induction Chemotherapy and Chemoradiation for Head and Neck Cancer: The Impact of Blood Transfusion on Treatment Outcome

https://doi.org/10.1016/j.ijrobp.2008.04.052Get rights and content

Purpose

Sequential treatment (chemotherapy followed by concomitant chemoradiation; CCRT) is increasingly being used for radical treatment of squamous cell cancer of the head and neck (SCCHN), which results in increased myelosuppression. In this study, we review the incidence of anemia and the effect of a policy of hemoglobin (Hb) maintenance by blood transfusion on disease outcomes in these patients.

Methods and Materials

Retrospective review of the records of patients with SCCHN treated with sequential CCRT formed the basis of this study. The incidence of anemia and statistics on blood transfusion were documented. For the purpose of outcome analyses, patients were divided into four categories by (1) transfusion status, (2) nadir Hb concentration, (3) number of transfusion episodes, and (4) number of units of blood transfused (NOUT). Data on 3-year locoregional control (LRC), relapse-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were analyzed.

Results

One hundred and sixty-nine patients were identified. The median follow-up was 23.6 months. The RFS (52% vs. 41%, p = 0.03), DSS (71% vs. 66%, p = 0.02), and OS (58% vs. 42% p = 0.005) were significantly better for patients who did not have a transfusion vs. those who did. The LRC, RFS, DSS, and OS were also significantly better for patients with nadir Hb level >12 vs. <12 g/dL and NOUT 1–4 vs. >4.

Conclusion

Our study seems to suggest that blood transfusion during radical treatment for SCCHN might be detrimental. Further research should be undertaken into the complex interactions among tumor hypoxia, anemia, and the treatment of anemia before making treatment recommendations.

Introduction

Until relatively recently, surgery and radiotherapy were considered the main treatments for patients with late-stage squamous cell cancers of the head and neck (SCCHN). However, in recent years, systemic chemotherapy has increasingly been incorporated into the treatment plan. As part of primary treatment, systemic chemotherapy can be administered before (induction or neoadjuvant chemotherapy) or during (concomitant chemotherapy) radiotherapy.

The rationale underlying the use of induction chemotherapy is that drug delivery is likely to be better in untreated well-vascularized tumors, and disease may be down-staged before definitive treatment and micrometastases may be targeted (1). Studies have demonstrated that chemotherapy can reduce the rate of distant metastases and improve survival 2, 3. Induction treatment with combined cisplatin and 5-fluorouracil (5-FU) (the PF regimen) yields a 5% improvement in 5-year survival 3, 4. Recently reported Phase III studies have demonstrated that the addition of a third drug (docetaxel) to cisplatin and 5-FU (as part of the so-called TPF regimen) results in superior progression-free and overall survival rates when compared with PF 5, 6. Taken together, these data suggest that induction treatment with two- and three-drug regimens will be increasingly used in the future.

Concomitant chemotherapy during radiotherapy improves locoregional control rates and survival (4). In addition, combining chemotherapy with radiation improves the rates of organ conservation (7). The meta-analysis by Pignon et al. (2000) (4) showed that cisplatin-containing concomitant chemotherapy conferred maximum benefit in patients with SCCHN. Single-agent cisplatin is the cytotoxic agent of choice for concomitant chemoradiotherapy.

The use of chemotherapy in patients with SCCHN results in increased complication rates. The incidence and severity of radiation-induced toxicities within the radiation fields (e.g., mucositis, skin reaction, dysphagia) are increased. However, cytotoxic chemotherapy also causes systemic effects, such as myelosuppression. The incidence of Grade 3 or higher (Common Technology Criteria for Adverse Events [CTCAE] v3.0 acute toxicity criteria) neutropenia ranges from 15% to 42% in studies using cisplatin-based chemotherapy 8, 9, 10. Thrombocytopenia Grade 3 or higher is less common with reported incidences of 2%–10%. The incidence of Grade 3 or higher anemia ranges from 2% to 35%. This latter toxicity may have significant bearing on treatment outcome because it is known that low hemoglobin (Hb) concentration is associated with reduced local control after chemoradiation in patients with SCCHN 11, 12. Therefore, any move to increase use of sequential induction chemotherapy followed by concomitant chemoradiation (CCRT) is likely to be associated with a greater incidence of treatment-induced anemia and a corresponding risk of an adverse impact on treatment outcome. However, there are currently no systematic analyses of the effect of a CCRT program on Hb levels, transfusion requirements, and treatment outcomes in patients with SCCHN. In this study we therefore reviewed the incidence of anemia in a large consecutive cohort of patients treated with CCRT for locally advanced SCCHN. Furthermore, we analyzed the effect of a policy of Hb maintenance by blood transfusion on locoregional control and disease-specific survival (DSS) and overall survival (OS) rates.

Section snippets

Patient treatment protocol

Patients with SCCHN treated between 2001 and 2005 at the Royal Marsden Hospital with sequential CCRT formed the basis of this study. A retrospective review of the case notes and pharmacy records of these patients was undertaken. Two cycles of cisplatin (75 mg/m2) on Day 1 and 5-FU (1,000 mg/m2) Days 1–4 was the standard regimen used for induction chemotherapy. In patients experiencing significant (Grade 3 or higher, CTCAE v 3.0) cisplatin-induced neuro-/oto-/nephrotoxicity, carboplatin (AUC 5)

Results

One hundred and sixty-nine patients treated with definitive sequential induction CCRT were identified. The patient demographics and tumor characteristics are detailed in Table 1. The median Hb during the 12 weeks of treatment was 13.8 g/dL (range, 9.6–16.9). Data were available on Hb level before induction chemotherapy in 165 patients (median 13.1 g/dL, range, 8.8–15.8). The majority of patients (76%) had Hb measurements every week during radiotherapy.

Twenty-one patients had Hb levels <12 g/dL

Discussion

Our study showed a 39% and 81% incidence of anemia (Hb <12 g/dL) during induction chemotherapy and concomitant chemoradiotherapy, respectively. These figures are lower than those documented in two other studies of sequential CCRT. Psyrri et al.(8) reported figures of 80% and 88%, respectively, and Vokes et al.(13) reported 97% and 100%, respectively. This difference is probably accounted for by the lower dose intensity of cisplatin (75 mg/m2 every 3 weeks), the use of 4 (rather than 5) days of

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This study has been accepted in abstract form for a poster discussion session at the American Society of Clinical Oncology annual conference, Chicago, IL, May 30–June 3, 2008.

C.M.N. and K.J.H. are joint senior authors.

Conflict of interest: none.

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