Prognostic Factors After Definitive Radio(Chemo)Therapy of Locally Advanced Head and Neck Cancer

Discussion

The prognoses of patients with SCCHN presenting with distant metastases or locally advanced unresectable disease are generally poor and require improvement (1-3, 6-8). For locally advanced disease, modern techniques of head-and-neck surgery and radiotherapy have already led to improved outcomes, which may be further enhanced with new chemotherapy approaches (9, 10). The application of personalized treatment programs may also result in better outcomes. Such programs should consider an individual patient's specific situation, including his prognosis. Therefore, the identification of prognostic factors is important. In this study, several potential predictors for LRC and OS were analyzed. In the multivariate analysis of LRC, pre-radiotherapy hemoglobin levels of 12-14 g/dl, lower T-category, lower N-category and female gender were independent prognostic factors. In the multivariate analysis of OS, pre-radiotherapy hemoglobin levels of >12 g/dl, lower N-category, KPS ≥80, female gender and the type of the concurrent chemotherapy were independent predictors. These results widely agree with those of previous studies of treatment of SCCHN demonstrating consistency of the results of this study (11-13). An impact of the tumor stage on outcomes was already shown for patients with locally advanced SCCHN. The prognostic role of the pre-radiotherapy hemoglobin was also reported before, for which two interpretations exist. The hemoglobin level may be a surrogate marker for more advanced underlying disease. However, it has also been suggested that hemoglobin levels are important for tumor oxygenation, which is important for the efficacy of radiation therapy (14, 15). The effect of irradiation widely depends on the induction of oxygen free radicals that lead to damage of the tumor cell DNA and, subsequently, the tumor cell itself. It is well-recognized that anemia, which is associated with a reduced oxygen-carrier capacity, has a detrimental effect on tumor cell oxygenation (14). In addition, it has been suggested that high concentrations of hemoglobin may also have a negative impact on tumor cell oxygenation due to a reduced perfusion of the small capillaries (16). Hemoglobin levels of 12-14 g/dl or 13-15 g/dl have been considered optimal for tumor oxygenation. Indeed, in the present study, hemoglobin levels of 12-14 g/dl were associated with a better LRC than levels >14 g/dl and <12 g/dl. This result supports the idea of an optimal range of hemoglobin levels in the light of tumor cell oxygenation. With respect to OS, both hemoglobin levels of 12-14 g/dl and >14 g/dl were superior to levels <12 g/dl, while the OS rates for 12-14 g/dl and >14 g/dl were similar. Thus, in addition to the aspect of tumor cell oxygenation, the hemoglobin level may also be a surrogate marker for advanced disease.

In the present study, the radiochemotherapy protocols, including three courses of 100 mg/m² cisplatin (on days 1, 22 and 43) or two courses of 20 mg/m² cisplatin (on days 1-5 and 29-33), resulted in better OS than the protocols that included weekly administration of cisplatin or cisplatin plus 5-FU. However, the retrospective design of the current study must be taken into account when using these findings to recommend a chemotherapy regimen. Additional (matched-pair) studies should be performed directly comparing two radiochemotherapy programs.

In contrast to other significant predictors, the total radiation dose (70 Gy vs. 60-66 Gy) had no significant impact on LRC or OS. This finding may be due to the relatively small number of patients (n=38) who received doses of 60-66 Gy. However, it may also be true that a total dose of 66 Gy is sufficient for definitive radio(chemo)therapy of advanced SCCHN when administered with chemotherapy. A randomized trial comparing 66 Gy to 70 Gy for definitive treatment of SCCHN is recommended.

In conclusion, this study demonstrated the prognostic significance of the pre-radiotherapy hemoglobin levels for definitive treatment of SCCHN. Furthermore, concurrent chemotherapy is mandatory to achieve optimal results. Cisplatin alone with three courses of 100 mg/m² (on days 1, 22 and 43) or two courses of 20 mg/m² (on days 1-5 and 29-33) appear most effective. However, further studies are required to identify the optimal chemotherapy program. A total radiation dose of 70 Gy may not be superior to lower doses, which needs to be properly investigated in a future randomized trial. These findings, regarding prognostic factors, can aid treatment recommendations and stratification of groups when designing prospective trials.