Definitive Intensity-modulated Radiation Therapy in Elderly Patients with Locally Advanced Oropharyngeal Cancer

Discussion

This study provided a reliable evaluation of the effect of sequential IMRT in elderly patients with locally advanced oropharyngeal cancer. Results suggested that definitive IMRT with standard fractionation was effective in reducing mortality and both local and distant recurrences, without deleterious effect on compliance and toxicity. The ACE-27 score was not related to survival and toxicity rates.

Although approximately 25% of patients with head and neck cancer are aged 70 years and over, over the past decade elderly patients have represented fewer than 10% of clinical trial participants (7, 8). This under-representation of the elderly suggests that it is necessary to better understand age-based differences in presentation, response to therapy and prognosis. Further studies should be designed exclusively for elderly patients. It is expected that they have similar comorbidities that could affect compliance with or response to treatment. Evaluation and quantification of comorbidity is paramount to stratifying elderly patients into groups with similar pre-treatment health condition that impacts on short-term mortality and the ACE-27 index is an established tool in head and neck squamous cell carcinoma assessment (8, 9). Interestingly, our results showed no significant differences in clinical outcomes, toxicity manifestation and compliance with IMRT. This favorable profile could be explained by the good performance of the enrolled patients. In fact, a clear distinct impact of the ACE-27 severity scores was shower here. Our results are in agreement with survival rates found in the study of Datema et al., in which the 2-year survival probability of a patient with ACE-27 score 1 was 67% against 75% for a patient with ACE-27 score 0 (9). To our knowledge, in the head and neck cancer scenario, there is only one published prospective study that required an age from 65 to 79 years (10). However, this study was performed to assess the efficacy and safety profiles of the induction chemotherapy, and did not contain enough RT data to allow a proper comparison of results. Based on five trials of the European Organization for Research and Treatment of Cancer restricted to patients receiving RT for head and neck cancer, Pignon et al. analyzed locoregional control, survival and side-effects in relation to the age of the patients (11). Globally, 1,589 patients were enrolled and 185 patients were over 70 years (11.6%). Although under-represented, the absolute number of elderly patients was considered sufficient to perform the analysis. Overall, acute RT tolerance was worse in elderly patients than younger patients, whereas there were no differences in term of local control and OS between age groups. The authors concluded that an age limit was not a good strategy to guide administration of head and neck cancer therapy. However, there are two main considerations. Firstly, their study had no information regarding comorbidity. Secondly, patient data were from 1980 to 1995 and tolerance rates may have been negatively influenced by RT technique. Recently, Nguyen et al. presented a series of 27 patients with locally advanced head and neck cancer aged ≥70 years treated with concurrent CRT (12). Only 11 cases had primary oropharyngeal neoplasia but no subgroup analysis for anatomic sites was available. The 2-year OS of the entire elderly cohort was 67.5%. In total, 16 patients developed grade 3 or more acute mucositis, seven had grade 3 or more hematological toxicity, five had severe skin reaction and three presented severe vomiting. The mean treatment break was 7 days. Our patients experienced a less severe toxicity profile and we believe this was because IMRT was not combined with chemotherapy. Moreover, if we compare results, our survival rate was better, but due to the short follow-up (median 12 months) observed by Nguyen et al., no definitive conclusions can be drawn.

Our study could be useful to identify the optimal therapeutic strategy in elderly patients with locally advanced oropharyngeal cancer. The use of sequential IMRT appears to be safe and efficacious. Our employed RT fractionation schedule is justified by radiobiological research and clinical data. It has been well demonstrated that hyperfractionation with dose escalation results in consistent survival benefit with an increase of severe acute side-effects, especially mucosal toxicity, compared with conventional fractionation (13-15). On the other hand, shortening the overall treatment time using accelerated fractionation improves locoregional control, but acute and late toxicities are also increased (16). Moreover, a recent meta-analysis showed an absolute survival benefit for altered fractionation of 3.4% at 5 years, but this benefit was limited to patients younger than 60 years of age (17). Therefore, considering that a consensus regarding hyperfractionation and altered fraction schedules has not yet emerged, and considering patient age and comorbidity, the higher toxicity risk outweighed the survival advantage and thus the conventional fractionation was chosen. In addition, the application of the IMRT technique was useful in reducing late toxicity, by sparing closely adjacent critical anatomic structures, such as salivary glands, pharyngeal constrictor muscles, mandible, temporomandibular joint and masticatory muscles.

However, our results should be viewed with caution. The retrospective nature of this analysis is the main limitation of the study. The sample size was relatively small, making results less robust. But homogeneity in the patient population and in the treatment approach, without missing data, represent the study strengths. Considering the lack of literature evidence on treatment recommendations for older patients with locally advanced oropharyngeal cancer, this study could be useful to assist the radiation oncologist in elderly patient counseling and clinical decision-making.