A novel finding of our study was that in long-term survivors who had received radiation treatment for oropharynx cancer and a low inadvertent accumulated dose towards the basal part of the brain and the pituitary, quality of life was compromised. In order to eliminate several confounders, patients included were highly selected well functioning patients without hypopituitarism and GH deficiency.
The reason for selecting this patient group for long-term studies of the effects of low dose radiation toward the basal part of the brain and the pituitary is that their radiotherapy has been standardised in our unit for the last two decades. Another reason is their favourable long-term prognosis obtained by using intense multimodal treatment that has increased the five-year survival rate, even in patients with advanced T3 and T4 tumours in the head and neck region . In this group of patients it was therefore possible to study the biological late effects after low-dose radiotherapeutic exposure.
The effects of low doses of ionizing radiation in infancy, such as in the treatment of haemangioma, have recently been studied and found to influence cognitive abilities in adulthood when the doses given to the brain were above 100 mGy . Furthermore, adults treated for childhood onset acute lymphatic leukaemia (ALL) with cranial radiotherapy using doses of 18–20 Gy developed GH deficiency and impaired neuropsychological performance, although self-reported QoL was not affected . Adults treated with radiotherapy for cancer of the nasopharynx and paranasal sinuses show radiation-induced vascular damage and cognitive decline at follow-up when total doses >40Gy were administered to the temporal lobe . Long-term studies in adults who have received low-dose radiation towards the brain in adulthood and where the possible neuroendocrine consequences have been accounted for have not been performed previously, to our knowledge. We therefore carefully selected patients with no detected neuroendocrine consequences of previous treatment. We also excluded the presence of GH deficiency using the insulin tolerance test.
We have in our patient group 6 of 15 patients with primary hypothyroidism, a condition that can affect QoL. During inadequate hypothalamic stimulation the pituitary may synthesise and secrete a TSH that is biologically less active and with a longer half-life . This may complicate the diagnosis of hypothyroidism in this patient population as some have received both radiation towards the hypothalamic-pituitary areas and the thyroid gland. However, as TSH synthesis and secretion is more resistant to radiation than GH and gonadotropins  the hypothalamic radiation is less likely to be a confounder of importance in this study as all patients tested normal for both GH and gonadotropic function. All patients with primary hypothyroidism were also fully replenished with T4 for more than 6 months before entering the case-controlled trial and their thyroid hormone concentrations and their QoL scoring were similar to those in the healthy matched controls. We therefore believe that the impact of hypothyroidism on the outcome of this study is most likely negligible .
In this study, we have determined the total radiotherapeutic doses to the hypothalamus and the pituitary. The hippocampus, which is a radiosensitive structure in the basal part of the brain, is also of interest because it is known that hippocampal damage might affect cognitive function and wellbeing . The hippocampal dose could not be calculated with good accuracy in our study, as the structure cannot be defined well enough on the dose planning CT. We therefore assume that the hippocampus received approximately the same dose as the hypothalamus, as these regions have the same distance from the base of the skull. A volumetric study of the hippocampus has been performed as part of the case-control study in order to further study this possibility [unpublished data].
Many patients treated with head and neck cancer suffer from decreased QoL due to xerostomia, trismus, and swallowing difficulties one to five years after treatment [9, 10]. Only a few studies have been performed using generic self-rating QoL questionnaires in patients with no sign of recurrence years after treatment [11, 12]. Hammerlid et al.  showed that patients still suffered from functional limitations related to the disease and its treatment three years after diagnosis and treatment of head and neck cancer. However, these problems did not generally affect their overall health-related QoL as assessed using disease specific cancer related QoL questionnaires. Others [26–28] have also reported similar findings. Pourel et al.  found that physical functioning, role of functioning, and pain score did not differ from the general population. Their findings indicate that coping processes strongly influence QoL in long-term survivors of cancer. Foley et al  showed, using semi-structured interviews with survivors of several cancers more than 15 years after their diagnoses that the majority had experienced either a positive influence or very little long-term impact on their lives demonstrating how well cancer patients incorporate the cancer experience into their overall life experience.
Our study addresses general well-being in long-term head and neck cancer survivors (4–10 years) in a case-controlled trial. We have used four generic questionnaires that have all been previously used in various patient groups and in the general population. Although the study is small, the results from three independent questionnaires consistently showed compromised QoL in patients. The various affected domains were also consistent: depression, anxiety, energy, and general well-being. In addition, patients tended to have reduced physical activity during leisure time. Previous studies on QoL in this patient group were cross-sectional case studies, whereas our study was designed as a case-control study also adjusting for socioeconomic status. We have not specifically determined the mechanism for our findings, but a causal relationship between low-dose radiotherapy towards the basal brain and reduced QoL is possible, as the role of several confounders were minimized in the trial design.