Since observations from the beginning of the last century, it has become well established that solid tumors may contain oxygen-deficient hypoxic areas and that cells in such areas may cause tumors to become radioresistant. Identifying hypoxic cells in human tumors has improved by the help of new imaging and physiologic techniques, and a substantial amount of data indicates the presence of hypoxia in many types of human tumors, although with a considerable heterogeneity among individual tumors. Controlled clinical trials during the last 40 years have indicated that this source of radiation resistance can be eliminated or modified by normobaric or hyperbaric oxygen or by the use of nitroimidazoles as hypoxic radiation sensitizers. More recently, attention has been given to hypoxic cytotoxins, a group of drugs that selectively or preferably destroys cells in a hypoxic environment. An updated systematic review identified 10,108 patients in 86 randomized trials designed to modify tumor hypoxia in patients treated with curative attempted primary radiation therapy alone. Overall modification of tumor hypoxia significantly improved the effect of radiotherapy, with an odds ratio of 0.77 (95% CI, 0.71 to 0.86) for the outcome of locoregional control and with an associated significant overall survival benefit (odds ratio = 0.87; 95% CI, 0.80 to 0.95). No significant influence was found on the incidence of distant metastases or on the risk of radiation-related complications. Ample data exist to support a high level of evidence for the benefit of hypoxic modification. However, hypoxic modification still has no impact on general clinical practice.

Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.

Many countries have implemented standardised cancer patient pathways (CPPs) to ensure fast diagnosis of patients suspected of having cancer. Yet, studies are sparse on the impact of such CPPs, and few have distinguished between referral routes. For incident cancer patients, we aimed to determine how often GPs suspected cancer at the time of first presentation of symptoms in general practice and to describe the routes of referral for further investigation. In addition, we aimed to analyse if the GP’s suspicion of cancer could predict the choice of referral to a CPP. Finally, we aimed to analyse associations between not only cancer suspicion and time to cancer diagnosis, but also between choice of referral route and time to cancer diagnosis. We conducted a population-based, cross-sectional study of incident cancer patients in Denmark who had attended general practice prior to their diagnosis of cancer. Data were collected from GP questionnaires and national registers. We estimated the patients’ chance of being referred to a CPP (prevalence ratio (PR)) using Poisson regression. Associations between the GP’s symptom interpretation, use of CPP and time to diagnosis were estimated using quantile regression. 5,581 questionnaires were returned (response rate: 73.8%). A GP was involved in diagnosing the cancer in 4,101 (73.5%) cases (3,823 cases analysed). In 48.2% of these cases, the GP interpreted the patient’s symptoms as ‘alarm’ symptoms suggestive of cancer. The GP used CPPs in 1,426 (37.3%) cases. Patients, who had symptoms interpreted as ‘vague’ had a lower chance of being referred to a CPP than when interpreted as ‘alarm’ symptoms (PR = 0.53 (95%CI: 0.48;0.60)). Patients with ‘vague’ symptoms had a 34 (95% CI: 28;41) days longer median time to diagnosis than patients with ‘alarm’ symptoms. GPs suspect cancer more often than they initiate a CPP, and patients were less likely to be referred to a CPP when their symptoms were not interpreted as alarm symptoms of cancer. The GP’s choice of referral route was a strong predictor of the duration of the diagnostic interval, but the GP’s symptom interpretation was approximately twice as strong an indicator of a longer diagnostic interval.