Alistair Hunter

Does the tumor microenvironment influence radiation-induced apoptosis?

Cytotoxic anti-cancer agents induce apoptosis in tumor and normal tissues. Therefore, it is important to investigate which factors determine these apoptotic processes and hence their likely impact on therapeutic gain. Radiation-induced apoptosis in tumors may be inhibited due to mutations of apoptotic elements or to tumor microenvironmental conditions arising from vascular insufficiency. Tumors typically contain regions of hypoxia, low glucose and acidosis. Hypoxic cells compromise treatment partly because of reduced fixation of damage during radiotherapy and partly because they promote a more malignant phenotype. There is also evidence that hypoxia may inhibit apoptosis. For some cell types, concurrent hypoxia may modulate radiation-induced apoptosis while, for others, post-irradiation hypoxia may be required. This may reflect the activity of different apoptotic pathways. Pathways involving mitochondrial components as well as regulation of SAPK and Fas have been implicated. In addition, several key stages in apoptosis are sensitive to depletion of cellular energy reserves, which results from hypoxia and low glucose conditions. There is also evidence that low pH in tumors can interfere with radiation-induced apoptosis, partly through cell cycle arrest and other undefined mechanisms. Conclusions: Hypoxia, low glucose and acidosis influence radiation-induced apoptosis and thus may be detrimental to radiotherapy.

Hypofractionated irradiation for non-small cell lung cancer

Large radiation fractions are an effective way of killing tumour cells but have generally been avoided in curative treatment of patients because of concerns of a disproportionate increase in late normal tissue toxicity. Radiobiological modelling of the effect of radiation on lung tumours and late-reacting normal tissues, which are more sensitive to large radiation fractions, has been undertaken. The biological effect of radiation on tumours is increased as the overall treatment time is shortened but this is not true for late-reacting normal tissue. Sample data are shown in which the relative increases in radiation effect on the tumour and late-reacting normal tissues are similar after hypofractionation. A favourable therapeutic ratio can be achieved because the bulk of normal tissue will receive a lower dose of radiation at a lower dose per fraction than the tumour, especially with current techniques where the volume of normal tissue irradiated can be sharply reduced. The clinical evidence confirms that lung toxicity is volume-dependent. It is the small Stage I and II tumours which are most likely to benefit from hypofractionated regimens, as the volumes to be treated are smaller and they have a lower incidence of distant metastases. Patients with Stage III tumours with favourable prognostic factors are nowadays treated with combined chemotherapy and radiotherapy and so for this group more conservative hypofractionation regimens are being explored. However, more advanced tumours may be treated with hypofractionation to lower total doses to achieve palliation and a modest degree of survival benefit.

Can radiation-induced apoptosis be modulated by inhibitors of energy metabolism?

Purpose: To determine the effect of the inhibitors of energy metabolism, 2-deoxyglucose (2DG) and sodium azide, on radiation-induced apoptosis. Materials and methods: Radiation-induced apoptosis was determined in U937 monocytic leukaemia cells exposed to energy inhibitors post-irradiation. Apoptosis was scored microscopically using morphological criteria. Glycolysis was determined by assessing glucose consumption and lactate production. Adenine nucleotide levels were measured using a luciferase assay after enzymatic conversion to ATP. Respiration was measured using a Clark-type oxygen electrode. Results: In addition to their apoptosis-inducing properties, both 2DG and azide modified post-irradiation apoptosis. 2DG induced apoptotic radiosensitization after exposure to lower concentrations (5 mM, 10 mM) up to 20 h post-irradiation while a level of radioprotection was found after 5 h exposure to higher doses up to 100 mM. By contrast, all doses of azide examined (5 – 50 mM) induced apoptotic radioprotection at all times examined. Glycolytic flux and ATP levels fell rapidly with increasing 2DG dose but energy charge remained unchanged. Glycolysis was less influenced by azide, with ATP levels being initially maintained after exposure but decreasing in a dose-dependent manner at 3 h post-irradiation. However, energy charge was unaffected by azide at the concentrations examined. Conclusions: Both 2DG and azide can influence radiation-induced apoptosis possibly through their effects on glycolysis and ATP levels. We suggest that modulation of energy metabolism provides mechanistic insight into radiation-induced apoptotic pathways.

Neutron versus photon radiotherapy for local control in inoperable breast cancer

Background and Purpose:By virtue of their high linear energy transfer (LET) characteristics the biologic effectiveness of neutrons is less dependent on tissue oxygenation tension and cell cycle phase as compared to that with photons. Hence, an improved clinical benefit is to be expected predominantly in large, hypoxic and slowly growing tumors. Since a short course of radiotherapy is required for clinical reasons, it prompted the authors to initiate a randomly controlled trial on locally advanced breast cancer.Patients and Methods:Between 1996 and 1999, 27 patients with locally advanced breast cancer were irradiated with photons (60 Gy, 30 fractions; 8 MV, 60Co) or neutrons (18 Gy, twelve fractions; 66 MeVp→Be). The mean tumor diameters were 699 ± 399 ml for the photon group and 1,097 ± 831 ml in the neutron group.Results:After a mean follow-up period of 21.5 months tumor involution was evaluated in 22 patients. Partial and complete remissions were registered in 6/10 patients of the photon group and 5/12 patients of the neutron group. Late grade 3–4 morbidity according to RTOG definition was scored in 5/10 patients in the photon group and in 6/12 patients in the neutron group. With regard to tumor control and late radiation morbidity no differences between the two treatment arms were observed.Conclusion:The underlying data indicate that no benefit is to be expected from neutron therapy in breast cancer.Hintergrund und Ziel:Die biologische Wirkung von Neutronen beruht im Wesentlichen auf der geringeren Abhängigkeit von der Sauerstoffkonzentration und der Zellzyklusphase im Vergleich zu dünn ionisierender Strahlung. Klinische Vorteile sind deswegen insbesondere bei großvolumigen, hypoxischen und langsam wachsenden Tumoren zu erwarten. Dies veranlasste die Autoren, eine kontrollierte, randomisierte Studie bei lokal fortgeschrittenen Mammakarzinomen durchzuführen.Patienten und Methodik:Zwischen 1996 und 1999 wurden 27 Patientinnen mit lokal fortgeschrittenen Mammakarzinomen mit Photonen (60 Gy, 30 Fraktionen; 8 MV, 60Co) oder Neutronen (18 Gy, zwölf Fraktionen; 66 MeVp→Be) bestrahlt. Die mittleren Tumorvolumina betrugen 699 ± 399 ml in der Photonengruppe und 1 097 ± 831 ml in der Neutronengruppe.Ergebnisse:Nach einer mittleren Nachbeobachtungszeit von 21,5 Monaten waren die Ergebnisse von 22 Patientinnen auswertbar. Partielle und komplette Remissionen fanden sich bei 6/10 Patientinnen aus der Photonengruppe und 5/12 Patientinnen aus der Neutronengruppe. Normalgewebsreaktionen Grad 3–4 entsprechend der RTOG-Definition wurden bei 5/10 Patientinnen aus der Photonengruppe und 6/12 Patientinnen aus der Neutronengruppe festgestellt. Somit ergab sich kein Unterschied in den Remissions- und Spätmorbiditätsraten zwischen beiden Behandlungsarmen.Schlussfolgerung:Aufgrund der vorliegenden Ergebnisse ist kein Vorteil einer Neutronentherapie bei Mammakarzinom zu erwarten.

Treatment of carcinoma of the anal canal at Groote Schuur Hospital

OBJECTIVES Chemoradiation is the treatment of choice for squamous carcinoma of the anal canal, resulting in the same local control rates as surgery but with the advantage of organ function preservation. We aimed to review all cases of anal canal carcinoma treated at Groote Schuur Hospital between 2000 and 2004 and to assess treatement outcome. METHODS The records for 31 patients presenting during this period were reviewed. Patient and tumour characteristics were recorded. Twenty-six patients were treated with chemoradiation. Local failure-free, colostomy-free and overall survival were calculated using the Kaplan-Meier method. RESULTS Compared with the literature, the median patient age was younger and the stage was more advanced in this study. The complete response rate for all stages with chemoradiation was 80%. The local failure-free survival at 5 years was 60.7%. Colostomy-free and overall survival at 5 years were 59.2% and 65.6%, respectively. CONCLUSIONS The patients presented with locally advanced disease. Chemoradiation is effective treatment for this group of patients and the majority avoid a permanent colostomy as they preserve anal sphincter function.

Radiation-induced apoptosis is modulated by the post-irradiation tumor microenvironment

The sensitivity of cells to radiation-induced apoptosis is considered to be low in solid tumors. This is thought to arise largely from inherent resistance caused by apoptotic pathway mutations. However, other factors may contribute to apoptotic resistance. Poor vasculature and abnormal tumor metabolism lead to a tumor microenvironment characterized by conditions of hypoxia, low glucose and extracellular acidosis. Hypoxia during irradiation is well known to cause resistance and is a barrier to successful treatment. We hypothesized that post-irradiation microenvironmental conditions can modulate radiation-induced apoptosis and that this may in part contribute to therapeutic resistance. In order to test this, radiation-induced apoptosis was assessed in U937 cells in suspension and in a novel multicellular agarose-diffusion-system. Post-irradiation hypoxia failed to modify the extent of apoptosis in suspension cells, suggesting that post-irradiation hypoxia may be of little consequence to apoptosis induction in this model. In contrast, low glucose post-irradiation significantly inhibited radiation-induced apoptosis. While short (5h) exposure to acidosis also appeared to inhibit radiation-induced apoptosis, the lack of modulation after extended (20h) exposure suggests that acidosis may only delay apoptosis. In the more complex agarose diffusion-limitation model, radiation-induced apoptotic sensitivity was found to be reduced in cells distant from the diffusion edge representing poorly perfused tumor cells in vivo. Overall, the results suggest that the post-irradiation tumor microenvironment may affect radiation-induced apoptosis and thus may influence therapeutic response. Therefore, the post-irradiation tumor microenvironment may be a target for therapeutic intervention.

Accreditation of training courses in good clinical practice

To the Editor: The Medicines Control Council of South Africa requires health care professionals and others involved in conducting clinical studies to attend a training course in good clinical practice (GCP) every 3 years. The need for standardised training and accreditation in South Africa is recognised. However, the way in which the accreditation of training courses is to be implemented from 2011 will result in conflicts of interest that would be best avoided.