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Katelyn Larger
12/6/17
Hockel M, Schlenger K, Mitze M, Schaffer U, Vaupel P. Hypoxia and radiation response in human
advanced stage cervical cancer. In this study, oxygenated and hypoxic tumors were compared to
investigate the effect that hypoxia has on overall and recurrence free survival. Tumor
oxygenation was measured for each patient using the Eppendorf probe. Patients were then
treated using either radiation therapy, induction chemo and then radiation therapy, or
The results showed that patients who presented with hypoxic tumors during treatment had a
“significantly worse disease free survival probability compared with better oxygenated tumors.” 1
These findings support the hypothesis that tumor hypoxia leads to radio-resistant tumors, which
study design. Using this observational design allowed researchers to collect data over an
extended period of time and also gave them the ability to assess outcomes as they occurred.
One of the major down sides to this type of study is that it can only show correlation, not
causation. Because the participants in this study had to have intermediate or advanced stage
cervical cancer, quota/purposive sampling had to be used. This unavoidable necessity caused
selection bias and diminished the external validity of the study. Though this study lacked
external validity, it was able to acquire reliable measurements throughout its entirety. The
Eppendorf probe that was used to measure tumor oxygenation is referred to as the gold
standard and is considered to be the “most accurate and reliable in determining tumor
oxygenation.”1 Because of this reliability, there was less error introduced into the study.
This study is relevant to my clinical practice because it sought to confirm the hypothesis
that tumor oxygenation has an effect on clinical outcomes for patients with cervical cancer. This
research is important because it helps to identify why recurrence is occurring and gives us
something to work towards correcting. With the data gathered from this study, it is clear that
hypoxia in tumors plays a role in overall and recurrence free survival. The authors of the study
state that there was a “significant correlation between the oxygenation status of normal
subcutaneous tissue in the mons pubis and the tumor oxygenation”1 meaning that oxygenation
of the patient may influence the oxygenation of the tumor itself. From this study, this
information could lead to new developments in how we view tumor oxygenation and even
Popple RA, Ove R, Shen S. Tumor control probability for selective boosting of hypoxic
selective boosting to hypoxic subvolumes. A Monte Carlo model of tumor control probability
was developed in order to draw these conclusions. This model separates a tumor into two
compartments: one that is to receive a primary dose of radiation and one that is to receive a
boost dose. These compartments were then made up of three subpopulations: oxygenated,
geometrically transient hypoxia (GTH), and geometrically stable hypoxia (GSH). The GTH
subpopulation consists of cells that are well oxygenated, but become hypoxic during radiation
due to transient ischemia. The GSH subpopulation consists of cells that are hypoxic due to a lack
of vascularity to the tumor. By using the model, it was found that targeting hypoxic subvolumes
with a boost increases tumor control. This finding is only true for tumors in which there is an
identifiable GSH subpopulation. With tumor that have a GTH subpopulation, the hypoxic
volume is not stable and may change during treatment, meaning that it cannot be targeted with
a boost effectively.
The authors of this study state that a Monte Carlo method was used to research the
effect that boosting hypoxic subvolumes has on tumor control probability. The benefit of using a
Monte Carlo method is that repeated random sampling is used in order to obtain data. By using
random sampling, the external validity of the study is enhanced. This also means that selection
bias was reduced. Though this study has validity, it falls short with reliability. There are a lot of
uncertainties that are associated with how tumors reoxygenate, meaning that obtaining the
exact same results would be extremely difficult. A disadvantage to this study is that qualitative
conclusions had to be drawn rather than quantitative. This is a slight disadvantage because
qualitative data requires additional time and money to analyze. Also, cells in vitro were used to
test this model. The authors state that “cell lines demonstrate that the in vivo clonogens tend to
be less radiosensitive than the in vitro cell lines and that the differential between oxygenated
and hypoxic cells is less.”2 This statement makes it apparent that the results of the study may be
different if the model were applied to in vivo cells. I think that further data should be collected
using this in order to fully understand how it is applied to hypoxic tumor cells in vivo.
identifies when boosting hypoxic subvolumes has an effect on tumor control probability.
Because hypoxic tumors are more resistant to radiation, it is important that we are able to still
effectively treat these tumors so that there is no recurrence. This study proposes the use of a
boost to the hypoxic subvolumes identified in tumors in order to increase tumor control
probability. With this knowledge, it is possible to create better outcomes for patients with
Bassler N, Toftegaard J, Luhr A, Sorensen BS, Scifoni E, Kramer M. LET-painting increases tumor
radiation to achieve better tumor control for hypoxic tumors. The experiments showed that “the
radiation dose required to achieve the same response is up to three times higher in hypoxic cells
than in cells with normal oxygen levels.”3 In order to increase tumor control for these
radioresistant hypoxic tumors, this study proposed the use of LET painting with high-LET ions
such as carbon-12 and oxygen-16. It was found that tumor control probability was increased in
tumors which had a hypoxic volume of 0.5cm3 or below with the use of carbon-12 ions. Tumor
control probability was also increased in tumors which had a hypoxic volume of 1cm 3 or more
The authors of the study state that they extrapolated data from a model that was
problem with this model is that there is always room for interpretation as to what tissue is
considered to be hypoxic. This interpretation causes a lack of reliability because from study to
study, it is not guaranteed that this interpretation would be replicated the same. The study also
used the TRiP98 treatment planning system. This system was recently extended to account for
hypoxia and was experimentally validated, enhancing the validity of the study. Additionally,
since this study involved in vitro experiments, the study states that it would be beneficial to
This study is relevant to my clinical practice because it explores the use of high-LET dose
painting to gain better tumor control in hypoxic tumors. The use of high-LET radiation can
increase damage to hypoxic tumors because it is not as dependent on the presence of oxygen as
low-LET radiation is. Due to the nature of high-LET radiation, it can cause increased damage to
normal tissue, which would increase late side effects. In order to avoid some of this extra
damage to normal tissue, the use of LET painting is proposed in this study. This means that high-
LET radiation would be restricted to the hypoxic cells of the tumor while low-LET radiation
References
1. Hockel M, Schlenger K, Mitze M, Schaffer U, Vaupel P. Hypoxia and radiation response in
tumor control probability in hypoxic tumors. Acta Oncologica. 2014; 53(1): 25-32.