Increasing Tumor Control for Hypoxic Tumors

Katelyn Larger

12/6/17
Hockel M, Schlenger K, Mitze M, Schaffer U, Vaupel P. Hypoxia and radiation response in human

tumors. Seminars in Radiation Oncology. 1996; 6(1): 3-9.

Hockel et al conducted a prospective study on 44 patients who had intermediate and

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

concomitant chemoradiotherapy. There was a median follow up of 42 months post treatment.

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

will increase recurrence rates and give poorer outcomes to patients.

The authors conducted a prospective cohort study, which is a type of observational

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

patient oxygenation in general during the course of radiation treatment.

Popple RA, Ove R, Shen S. Tumor control probability for selective boosting of hypoxic

subvolumes, including the effect of reoxygenation. International Journal of Radiation

Oncology*Biology*Physics. 2002; 54(3): 921-927.

Popple et al conducted a study in order to draw qualitative conclusions on the use of

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.

This study is relevant to my clinical practice because it developed a method that

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

tumors that have hypoxic subvolumes.

Bassler N, Toftegaard J, Luhr A, Sorensen BS, Scifoni E, Kramer M. LET-painting increases tumor

control probability in hypoxic tumors. Acta Oncologica. 2014; 53(1): 25-32.

Bassler et al analyzed in vitro experiments to draw conclusions on using high-LET

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

with the use of oxygen-16 ions.

The authors of the study state that they extrapolated data from a model that was

previously published, known as the repairable-conditionally repairable (RCR) model. The

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

have in vivo experiments to back up the data.

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

would be used for the treatment of the oxygenated cells.

References
1. Hockel M, Schlenger K, Mitze M, Schaffer U, Vaupel P. Hypoxia and radiation response in

human tumors. Seminars in Radiation Oncology. 1996; 6(1): 3-9.

2. Popple RA, Ove R, Shen S. Tumor control probability for selective boosting of hypoxic

subvolumes, including the effect of reoxygenation. International Journal of Radiation

Oncology*Biology*Physics. 2002; 54(3): 921-927.

3. Bassler N, Toftegaard J, Luhr A, Sorensen BS, Scifoni E, Kramer M. LET-painting increases

tumor control probability in hypoxic tumors. Acta Oncologica. 2014; 53(1): 25-32.