The Treatment of Prostate Cancer to Limit the Dose to Organs at Risk

Katelyn Larger

04/24/17
Fang P, Mick R, Deville C, Both S, Bekelman JE, Christodouleas JP, Guzzo TJ, Tochner Z,

Hahn SM, Vapiwala N. A case-matched study of toxicity outcomes after proton therapy and

intensity-modulated radiation therapy for prostate cancer. Cancer. 2015; 121(7), 1118-1127.

The authors of this article discussed genitourinary (GU) and gastrointestinal (GI)

toxicities when comparing IMRT to proton therapy treatment of the prostate. 188 patients with

prostate cancer (with no extraprostatic disease or pelvic lymph node involvement) were matched

according to their age, risk group, and prior GU or GI disorders. Half were treated with IMRT

and the other half were treated with proton therapy. By using the International Prostatic

Symptom Scale (IPSS), GU and GI toxicities were scored on a scale of 0-5. Majority of the 188

patients reported a score of 1 or less for acute and late GU and GI toxicities for both IMRT and

proton therapy. It was found that dose volumes to the prostate did not differ significantly

between the two groups and that bladder and rectum doses were significantly lower in the proton

therapy group. While the dose to the bladder and rectum were reduced in the proton therapy

group, after adjusting for confounding and predictive variables the risk for GU and GI toxicity

did not differ significantly between the two treatment groups.

The authors state that the study conducted used matched pairing of IMRT and proton

therapy patients with prostate cancer. 188 patients were matched from a greater pool of patients.

Conducting a matched study reduced patient selection bias, which was most likely done due to

the fact that the study could not use random sampling. Since the participants had to have prostate

cancer, the study was required to use quota/purposive sampling instead of random sampling,

which added to selection bias. The study was able to increase the internal validity by using single

blinding when matching patients. The study did fall short, however, when correcting for
confounding variables that could affect the studies outcome. The study states that the “internal

validity suffered from substantial confounding as well as exposure and misclassification biases.”1

The fact that confounding variables were not corrected for makes the data produced by the study

not as reliable and also reduces the internal validity of the study.

This study is relevant to my clinical practice because toxicity outcomes of IMRT versus

proton therapy when treating prostate cancer were discussed. Decreasing GU and GI toxicity

when treating prostate cancer is important when looking at patient quality of life after treatment.

This study originally found a significant difference in dose to the bladder and rectum when

comparing IMRT to proton therapy, but after correcting for confounding variables there was no

longer any significance. I think further studies need to be conducted that control for confounding

factors. Using the results from this study, I do not think using proton therapy to treat prostate

cancer would produce much of a difference in patient outcome in regards to GU and GI toxicity.

Sonny DY, Herfarth KK, Uhl M, Eble MJ, Pinkawa M, Van Triest B, Kalisvaart R, Weber DC,

Miralbell R, Deweese TL, Ford EC. A multi-institutional clinical trial of rectal dose reduction

via injected polyethylene-glycol hydrogel during intensity modulated radiation therapy for

prostate cancer: analysis of dosimetric outcomes. International Journal of Radiation

Oncology*Biology*Physics. 2013; 87(1), 81-87.

The authors of this article discussed the use of a prostate-rectum spacer to reduce dose to

the rectum when treating prostate cancer. 45 patients that had prostate cancer had CT scans and

then were rescanned after a hydrogel spacer had been injected. After the scans were done, two

IMRT treatment plans were created of each patient: one with the spacer and one without. These
plans were then compared and a significant reduction in rectal dose was seen across all levels of

dose (volume receiving 75Gy through volume receiving 10Gy in 5-10Gy increments).2 When the

P value is below .05, it is significant. The P value was under .02 for all levels. These results were

still considered significant when taking into account the fact that there was variability in plan

conformity, target definitions, and injection results.

The study that was discussed in this article is a nonrandomized clinical trial. It was not

able to use randomization when selecting participants because the patients had to have prostate

cancer. A quota/purposive sample had to be done, which consequently reduced the external

validity of the clinical trial. The study controlled for confounding variables by using IMRT and

similar beam arrangements for both sets of treatment plans, which improved the internal validity

of the clinical trial. There were some factors that could not be controlled, such as the

reproducibility of the injections of the hydrogel spacers as well as patient bladder size between

the first and second CT scans. These two things may make it hard to reproduce the study exactly,

which would reduce the reliability. The authors also state that there is a possibility that there was

planning bias with more effort placed into reducing the rectal dose for the post injection plan.2

This bias could have been avoided if the study had blinded those who were responsible for

producing the treatment plans.

This study is relevant to my clinical practice because it explores the use of hydrogel

spacers with IMRT to reduce the dose to the rectum when treating prostate cancer. Reducing the

dose to the rectum is one of the most challenging aspects of treating the prostate. Being able to

reduce the dose to the rectum would be very beneficial to the future treatment of prostate cancer

and would improve the outcomes of those being treated. I do think that there are some things that

need to be explored more in regards to the spacers. The study fails to discuss the safety or
limitations of these spacers, which I think should be studied if it has not been already. I also

think that studies on how fast these spacers absorb into the patient would be important due to the

length of most prostate treatments. It would not be good for treatment if the spacers changed

volume throughout the treatment. Other than these concerns, I think that the spacers seem like

they could significantly change the dose that the rectum will receive in patients being treated for

prostate cancer.

Quigley MM, Mate TP, Sylvester JE. Prostate tumor alignment and continuous, real-time

adaptive radiation therapy using electromagnetic fiducials: clinical and cost-utility analyses.

Urologic Oncology: Seminars and Original Investigations. 2009; 27(5), 473-482.

The authors of this clinical trial discussed the use of calypso to aid in the treatment of

prostate cancer in order to reduce the dose to the surrounding healthy tissue. The authors state

that by only using marks on the skin and imaging prior to treatment, there is still “uncertainty as

to the exact tumor location during radiation”3 because of possible patient and/or organ movement

during treatment. The clinical trial included 41 patients who were diagnosed with early stage

prostate cancer. These patients were treated with EBRT and had fiducial markers implanted for

the use of calypso. There was a direct comparison of the calypso done with a currently marketed

kV x-ray positioning system. The comparison found a mean difference of displacement of 3mm

between the two systems.

The clinical trial ran into the problem of not being able to use random assignment due to

the nature of the study. Because patients had to be diagnosed with prostate cancer, a

quota/purposive sample had to be done, which added selection bias and decreased the external
validity of the clinical trial. The transponders, which were used in conjunction with calypso were

functional over the entirety of the study, making sure that the data collected from them is

reliable. The biggest thing that this clinical trial did not do is have long term follow-ups of

patients post treatment. Because they do not have a follow-up it is hard to know the reliability of

the results of the study. The authors are assuming that because the rectum was less affected by

radiation that the patients had less late term toxicity. I believe that long term follow-up should be

included in the study in order to verify this information.

This study is relevant to my clinical practice because it explores the use of calypso being

paired with the treatment of prostate cancer in order to reduce the dose to the rectum. Calypso

continuously monitors the placement of the prostate during treatment and stops treatment if the

prostate were to move out of a certain range. The authors state that the use of calypso “allows

clinicians to reduce treatment margins and to deliver higher doses of radiation in fewer

treatments for prostate cancer.”3 With the information from this study, it seems that calypso

helps with positioning of the prostate and, therefore, is able to reduce the dose to the rectum. I

would say that the use of calypso would be a worthwhile technology to incorporate into the

treatment of prostate cancer. But, as stated before, the study does not include long term follow-

up, which makes it hard to know for sure if the use of calypso reduces long term toxicity to the

rectum.
 References

1. Fang P, Mick R, Deville C, Both S, Bekelman JE, Christodouleas JP, Guzzo TJ, Tochner

Z, Hahn SM, Vapiwala N. A case-matched study of toxicity outcomes after proton

therapy and intensity-modulated radiation therapy for prostate cancer. Cancer. 2015;

121(7), 1118-1127.

2. Sonny DY, Herfarth KK, Uhl M, Eble MJ, Pinkawa M, Van Triest B, Kalisvaart R,

Weber DC, Miralbell R, Deweese TL, Ford EC. A multi-institutional clinical trial of

rectal dose reduction via injected polyethylene-glycol hydrogel during intensity

modulated radiation therapy for prostate cancer: analysis of dosimetric outcomes.

International Journal of Radiation Oncology*Biology*Physics. 2013; 87(1), 81-87.

3. Quigley MM, Mate TP, Sylvester JE. Prostate tumor alignment and continuous, real-time

adaptive radiation therapy using electromagnetic fiducials: clinical and cost-utility

analyses. Urologic Oncology: Seminars and Original Investigations. 2009; 27(5), 473-

482.