Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 13, 2009
Presenter: Dr. K. Herfarth
Presenter's Affiliation: Heidelberg, Germany
Type of Session: Scientific
This presentation is a discussion of the current research projects that are ongoing at the Heidelberg heavy ion facility, as well as planned future studies. The presentation began with a discussion of data that support the use of dose escalation in the treatment of prostate cancer (Zelefsky et al. 2001). It was noted that higher doses were related with higher rates of relapse free survival, and that doses up to 81 Gy have been shown to be well tolerated. Data from Memorial Sloan Kettering (MSK) were then presented regarding patients who were treated to 86.4 Gy, which suggested that outcomes may be better and that this dose is tolerable.
Data regarding hypofractionation in prostate cancer were then presented. Due to the relatively low alpha/beta ratio seen in prostate cancer, it has been theorized that larger fractions may have greater effect on the prostate cancer with similar rectal toxicity compared with standard fractionation (Fowler et al. IJROBP 2003). It was suggested that 4.7 Gy fractions in 10 treatments could be effective with similar rectal toxicity. Data examining the use of 2.5 Gy fractions in 28 treatments were then presented suggesting that outcomes were good compared with historical controls (Kupelian 2008). Work from M.D. Anderson was then shown, which suggested that rectal toxicity appears to depend on the volume and dose that the rectum receives. It appears that large volumes of the rectum receiving a lower dose is worse than when a small amount of rectum receives a higher dose (Kuban, 2008). Other techniques to decrease rectal toxicity were then discussed, including the use of onboard imaging to check for variability in rectal filling. The use of Calypso to account for prostate motion was also discussed. Lastly, the use of an injectable matrix into the space between the rectum and prostate to decrease rectal dose was also discussed (Augmenix).
The question was then asked, can we do better by using heavy ions to treat prostate cancer? There are a number of Japanese studies which have examined the use of hypofractionated carbon ion therapy in prostate cancer. A phase I/II trial examining dose escalation in prostate cancer patients from 54 to 72 CGE using 20 treatments over 5 weeks found that there were good outcomes compared with historical controls, but there was relatively high rectal and bladder toxicity (Akakura, Prostate, 2004). A second study from Japan investigating carbon ion therapy used a dose of 66 CGE in 20 fractions (Ishikawa, IJROBP, 2006). Rectal dose was limited to less than 50 CGE, and the median follow up was 56 months. This study demonstrated good outcomes and a tolerable toxicity profile. They also found that high risk patients appeared to benefit from the addition of hormone therapy when treated with carbon ion therapy. Another study by Tsuji et al. (IJROBP, 2005) demonstrated >95% biological progression free survival at 5 years.
The current research projects at Heidelberg University were then discussed. A study was started in 2006 using a carbon ion scanning beam to boost patients with prostate cancer. Patients were treated with 18 CGE in six fractions using carbon ions, and then treated with 60 Gy using IMRT in 2 Gy fractions. However, it was noted that this study is currently on hold due to beam availability. Trials which are scheduled to open were then discussed. The first study is a prospective study to compare the use of proton therapy with carbon ion therapy for the treatment of prostate cancer. Patients to be included would be those with histologically proven prostate cancer with <20% risk of lymph node involvement. Patients would then be randomized to treatment with either 2.5 CGE fractions in 28 treatments using protons versus the same dose using carbon ions. The primary endpoint would be biochemical progression-free survival, and the secondary endpoint would be toxicity. The PLATIN trial was also mentioned, which is a five-arm study investigating the use of hormone therapy and carbon ion therapy in patients being treated definitively (2 arms), patients being treated post operatively (2 arms), and patients who require a resection after radiation (1 arm).
In conclusion, heavy ion therapy will continue to improve, and further studies are being conducted at present at Heidelberg. There are numerous clinical implications related to these trials. Heidelberg, as well as several other institutions, are comparing proton therapy with photon-based therapy, and there are a number of institutions that are already comparing the use of carbon ions with protons and photons. These studies will be critical due to the cost of both carbon ions and protons. Hypofractionation is of great interest in prostate cancer, and if an equivalent dose can be delivered safely, this may greatly improve prostate patients’ quality of life. The improved dose distribution seen with protons and carbon ion beams make their use in hypofractionation attractive. However, caution is needed, as often times treatment-related toxicity is not seen for years or even decades after treatment, and thus long term follow up is needed from these studies. However, if hypofractionation can be done safely, it has the additional benefit of potentially offsetting some of the increased cost related to proton and carbon ion therapy making its cost more comparable to IMRT.