**8. References**

230 Prostate Cancer – Diagnostic and Therapeutic Advances

Several future implications have already been discussed above. One of the most important developments for bone seeking radiopharmaceuticals will be individualized medicine. The search for an optimized balance between efficacy and toxicity will be found rather in an individualized treatment plan than in new agents. Good predictors of efficacy and toxicity are needed for treatment monitoring. Several potential candidates were described above. They may be found in clinical evaluation, imaging and several laboratory parameters. A combination of these parameters may lead to a prediction model which may be used in

Multimodality treatment has also been described above. Many combinations have potential. It has to be investigated which regimen will be most effective. Besides a direct anti-tumor effect which may be reached with chemotherapy (i.e. docetaxel), it is recognized that treatment directed to the bony environment may add to the overall efficacy of the treatment regimen. Bone seeking radiopharmaceuticals are bone-directed and may be of value in combination with other treatment modalities. Besides combinations with chemotherapy or bisphosphonates other interesting combinations may

An important other issue is the timing of treatment with bone seeking radiopharmaceuticals. The frequency and interval of sequential treatment should be considered. Bone seeking radiopharmaceuticals are mostly used as a single shot treatment. When patients respond to the treatment repeated treatment is considered. In most instances this does not happen with a planned interval in mind but rather when symptoms reappear after an initial response. In fact this might be too late. It seems better to treat patients sequentially before symptoms reoccur. This was confirmed in a randomized controlled trial in prostate cancer patients treated with two dosages of 1.1 mCi 188Re-HEDP with an interval of eight weeks compared to single shot treatment. They did not only find an improved pain response with longer duration but surprisingly an improved survival as well (Palmedo et al. 2003). Safety of repeated treatment with bone seeking radiopharmaceuticals was also confirmed (Sartor et al. 2007). This enhancement of efficacy may be attributed to chronic inhibition of osseous metabolism preventing cancer cells to thrive in the bony environment. Most other oncologic compounds are used in a repeated fashion using several cycles to reach sufficient effect. It should be investigated which multiple treatment regimen is most suitable for bone seeking radiopharmaceuticals, and whether it is safe and more effective. It may be suggested that the best result in hormone-refractory will be reached using a multimodality treatment regimen with fractionation of all treatments to be effective over a prolonged period of time.

Treatment with bone seeking radiopharmaceuticals in patients with multiple painful skeletal metastases is safe and effective when proper protocols are being used. Important improvements may be found in multimodality treatment in long-term treatment regimens and in individualized patient management. Identification of powerful indicators of toxicity and efficacy may guide patient selection and therapy monitoring to optimize the patient's outcome. This may possibly lead us beyond pain palliation towards

**6. Future prospects** 

daily practice.

**7. Conclusion** 

improvement of survival.

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**11** 

**Cancer Radiotherapy** 

 *Klinikum Offenbach GmbH* 

*1Sweden 2Germany 3USA* 

*3Department of Radiological Sciences* 

Panayiotis Mavroidis1, Dimos Baltas2, Bengt K. Lind1 and Nikos Papanikolaou3 *1Department of Medical Radiation Physics Karolinska Institutet and Stockholm University* 

*2Department of Medical Physics & Engineering, Strahlenklinik,* 

 *University of Texas Health Science Center, San Antonio, Texas* 

**Use of Radiobiological Modeling in Treatment** 

**Plan Evaluation and Optimization of Prostate** 

There are many tools available that are used to evaluate a radiotherapy treatment plan, such as isodose distribution charts, dose volume histograms (DVH), maximum, minimum and mean doses of the dose distributions as well as DVH point dose constraints. All the already mentioned evaluation tools are dosimetric only without taking into account the radiobiological characteristics of tumors or OARs. It has been demonstrated that although competing treatment plans might have similar mean, maximum or minimum doses they may have significantly different clinical outcomes (Mavroidis et al. 2001). For performing a more complete treatment plan evaluation and comparison the complication-free tumor control probability (*P*+) and the biologically effective uniform dose ( *D* ) have been proposed (Källman et al. 1992a, Mavroidis et al. 2000). The *D* concept denotes that any two dose distributions within a target or OAR are equivalent if they produce the same probability for

tumor control or normal tissue complication, respectively (Mavroidis et al. 2001).

In this chapter, the importance of the *P D* diagrams is illustrated. These diagrams provide important information by combining the radiobiological data of the organs involved with the dosimetric information of the delivered dose distribution (Mavroidis et al. 2010). It would increase the flexibility and clinical application of the *P*+ index if in its original definition the different terms related to the tumor control and normal tissue complication probabilities were accompanied by some weighting factors, which could be adjustable by the clinicians depending on the important of the different clinical endpoints used (Mavroidis et al. 2011). In practice the *P*+ index finds the pure benefit from the treatment by subtracting the normal tissue complication probabilities from the tumor control probability.

**1. Introduction** 

