*9.4.2 Remodeling is facilitated by initiating the radiotherapy of bone metastasis*

With the location of the tumor cell in the bone, begins the process of damaging its compact structure. Stromal and pro-inflammatory cells recruited by tumor cells such as macrophages, neutrophils, T cells, and mastoid cells produce and release many mediators that act on osteoblasts, osteoclasts, and nerve endings at this level. The most important is the endothelin which initiates the process of stimulating osteoblasts that releases the so-called RANKL which is an activator that initiates the maturation and proliferation of the osteoclasts. Osteoclasts promote demineralization, destruction, and bone lysis. They stimulate macrophages to produce pro-inflammatory cytokines (TNF-alpha, IL-ß, and IL6) and pain-inducing prostaglandins by binding them to receptors in neuronal sensors (**Figure 13**).

#### **Figure 13.**

*Left: Bone metastasis with the destruction of the vertebra (non-small cell lung cancer) and with the invasion of the paravertebral muscle (treated at an oncology center with a single fraction of 8 Gy). Subsequently, the patient died with only this distant metastasis. Right: Mechanisms from the initiation of bone metastasis (activation of osteoclast) followed by osteolysis and the mechanism of central pain transmission [11].*

All therapeutic interventions must be individualized and directed in order to reduce pain so that an improvement in the quality of life should be achieved, and thus, facilitate to prolongation of life with longer survival. Only by reducing pain will not be achieved an improvement in survival, this action must also be sustained by total destruction of the tumor itself. A single dose of 8 Gy applied to a single bone metastasis to a vertebral body will bring a reduction in pain, but the patient will not have a longer survival if the metastasis itself is not destroyed, which with only 8 Gy cannot be achieved. The possible right treatment could be the application of an initial dose of 8 Gy, which makes it possible to reduce pain and continue irradiation with fractional doses of 2 or 3 Gy up to a total dose equivalent to 40 Gy at the level of the vertebral body, a dose that also allows the destruction of tumor cells.

This kind of "palliation" is recommended in the guidelines and applied in clinical activity. The misunderstanding of the differentiated action of high single doses can lead only to pain control (success rate of 45%) but only for lasting few days. "Improved quality of life for only a few days" is paid for by subsequent death, due to the insufficient dose applied to control the tumor itself for years.

Bone remodeling is a continuous process initiated by the action of radiotherapy or/and bisphosphonate on osteoclasts and thus allows osteoblasts to initiate the remodeling phase with bone formation, especially at the periosteum and endosteum level. Here it should be remembered the importance of the action of the macrophage at this level called **osteomacs** which has the most important role in the "remodeling" of the bone. It should be remembered that in general the skeletal system has the capacity to maintain the stability and functional malleability of the entire bone system and that annually 10% of the bone system is renewed. So, in 10 years we take advantage of a "physiological" remodeling and maintenance of our entire bone system.

Tanaka et al. [12] reported a combined treatment with zoledronic acid and fractional radiotherapy applied to metastasis in a vertebral body, that affected the stability of the spine. The clinical result of this combined treatment in which the total dose in that fractionation allowed to stop the action of osteoclasts and initiate **osteomacs activity** with the result of "remodeling" and healing of the vertebral body using the initial matrix of the vertebral body it is shown in **Figure 14** [6].

#### **Figure 14.**

*Left: Complete remodeling of vertebral metastasis. Improvement of osteolytic metastasis from a vertebral body after administration of zoledronic acid and external radiotherapy with 28 Gy in seven fractions [12]. Right: The role of the RANKL/RANK system and the mechanism of action of Denosumab in bone pain. X = stop [11].*

#### *9.4.3 Remodeling of multiple bone metastasis with bone destruction*

Radiation therapy of multiple bone metastases and complete destruction of the right coxo-femoral joint of breast cancer in the bone pelvis is presented. Restitutio ad integrum of all bone metastases and especially of the right coxo-femoral joint with the restoration of the acetabulum was possible.

Patients with multiple pelvic bones metastases, like the one presented below, could profit from whole pelvic bone radiotherapy. The patient was irradiated with a 2 Gy daily fraction to a total dose of 40 Gy. The protection of organs at risk as the bladder, small bowel, rectum, and sigmoid was possible. Multiple lytic bone lesions and complete destruction of the acetabulum were present. Two years later all bone lesions and the acetabulum destruction were in complete restitution, as shown in the **Figure 15** [6].

#### **Figure 15.**

*Dose distribution of the whole pelvic bone radiotherapy (left side), bone reconstruction after radiotherapy (middle), and clinical situation 2 years later (right side).*

#### **Figure 16.**

*Remodeling at the vertebral body, evolution, and irradiation plan of a vertebral body metastasis.*

### *9.4.4 Remodeling of vertebral metastases*

Restoration of the shape of the thoracic vertebra after surgery and postoperative radiotherapy of bone metastasis of breast cancer in the thoracic spine at the level of T11 is shown in **Figure 16**.

In the previous images can be observed osteolysis produced by tumor cells located in the vertebral body at the beginning endosteal, which activates the osteoclasts and starts the destruction of the periosteum, compromising completely the stability of the vertebrae. In this case, 10 fractions of 3 Gy were applied, which made it possible to initiate the remodeling process and through the action of osteomacs and osteoblasts appeared "the new" remodeled bone that followed exactly the initial matrix of the vertebral body, being thus possible an ad integrum reconstruction of the final shape of the vertebral body after radiotherapy [6].

## **10. Conclusion and final remarks**

The progress in radiotherapy is a result of improved imaging methods (CT, MRI, PET/CT) and as well as developed planning and dose delivery methods as VMAT, Rapid Arc, and Tomotherapy, techniques based on individually defined target volumes. Optimal dose delivery to CTV and GTV and limited dose delivery to organs at risk as lung parenchyma, brachial plexus, myocardial tissue, and axillary vessels is now possible. Higher tumor control rates with less acute and late side effects make now possible the improvement of the quality of life [5]. Remodeling of ECM of TME should be a reality if adequate irradiation technique and proper fractionation and the total dose are optimally selected.

Radiotherapy is an integral modality of cancer treatment. Changes in TME produced by therapy have fundamental consequences and make possible the cure of cancer. These processes are spatially and temporally regulated to preserve the homeostasis of tissues and involve the interplay of different cell types. Tissue homeostasis is maintained by REMODELING of BASEMENT MEMBRANE as was noted in many of the cases presented in this chapter. Different compartments of TME are closely related to and contribute not only to tumor progression but also to its response to treatment.

We should not forget that TME is affected by different therapeutic modalities. Changes in TME make possible: reduced tumor burden, improvement of oxygenation by normalization of the vasculature, reduced radio resistance, and improvement of the access of chemotherapy and immunotherapy to the tumor.

ECM remodeling is essential and tightly regulates physiological processes in development and in restoring tissue homeostasis during wound repair.

Knowledge regarding ECM dysregulation in the design of anticancer therapy is necessary. With the advances and interdisciplinary integration, progress in an anticancer strategy targeting TME and ECM components could improve the quality of life of cancer patients.

*The Remodeling in Cancer Radiotherapy DOI: http://dx.doi.org/10.5772/intechopen.102732*
