The Remodeling in Cancer Radiotherapy

Abstract

Remodeling is a new concept used to describe the effects of cancer cells properties to modify the extracellular microenvironment (ECM) to favor the proliferation, invasiveness, migration, and metastatic potential of the tumor. All these characteristics are determined by both the direct and indirect interactions of the cancer cells, with components of their microenvironment. The remodeling concept described in this chapter considers the changes produced by the local treatment alone, or in combination with systemic treatments on local advanced primary tumors or bone metastases (vertebral body or pelvic bones). The cases presented considered locally advanced cancer that disturbed the local anatomy at different levels as chest wall, the skin of the face, eye orbit, and vertebral or pelvic bones. Changes in the extracellular microenvironment, after the applied treatment, normalized all or only in special parts of the extracellular matrix, with a remodeling organ-specific process to the treated tumor bed. In some of these cases was reached a restitutio till to the most important component, the basal membrane. The four phases of the healing process of lesions produced by radiotherapy (the hemostasis, inflammatory, proliferative, and remodeling phase) and the possible changes at the level of ECM were here analyzed.

1. Introduction

There has been a massive shift in our approach to understand the biology of solid tumors in the last decades. While research centered for a long time nearly exclusively on the individual tumor cells, the process leading to their transformation, or conveying their malignancy, and the tumor as a complex organ, meanwhile the term tumor microenvironment (TME) is used, to describe the entirety of the tumor components that are not malignant by themselves. Thus, the TME consists of the tumor vasculature, connective tissue, infiltrating immune cells, and the extracellular matrix (ECM). Increasingly, all these individual components of the TME became the focus of new research communities within the fast-growing cancer field. The ECM is probably the component of the TME that initially received the least attention, but this also changed considerably over the last decade. The numerous articles have, bit by bit, complemented our understanding of the tumor ECM and its role in malignancy and response to therapy [1].

Cancer represents a dysregulation of the body’s normal, controlled cellular programs. Malignant cells are able to confer enhanced proliferation, resistance to apoptosis, or motility that allows tumors to metastasize (colonize) the distant organs, which is the most lethal aspect of cancer. Tumor cells also require the collaboration of the tumor microenvironment (TME) for growth and progression [2].

Tumor hypoxia or increased inflammation in the TME modifies tumor ECM components and increases collagen deposition, ECM density, and stiffness. In addition, it is known that adhesion to the dense ECM modifies the radiation sensitivity of cancer cells.

Radiotherapy is considered as one of the potentially curative modalities for cancer. The tumor ECM might play a pivotal role in resistance and recurrences to radiotherapy in different cancers.

2. Remodeling as part of cancer development

Recent concepts of ECM remodeling shaping tissues for tumor cells to invade and metastasize during cancer development are discussed in the literature. Increasing understanding of these processes opens up the possibilities of therapeutic approaches to target the aberrant ECM and/or the underlying pathologic mechanisms of its remodeling and prevent malignancy. Changing single elements can turn over the delicate balance of ECM remodeling events.

It is not surprising that cancer cells modify all four ECM remodeling mechanisms, creating a cancer-supporting matrix that actively contributes to the pathology of the tumor.

The tumor microenvironment regulates cancer initiation, progression, and response to therapy. The immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. Potiron et al. [3] have shown that RT-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy.

Radiotherapy (RT) induces vascular remodeling, accompanied by decreased hypoxia and/or increased perfusion. In a low dose regime (2 Gy/fraction) it is a common effect. Intra-tumoral doxorubicin distribution was improved.

These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution and could be an alternative chemo sensitization strategy.

Even in the era of targeted therapies, the limited distribution of drugs remains a challenge. This is part of the abnormal tumor vasculature, which has developed as a function of anarchic tumor expansion. The resulting network is tortuous, over-branched, variable in diameter, and abnormally permeable [3]. The consequence is reduced blood flow. Additional tumor cell density creates a compressive environment that blunts the endothelial lumen and limits the extravasation of molecules because of high interstitial pressure. The abnormal vasculature generates hypoxia and acidosis, leading to metabolism switch and the emergence of therapeutic resistance. Moreover, destructing angiogenesis or altering vascular maturation could favor metastasis.

External radiotherapy is today a standard treatment for about half of cancer patients, either alone or in combination with surgery and/or chemotherapy, given in a fractionated regimen of about 2 Gy/day, over a course of several weeks, to achieve a total dose of 32–80 Gy, depending on tumor type and location. Endothelial deaths after irradiation might be trigger only above 5–10 Gy.

Ultimately, RT leads to the destruction of target tissues. However, this process is gradual and allows time for complex biological phenomena to occur. Potiron et al. [3] have shown in a xenograft prostate model that RT induces perivascular coverage of tumor micro-vessels.

Pericytes belong to a versatile cell population, whose function and origin are still under debate. Their interaction with endothelial cells is dynamic during vascular development and maturation. The lack of pericytes impairs vascular function and favors metastasis. Whether pericytes contribute to upregulating perfusion in a radiotherapy context is not completely elucidated. The function of pericytes in regulating blood flow is currently questioned [3].

3. Target volume definition, clinical target volume, and radiotherapy

The treatment of locally advanced cancers patients is a subject of debate in the last decades. A complex treatment including surgery, chemotherapy, hormone therapy, and radiotherapy is a standard today. New concepts had to be developed since the progress in diagnostic methods, tumor characterization, and progress in treatment delivery (more aggressive surgery and radiotherapy) made possible new approaches for locally advanced cancers.

In recent decades, tumor imaging by the introduction of computer tomography (CT), magnetic resonance imaging (NMR), and of positron emission tomography (PET/CT) made possible real progress in radiotherapy. From the 2D radiotherapy standard routine, for example, in breast cancer radiotherapy, a transition to 3D radiotherapy was possible. The high frequency of acute and late side effects to the normal structures around the real target volume (the breast tissue, chest wall, and lymphatic areas as axilla, internal mammary chain, and supraclavicular lymph nodes) made necessary new developments. The most important step forward was realized by the introduction of the concept of the anatomical defined clinical target volume (CTV) which included the microscopical disease and the gross tumor volume regarding the macroscopic visible tumor (GTV). The normal tissues around the above-defined target volumes were the loco-regional lymphatics (axillary nodes, internal mammary chain node, and the supraclavicular lymphatics), the brachial plexus, the lung tissue, the myocardium, and the ribs are so, well visualized. The concept of target volumes and real advanced conformal radiotherapy to apply the necessary curative dose to the CTV and GTV and to reduce the dose delivered to the organs of risk was developed and routinely applied, in the late eighties, by the team conducted by professor W. Bohndorf at the University of Würzburg, Germany. The initial concept of target volume definition was published by Richter and Bohndorf [4]. The development of conformal irradiation techniques to cover the CTV and GTV and to reduce the applied dose to the organs at risk was realized by the department of medical physics conducted by professor Richter (Figure 1) [6].

Figure 1.

PTV (planning target volumes) (left side), [5] and CTV and GTV and the organs at risk (middle and right side) for advanced breast cancer radiotherapy [6].

Reducing the irradiated volume by irradiation of a well-defined GTV (gross tumor volume) and CTV (clinical target volume) made it possible for the application of larger total dose of irradiation and a reduction of the acute and late side effects. These irradiated volumes included the tumor microenvironment (TME) which contains the tumor cells and the remodeled tissue now defined as the extracellular microenvironment (ECM).

4. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy

Solid tumors are complex organ-like structures, that consist not only of tumor cells but also of the vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differ significantly from that of normal organs. Intra-tumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence the malignancy and growth of the tumor but also its response toward therapy. Understanding of particularities of the ECM in the solid tumor is required to develop approaches to interfere with its negative effect.

In this chapter, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radiotherapy [1].

The effect of ionizing radiation on cells is also strongly dependent on their oxygenation status. Hypoxia significantly impairs the effectiveness of radiotherapy.

5. Remodeling, cellular aspects at the level of the extracellular matrix

The influence of ionizing radiation at the tumor tissue and cell level and the processes of reducing the side effects of radiation are schematically represented in Figure 2.

Figure 2.

Schematic representation of radiation action at the tumor cell level (at the bottom) and of the remodeling and scarring process (at the top of the figure) [7].

At the top of the image are represented the four phases of the healing process of lesions produced by surgery or radiotherapy namely the phase of hemostasis, inflammatory phase, proliferative phase, and the remodeling phase.

At the bottom of the image are shown schematically the biological processes as a result of the action of radiation on the tumor DNA and due to double-stranded lesions that are irreversible, which finally facilitates the destruction of tumor cells by initiating the process of cell death called apoptosis. This explains how local tumor control is possible. Optimizing this process of tumor destruction and restoring the structures of the peritumoral tissue makes possible the remodeling process in which the healing process is present [6].

The role of the extracellular matrix and cellular regulators in the plasticity of tumor cells are schematically rendered in Figure 3. The destruction of the tumor following irradiation makes it possible to restore the basal membrane and sometimes even remodeling with restitutio ad integrum in the tumor bed is possible.

Figure 3.

Schematic representation of pathophysiological processes that demonstrate the cellular plasticity of tumor cells in the invasion process with tumor progression and metastasis (on the left side) [8] and restoration of the basal membrane and epithelium after tumor destruction by irradiation (on the right side).

Tissue restoration ad integrum after the destruction of malignant tumor and restoration of the basal membrane is shown below [6].

6. Remodeling of normal tissue to TME

In the next three pictures, we visualize the remodeling process from “normal” ECM of the normal state of the rectum to the appearance of the tumor microenvironment (TME), with two well-defined parts: the proliferative well-vascularized peripheral one and a central necrotic part (in the middle). Six weeks after neoadjuvant radio-chemotherapy, a partial remission with a complete disappearance of the well-vascularized macroscopic part of the tumor was reached (right) and a remnant scar at the site of the necrotic part of the treated primary rectal cancer was noted.

The representation of the complex process from a normal rectal mucosa state (left picture) to the state in which rectal cancer with its central necrotic part and the peripheral well-vascularized part (in the middle), under neoadjuvant radio-chemotherapy was reduced to scar tissue (right picture) is shown in Figure 4. This is the visualized tumor response after 56 Gy was applied in 28 fractions on the macroscopic visible tumor (in the middle). The histologic examination of the scar revealed only remnant tumor cells in the lymphatics (LVI). One year later, the patient developed multiple brain metastases.

Figure 4.

Normal rectal mucosa before tumor appearance (left), with macroscopic tumor (middle) and 6 weeks after radio-chemotherapy (right) and before surgery.

Above is a schematic representation of the ECM at the level of the normal rectum (left side), of the tumor microenvironment (TME) of the rectal tumor (in the middle), and the “remodeled” TME with the complete destruction of the tumor now “remodeled ECM” and a recovered basal membrane (right side) (Figure 5).

Figure 5.

Schematic representation of the ECM in normal tissue (left), TME in tumor tissue (middle), and ECM modified after radiation therapy (right) [1].

The “Remodeled” ECM after treatment became more abundant, denser, stiffer, with more fibroblasts and collagen.

7. Wound healing and tissue repair process

Besides the tumor destruction by radiotherapy which includes the remodeling process to normalize the ECM, in which the tumor cells were killed, an additional process defined as wound healing, that includes the process of restauration of the processes produced by the irradiation of the normal tissues around the tumor, or in the tumor bed, described as acute and late side effects is present.

The complexity of the “healing” after surgery and the tissue repair process after radiotherapy, with the representation of the 4 phases of healing that are partially overlapping, is shown in the figure (Figure 6).

Figure 6.

Left side: Stages of the process of healing after surgery and radiotherapy with their overlapping (on the time scale): Inflammatory phase, proliferation, and tissue remodeling with collagen accumulation in the terminal phase [9]. Right side: Overlapping of wound healing [10].

8. “Remodeling” at the vascular level of malignant tumors

The local tumor progression is also facilitated by the production of a new vascularization with “neogenesis vessels” as shown in Figure 7. The neoformation vessels have an increased permeability, that facilitates the process of remote metastasis. At the tumor level occur several processes such as angiogenesis, lymph angiogenesis, vascular permeability, and all the consequences of these processes (tumor hypoxia, vascular fragility, aggressiveness) [6].

Figure 7.

Processes induced at the tumor vascular level and the possible vascular “normalization” through therapy (chemotherapy and radiotherapy) [2].

The action of radiotherapy at the level of tumor vascularization allows a normalization, that is, a vascular “remodeling” with all the advantages resulting from it (better oxygenation of tissues, more efficient action of cytostatics and radiation, reduction of hemorrhages).

9. Clinical aspects of remodeling

9.1 Remodeling of a skin tumor

We present here the clinical evolution of a basal cell carcinoma (basalioma) located on the face of a 100-year-old patient (Figure 8).

Figure 8.

The evolution of the remodeling of a basal cell carcinoma at the level of the right temple. Tumor before and during the application of local electron radiotherapy (flap applied to the irradiated area). After applying the first seven fractions of 2 Gy, the next 6 days were applied two daily fractions of 3 Gy (6 hours apart). The last 10 fractions of 2 Gy were applied until the total dose of 70 Gy was reached.

This case demonstrates the ability of “remodeling” at the level of this skin tumor and of the healthy peritumoral tissue, when the primary tumor is irradiated with a high total dose and fractionation that allows tumor control and does not produce side effects on these structures at high risk of the applied dose. In this case, the healing action was initiated and completed by the activity of macrophages and the stimulation of fibroblasts present at this level with a role in limiting side effects.

The action of fibroblasts contributed to the remodeling process with a favorable final result, in which not the slightest signs of scarring can be seen. Thus, it was possible to “remodel” at this level all the structures initially involved and disturbed through the tumor process. The skin, including the basal membrane, was completely restored, without the formation of a scar, acute skin side effects have been reduced.

9.2 Remodeling of an orbital tumor

The treatment of patients with advanced local orbital and facial cancer has been a much-debated topic in recent decades. At the end of the last decade, the complex treatment has included radical surgeries such as enucleation, reconstructive plastic surgery, chemotherapy, and radiation therapy. All these interventions were accompanied by accentuated side effects. New concepts could be developed due to advances in the diagnostic methods, tumor characterization, and the progress in the application of treatment (conservative surgery or high-dose radiotherapy) for cancer located in the orbit and the soft parts of the face.

We are going to present here the clinical evolution of an orbital advanced cancer and infiltration of the facial skin, in a 90-year-old patient, who presented in our department. This patient was treated with IMRT radiotherapy (intensity-modulated radiotherapy) with TOMOTHERAPY at the POLISANO Radiotherapy Center, Sibiu. Histopathological and immunohistochemical examination classified the lymphoma as a B-cells non-Hodgkin’s lymphoma (NHL). The patient had two locations, one on the right orbita and the other suborbital and paranasal on the left side. Both locations were irradiated at the same time. A complete clinical remission was obtained for both locations.

The frequency of orbital tumors is low, representing only 0.1% in general and only 20% of all orbital diseases. The most common type of orbital tumor is non-Hodgkin’s lymphoma. It generally manifests at the level of the ocular appendages, in 45–75% of cases being the extranodal lymphoma of the marginal area. Follicular lymphoma occurs in 15–30% of cases and diffuse B-cell lymphoma occurs in only 10% of cases. From a topographic point of view in 30–80% of cases, the conjunctiva is affected, in 10–50% the retrobulbar tissue, and in 10–55% the lacrimal gland. Radiotherapy is the method of choice in the treatment of orbital lymphomas. Multiple studies have reported satisfactory results by applying total doses between 24 and 46 Gy in standard fractionation with 1.8–2.0 Gy per fraction. The average total dose applied is 32 Gy.

The anatomy of the orbit and the extreme radio sensitivity of the various components of the orbit are a challenge for radiotherapy and radiotherapist. The orbital tumors occupy the space between the eyeball and the bony wall of the orbit. These include tumors of the eye that invade the orbit as well as ancillary structures such as sinuses, orbital bones, and the central nervous system.

9.2.1 Radiotherapy of an orbital tumor

The case of the 90-year-old patient demonstrates the capacity of “remodeling” that exists in healthy peritumoral tissues when the primary tumor is irradiated with a high total dose and fractionation that allows tumor control and does not produce side effects in organs and structures at high risk at the applied dose. In this case, the healing action was initiated and completed by the activity of macrophages and the stimulation of fibroblasts present at this level with a role in limiting side effects. The action of fibroblasts contributed to the remodeling process with a favorable final result, in which not the slightest signs of scarring are seen. So, it was possible to “remodel” at this level all the structures initially involved in the tumor process: the patient’s eyeball with the soft parts of the orbit and the facial skin. The skin is completely restored without the formation of a scar. Acute skin side effects have been reduced.

In the healing process, the role of macrophages is to remove damaged tumor cells by double-stranded damage to tumor DNA. In this case, the process of fibrosis at the level of the tumor bed was not noticed. The target volume had two components, namely the macroscopic tumor evaluated by imaging using a CT examination with and without a contrast agent and an MRI examination, also with and without a contrast agent. The irradiation plan was performed and subsequently applied at a TOMOTHERAPY machine (Polisano Center in Sibiu) developed under the instructions of Dr. Adrian Moga.

There is a wide spectrum of radiation tolerance between the various components of the orbital region. While the lens and the lacrimal gland are the most sensitive and their functionality is profoundly affected by doses above 10 Gy in standard fractionation, other structures such as the optic nerve tolerate doses up to 40–46 Gy.

The initiation of the radiological treatment was performed by performing a CT examination with the necessary means of contention. The irradiation plan with the information on the applied doses and at the level of the so-called radiosensitive structures DVH (dose-volume histogram) are reproduced in Figure 9.

Figure 9.

Delineation of the macroscopic tumor masses by GTV (gross tumor volume) corresponding to the two tumor manifestations (right orbit and left suborbital and paranasal lesion). Irradiation plan with isodose distribution and volume dose histogram (DVH). The macroscopic tumor (GTV) obtains the maximum dose over the entire volume while the OR (organs at high risk of irradiation) such as the right and left eyeballs are underdosed, thus being protected to the maximum.

The response to radiotherapy of the 90-year-old patient with an orbital tumor, non-Hodgkin’s lymphoma, manifested in the soft parts of the face and the right orbit, with the initial clinical situation until the complete response after radiotherapy is shown in Figure 10.

Figure 10.

Left: Anatomical details at the level of the orbit and of the cheek. Right: Orbital tumor and invasion of the skin of the face (peritumoral infiltrative process and huge area of necrosis) before starting the radiation and after completion of radiation therapy with “Remodeling” ad integrum (preserved own eyeball).

9.3 Remodeling of a locally advanced breast cancer

We present here the clinical situation of a local advanced breast cancer in women aged 82 who presented in our department and was treated by a conformal 10 fields of radiotherapy (Figure 11).

Figure 11.

The clinical case of a local advanced breast cancer with sternal infiltration and internal mammary chain lymph node involvement before and after high dose radiotherapy. Upper line: Clinical response to a high total dose of 72 Gy. Lower line: (left) in the primary series a total dose of 50 Gy in 25 fractions and (right) an additional boost of 22 Gy in 2 Gy fractionation was applied.

This case demonstrates the “remodeling” ability that exists in healthy tissues surrounding the tumor bed. In this case, the healing action was completed by macrophages and fibroblasts present at this level. The action of fibroblasts has contributed to the collagen formation process to be present and to make possible “remodeling” at this level of all the structures initially involved: skin, ribs, pericardium, sternum, etc. Visible is the presence of an extensive area of collagen in the extensive scar.

In the healing process, the role of macrophages was the removal of damaged tumor cells by the double-strand lesion at the level of tumor DNA. There was no pulmonary fibrosis that usually accompanies post-radiotherapy healing [6].

9.4 Remodeling of bone metastases

Radiotherapy is the most important treatment for bone metastases. Long-term local control of the disease is possible.

In Figure 12 we present a patient treated over years with bone metastases throughout the skeleton and taking advantage of radiotherapy with standard doses of 2 Gy per fraction and an accumulated total dose of 676 Gy to achieve tumor control. A survival of almost four years was possible. The primary tumor in the breast was treated by surgery followed by adjuvant chest wall radiotherapy in 1979. The first bone metastasis was irradiated in 8/1993 and the last palliative radiotherapy was applied in 5/1997 [6].

Figure 12.

Irradiated regions of the bone skeleton in a patient with a breast tumor who survived 4 years with radiation therapy.

9.4.1 Bone metastasis and remodeling processes in the extracellular matrix

Cellular processes at the level of bone metastasis: after homing of tumor cells endosteal, the tumor cells release endothelin, which, through its appropriate receptors, interact with osteoblasts to stimulate their proliferation. This leads to the formation of new bone and growth, but such bone is weak and prone to fracture. Activated osteoblasts release receptor activator, that signals the proliferation and maturation of osteoclasts. They stimulate macrophages to produce pro-inflammatory cytokines and prostaglandins, which induce pain by binding to their receptors on sensory neurons.

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).

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.

Figure 16.

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

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.