Brain Metastases from Primary Tumors, Volume 3: Epidemiology, Biology, and Therapy of Melanoma and Other Cancers

States

Volume 1—Contributions

1. Brain Metastases

2. Epidemiology of Central Nervous System Metastases

3. Involvement of the CXCL12/CXCR4/CXCR7 Axis in Brain Metastases

4. Non uniform Distribution of Metastatic Intracranial Tumors in Cancer Patients

5. Targeting Angiogenesis, Enhancing Radiosensitization and Crossing the Blood–Brain-Barrier for Brain Metastases

6. Second Malignancies in Children Following Treatment for Neuroblastoma

7. The Role of Chemotherapy in Metastatic Brain Tumors

8. Multiple Metastases to the Brain from Primary Cancers: Whole Brain Radiotherapy

9. Synovial Sarcoma Metastasized to the Brain

10. Multiple Small Brain Metastases with Limited Focal Brain Edema from Non small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations

11. Brain Metastases of Patients with Lung Adenocarcinoma: Epidermal Growth Factor Receptor Mutations and Response to Whole-Brain Radiation Therapy

12. Metastatic Spread of Lung Cancer to Brain and Liver: Role of CX3CR1

13. Solitary Brain Metastasis from Non small Cell Lung Cancer: Treatment with Linac-Based Stereotactic Radiosurgery

14. Brain Metastases from Non small Cell Lung Cancer: Clinical Benefits of Erlotinib and Gefitinib

15. Bispecific Targeted Toxin DTATEGF Against Metastatic NSCLC Brain Tumors

16. Intracranial Disease in Patients with Non small Cell Lung Cancer: Treatment with Erlotinib

17. Radiation Management of Synchronous Brain Metastases from Non small Cell Lung Cancer

18. Brain Metastasis After Prophylactic Cranial Irradiation in Patients with Small Cell Lung Cancer

19. Brain Metastasis from Small Cell Lung Cancer with High Levels of Placental Growth Factor

20. Brain Metastases from Lung Cancer

21. Lambert-Eaton Myesthenic Syndrome and Brain Metastasis from Occult Small Cell Lung Carcinoma: A Clinician’s Perspective

Volume 2—Contributions

1. Brain Metastasis from Solid Tumors

2. The Role of Surgical Resection for Metastatic Brain Tumors

3. Whole-Brain Radiotherapy for Brain Metastases: Is the Therapeutic Window Enlarging?

4. Brain Metastasis in Patients with Non small Cell Lung Cancer: Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

5. Brain Metastasis from Non small Cell Lung Cancer: Use of Epidermal Growth Factor Receptor and HER2 Status for Targeted Therapy

6. Brain Metastases from Non small Cell Lung Cancer: Current Evidence in Management Using Tyrosine Kinase Inhibitor and Whole-Brain Radiation Therapy

7. Brain Metastasis in Patients with Non small Cell Lung Cancer: Immunohistochemical Markers

8. Brain Metastasis from Breast Cancer: Molecular Mechanisms

9. New Targeted Therapies for Brain Metastases from Breast and Lung Cancer and Melanoma

10. Breast Cancers with Brain Metastases

11. Brain Metastases in Melanoma Patients: Treatment with Adjuvant Postoperative Whole-Brain Radiotherapy

12. Melanoma Progression in the Brain: Role of Pericytes, the Basal Lamina, and Endothelial Cells in Tumor Vascularization

13. Brain Metastases from Esophageal Cancer in the Presence of HER-2 Overexpression

14. Brain Metastasis from Renal Carcinoma: Locoregional and Systemic Treatments

15. Gastrointestinal Cancer and Brain Metastasis Outcomes and Management

16. Brain Metastasis of Colorectal Cancer: Microenvironment and Molecular Mechanism

17. Brain Metastasis from Nasopharyngeal Carcinoma

Part I

Molecular Mechanisms

Outline

Chapter 1 Introduction

Chapter 2 The Management and Biology of Metastatic Cancers to the Brain

Chapter 3 Melanoma Metastases Are Underrepresented in Cerebellum Compared with Metastases from Colorectal Cancers

Chapter 4 Risk Reductions of Recurrence and Mortality in Melanoma Patients Using IFN-α

Chapter 5 Brain Metastases from Melanoma

Chapter 6 Pathobiology of Brain Metastases: Molecular Mechanisms

Chapter 7 Role of CDKN2A Mutations and Other Relevant Genes in Melanoma Predisposition

Chapter 8 The Role of the Receptor for Advanced Glycation End Products in Malignant Melanoma

Chapter 9 Hydrogen Sulfide Pathway and Cancer

Chapter 10 Brain Metastasis from Esophageal Cancer

Chapter 1

Introduction

M.A. Hayat

Abstract

Each of the ~10¹³ cells, including brain cells (86 billion), in the human body is subjected to tens of thousands of DNA aberrations. If these lesions are not repaired or removed immediately, the result would be mutations, some of which may threaten cell or organism viability. As if this attack is not damaging enough to health, primary cancer transmission from various organs to the brain result in serious health problems, which are discussed in this chapter. Specifically, dissemination of cancer cells from breast and esophagus and melanoma to the brain (intracranial brain cancer) is detailed here. Accumulation of DNA lesions in the brain is associated with neurodegenerative disorders such as ataxias, Alzheimer’s, Parkinson’s, and Huntington’s diseases.

Clinical treatments (surgery, stereotactic radiosurgery, whole brain radiation therapy, and chemotherapy) for patients with metastatic brain cancer are discussed. A large number of human monoclonal antibodies used for patients with melanoma and cancers of breast and esophagus are also discussed. For patients with esophageal cancer, esophagectomy is presented. Advantages and limitations of each treatment used alone or in combination are included. Mutations in melanoma are described.

Keywords

Brain cancer; esophageal cancer; metastasis; melanoma; human monoclonal antibodies; neurodegenerative disorders

Outline

Melanoma 7

Treatment 8

Breast Cancer 12

Treatment 12

Esophageal Cancer 14

Treatment 15

References 17

In human history, immortality has been one of the most cherished, but unrealistic, wishes of human beings. Indeed, we are still hoping to cure serious diseases to achieve immortality, but medical treatments have been proven to result in less than impressive success. An excessive emphasis on medical therapies has diverted attention from nontherapeutic efforts to prolong healthy life, that is, to slow down the inevitable aging process. In fact, unfortunately some treatments may shorten life instead of prolonging it.

Aging has so permeated our lives that it cannot be stopped, but it can be delayed. Under the circumstances, time is our only friend. Because the aging process is accompanied by disability and disease (e.g., cancer and Alzheimer’s and Parkinson’s conditions), and cannot be prevented, it seems that slow aging is the only way to have a healthy longer life. In general, aging can be slowed down by not smoking or chewing tobacco, by preventing or minimizing perpetual stress (anger, excessive competition), by abstinence from alcoholic beverages, by having regular exercise and sleep, and by having a healthy diet. There is no doubt that regular physical activity is associated with a reduced risk of mortality, and contributes to the primary and secondary prevention or delay of many types of diseases, including cancer. Discipline is required to attain this goal.

Cancer constitutes a group of diseases characterized by uncontrolled growth and spread of abnormal cells, and if the spread is not controlled, it can result in death. Cancer is caused by both external factors (tobacco, chemicals, radiation, and infectious organisms) and internal factors (inherited mutations, somatic mutations, hormones, and immune conditions) (WHO). Perpetual stress also plays a part in the development of cancer and other diseases. Although anyone can develop cancer, the risk of developing cancer increases substantially with age.

Incidence of cancer is increasing due to aging and growth of the world’s population despite the introduction of better and faster diagnosis and more effective treatments. In 2012, 14.1 million new cases of cancer were diagnosed worldwide, and 8.2 million people died; approximately, 32.6 million people were living 5 years after being diagnosed with cancer (Center for Disease Control [CDC]) (Jemal et al., 2010). By 2025, 19.3 million new cases of cancer are expected to be diagnosed each year. In 2012, the most common cancers diagnosed worldwide were 1.8 million (lung cancer), 1.7 million (breast cancer), 1.4 million (colorectal cancer), 1.1 million (prostate cancer), 952,000 (stomach cancer), 782,000 (liver cancer), and 528,000 (cervical cancer). The frequency of cancer varies by geographic areas, especially in developed countries versus developing countries.

A total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the United States in 2015 (American Cancer Society, CDC). Cancer is a major public health problem worldwide, and is expected to surpass cardiovascular diseases as the leading cause of death in the next few years.

Estimated new major cancer cases and deaths in the United States in 2015 are (Siegel et al., 2015):

The development of cancer requires a series of exceedingly complex multiple steps that may occur during many years. Cancer needs to be diagnosed at an early stage, or even before cells become cancerous (removal of precancerous lesions) when it may be treatable. When cancer becomes metastatic, the treatment becomes difficult. Metastasis formation is responsible for most cancer deaths. Metastatic dissemination is a very complex, slow, and inefficient process. In order to understand brain metastasis from primary cancer, we need to comprehend how cancer cells escape from the primary tumor site, intravasate into blood vessels, accumulate in brain capillaries, survive the hematogenous dissemination to the brain, extravasate and proliferate and develop angiogenic ability to establish brain metastases. A diagrammatic, simplified representation of this process is shown in Fig. 1.1. However, the dissemination cannot be explained simply by blood or lymph drainage from the primary tumor. Metastatic colonization is strongly influenced by the interaction of primary cancer cells with host cells present or recruited to the microenvironment into a structure called the metastatic niche (Ordóñez-Morán and Huelsken, 2014). This local environment is responsible not only for the initial metastatic colonization of the host tissue but also for the progression of the disease. To succeed in finding an effective use of therapeutic drugs, we should also understand better the immunologically distinct space that excludes drug macromolecules from the brain.

Figure 1.1 Simplified, schematic illustration of melanoma brain metastasis. (A) Primary melanoma tumor cells intravasate into blood circulation after escaping from the melanoma tumor. (B) These cells are arrested in the capillary bed. (C) These cells subsequently extravasate into the brain parenchyma cells. Both intravasation and extravasation are mediated by STAT3 and neurotrophin signaling. (D) Melanoma cells either multiply along blood vessels (cooption) and/or establish angiogenesis. (E) Beta 1-integrin and vascular endothelial growth factor-A are associated with this process. Each step is regulated by genes and signaling pathways (Kenchappa et al., 2013).

Brain metastases are the most common intracranial neoplasms in adults, and occur in 20–40% of cancers. It is estimated that 100,000–170,000 persons are inflicted by metastatic brain cancer per year in the United States. Generally, intracranial metastatic lesions are more common than primary tumors of the brain (Gavrilovic and Posner, 2005). Metastatic brain tumors are 10 times more common than primary brain tumors, and represent 20–40% of all intracranial neoplasms in adults (Go et al., 2011). Approximately, 10–20% of all brain metastases are single tumors, and the remaining are multiple tumors. Lung, breast, colon, and kidney cancers and melanoma commonly spread to the brain. Breast and kidney cancers often cause single brain tumors, while lung cancer and melanoma tend to cause multiple brain tumors. Approximately, 85% of metastatic lesions are located in the cerebrum, while the remaining are located in the cerebellum. Autopsy analyses have shown that the incidence of brain metastases is as high as 30% in patients with breast cancer, 40% in those with lung cancer, 75% in those with melanoma, and 6% with those with kidney or bladder cancer. Brain metastases are among the most devastating and debilitating complications of lung cancer, breast cancer, unknown cancer, and melanoma. Patients with brain metastases often develop serious deterioration in neurological and neurocognitive functions. Intracranial bleeding is one of the fatal complications encountered in the patients. Treatments for patients with brain cancer are summarized below.

Treatments used for patients with metastatic brain cancer include neurosurgery, stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and chemotherapy; they are used alone or in combination. Neurosurgery is used for patients with a few metastatic lesions provided the lesions are surgically accessible and the patient can tolerate the operation. Surgical resection may immediately eliminate life-threatening or symptom-generating mass effect and eliminate the source of perifocal edema. Surgery is also of value when the diagnosis is uncertain. To reduce the risk of tumor recurrence and leptomeningeal spread en bloc approach rather than piecemeal method has been used. SRS has certain advantages: it is largely noninvasive, does not require general anesthesia and is performed on an outpatient basis (Atalar et al., 2013).

SRS is offered as an alternative to neurosurgery for patients with a few lesions which cannot be surgically removed (Yamamoto et al., 2014). WBRT can also be applied in conjunction with neurosurgery or SRS. Surgery plus WBRT shows overall survival benefit (Kocher et al., 2011). WBRT (30 Gy in 10 fractions) is the current standard of cure for patients with five or more brain metastases. However, the use of WBRT is controversial. Some studies have demonstrated superior outcomes, whereas some other studies report negative impact on neurorecognition (Brown et al., 2013; Gondi et al., 2013). Typical side effects of WRBT include hair loss, fatigue, memory loss (long-term due to hippocampal neural stem cell injury), headache, skin erythema, serous otitis, leukoencephalopathy, and somnolence (rare). Is WBRT necessary after surgery? Yes, because addition of WBRT even after complete tumor resection decreases intracranial failure and local recurrence. Finally, WBRT retains an important place in the management of brain metastasis (Choi Clara et al., 2012). Advantages and limitations of the WBRT are discussed in this volume. Use of immunotherapy for patients with brain metastasis is also discussed in this volume and by Powell and Dudek (2009).

Primary tumor ulceration is the strongest predictor of brain metastases development, and remains an independent predictor of decreased brain metastasis survival after treatment (Zakrzewski et al., 2011). The importance of determining the characteristics of primary melanoma, especially ulceration, cannot be overemphasized. Such information will help in the development of risk stratification of a treatment and surveillance protocols early in the clinical course. The information regarding the biology of ulceration and molecular mechanisms underlying its adverse impact on clinical outcome is equally important.

Admittedly, results of standard treatments mentioned above have been less than impressive. However, the situation is not as grim as it seems. It is pointed out that the choice of WBRT alone or SRS or surgical resection alone or combination of these treatments needs to be individualized based on patients overall prognosis. Recently introduced therapies, including multidisciplinary approach, may lead to encouraging positive treatment results.

Melanoma

Between two and three million nonmelanoma skin cancers and 132,000 melanoma skin cancers occur globally each year (WHO). However, the incidence of both of these cancer types has been increasing during the past decades. It is estimated that one in every three cancer types diagnosed is a skin cancer, and one in every five Americans will develop skin cancer in their lifetime. Because ozone levels are depleting, the atmosphere is losing its protective filter function, and thus more solar UV radiation is reaching the surface of the earth. It is estimated that a 10% decrease in ozone levels will result in an additional 300,000 nonmelanoma and 4000 melanoma skin cancer cases (WHO). For example, the incidence of melanoma increased from 15/100,000 persons in 1986 to more than 25/100,000 persons in 2006 in the United States.

Melanoma is a malignant neoplasm that occurs mostly in adults, and may originate de novo from a pigmented naevi (a benign localized overgrowth of melanin-forming cells of the skin). It can also begin in other pigmented tissues such as in the eye or the intestines. The most aggressive type of skin cancer, melanomas typically grow in densely packed cellular nests that contain minimal extracellular matrix (fibronectin, collagen, or laminin). Because of subtle differentiating features, potential for both under- and overdiagnosis of melanoma is not uncommon. This pitfall is especially common in the diagnosis of rare and unusual melanoma variants and melanoma resembling those in typical melanoma. These features include irregular functional components with pagetoid spread, melanocyte atypia, lack of dermal maturation, dermal mitotic activity, intense melanin pigmentation, a desmoplastic stromal response, and dermal regression. Benign melanocytic lesions are difficult to differentiate from naevi. We need improved understanding of the molecular drivers and heterogeneity of this disease.

One of the most common and serious complications of melanoma is the development of central nervous system (CNS) metastases. The frequency of metastasis is estimated to be 40% or even more in melanoma patients (Soffietti et al., 2002). Primary melanoma tumor ulceration is associated with poor prognosis. Tumor-related inflammation is associated with upregulation of proinflammation cytokines, which is associated with ulceration. Approximately, 75% of patients with metastatic melanoma develop brain metastases during the course of their disease. Melanoma is the third most common diagnosis among patients with brain metastases, after lung and breast cancer. Spread of melanoma to the brain is an ominous event. Brain metastasis is a major cause of death in melanoma patients, the frequency of which is on the rise. However, despite these poor outcomes, approximately 5% of patients with brain metastases from melanoma are long-term survivors. The identification of factors that can predict outcomes may benefit the clinical management of these patients. The era, pattern, and timing of melanoma brain metastases have been found to be strongly associated with survival. Other factors involved are less than three parenchymal metastases, leptomeningeal involvement, and the development of brain metastases after prior systemic therapies. A solitary brain lesion, surgical treatment, and a good Karnofsky Performance Status indicate a good prognosis (Celix and Silbergeld, 2014).

Recent developments in melanoma therapy have influenced the management of metastatic melanoma patients. Approximately, 50% of melanomas have an activating mutation in the gene encoding the serine-threonine protein kinase (BRAF), and approximately 95% of these mutations result in substitutions of other amino acids at the V600 site, most frequently lysine (V600K). All of these mutations increase the catalytic activity of BRAF. Melanoma patients with brain metastases harboring BRAF mutation are a distinct subgroup with a favorable response to vemurafenib and radiation therapy and acceptable morbidity. Nevertheless, an effective treatment for melanoma brain metastasis is not available. Therefore, it is essential to develop an efficient therapy to prevent such brain metastasis. An essential prerequisite to achieve this goal is to identify molecules expressed by brain-metastasizing melanoma cells, which are involved in the targeted migration of such cells to the brain (Klein et al., 2012). These molecules sustain melanoma cell survival and promote their propagation in the brain. The development of an efficient therapy against brain metastasis will be helped by understanding the interactions of these molecules with the microenvironment of the brain tissue. Chemokines present in the primary tumor cells are thought to be involved in the formation of metastasis. It has been reported that interactions between chemokine receptors CCR3 and CCR4 expressed by brain-metastasizing melanoma cells and the corresponding ligands in the brain tissue may be involved in the targeted migration of tumor cells to the brain (Izraely et al., 2010). It is likely that CCR4 ligands expressed in the brain interact with the CCR4-expressing melanoma cells, thereby directing them to the brain (Klein et al., 2012). It is concluded that the metastatic brain microenvironment plays a part in shaping the malignancy phenotype of melanoma cells.

Treatment

A meaningful improvement in overall survival of patients with metastatic melanoma has been an elusive goal. However, the development of new therapies for melanoma has offered new hope to investigators. Examples are BRAF inhibitors and ipilimumab. Nevertheless, treatment of intracranial disease remains a challenge, and there are many unanswered questions. Some of these questions can be answered when targeted therapies are incorporated into the multimodality management of melanoma brain metastasis. Also, improvements in the blood–brain-barrier (BBB) penetrance need to be a priority.

Two therapies against metastatic melanoma approved by the FDA are high dose interleukin-2 and dacarbazine; each is associated with response rates of only 10–20%, and a small percentage of complete response (Flaherty et al., 2010). However, neither improves overall survival. The median survival of patients treated with dacarbazine is shorter than 8 months (Bedikian et al., 2006). Most of the standard treatments used against melanoma or brain metastasis from melanoma are summarized below.

1. Neurosurgery or SRS. Neurosurgery is offered to patients with single or a few metastatic lesions, provided brain lesions are surgically accessible and the patient can tolerate the operation (Staudt et al., 2010). Patients treated with conventional neurosurgery or SRS comprise the group with the highest overall survival, which is comparable with the overall survival of general stage IV melanoma patients (Staudt et al., 2010). Applied treatment and serum lactate dehydrogenase levels are independent predictors of survival of patients with brain metastasis from cutaneous melanoma.

2. Ipilimumab. Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4), and improves survival of patients with unresectable stage III and stage IV melanomas (Margolin et al., 2012). This treatment is also effective against brain metastasis from melanoma, especially when metastases are small and asymptomatic. The approved dose of ipilimumab is 3 mg/kg by intravenous infusion given every 3 weeks for 4 doses (Hodi et al., 2010). No unexpected toxic effects were reported by Margolin et al. (2012). Although this antibody shows a prolonged overall survival of patients with advanced melanoma, its role has decreased with the development of pembrolizumab and nivolumab, which target PD-1; these two antibodies comparatively are more active and show less adverse effects. Ipilimumab is a complex drug with adverse events occurring in 40% of patients (Eggermont et al., 2014). This antibody shows a wide range of immune-related and other adverse effects, including enterocolitis, dermatitis, endocrinopathies, hepatitis, and hypophysitis (inflammation of the pituitary gland), and other organ systems may also be involved. Ipilimumab has also been used in combination with three other drugs, which are described below.

3. Ipilimumab/Interleukin-2. This is an immune therapy comprising the immune regulatory antibody directed against the cytotoxic T-lymphocyte antigen 4 (CTLA-4 mAb) (Pedersen et al., 2014). Interleukin-2 (IL-2) is an immune stimulatory cytokine that stimulates the proliferation and differentiation of native T cells into antigen-specific effector T cells, triggering the release of other immune-stimulating cytokines (Pedersen et al., 2014).

4. Ipilimumab and vemurafenib. Both ipilimumab and vemurafenib have FDA approval for the treatment of advanced melanoma. The former is an anti-CTLA-4 monoclonal antibody that enhances cellular immunity and reduces tolerance to tumor-associated antigens (Fonkem et al., 2012). Vemurafenib is an inhibitor that blocks the abnormal signaling for melanoma cellular growth in tumors that carry the BRAFV600E mutation (Fonkem et al., 2012).

5. Ipilimumab and nivolumab. According to the study by Larkin et al. (2015), among previously untreated patients with metastatic melanoma, nivolumab combined with ipilimumab resulted in significantly longer progression-free survival than with ipilimumab alone. The negative aspect of using combined treatment with two antibodies apparently consists of more adverse