JOURNAL OF CRITICAL REVIEWS
ISSN- 2394-5125 VOL 7, ISSUE 11, 2020 A REVIEW ON DIAGNOSIS AND TREATMENTS OF BLOOD CANCER
Zhu Miaocen National Junior College, Singapore Email: [email protected]
ABSTRACT : Cancer, a genetic disorder, displays multiple hallmark characteristics including sustaining prolif- erative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune de- struction. These hallmark characteristics of cancer enable it to jeopardise healthy cells and hinder their normal functioning. Blood cancer, in particular, has similar hallmark characteristics which then cause multiple fatal symptoms. As early diagnosis is the key in successful cancer treatment and yet most symptoms only emerge in the advanced stage of cancer, various diagnosis tools including radiology, cytology and histology are used to achieve early blood cancer diagnosis and thus to largely increase the chance of survival. Depending on individ- ual patients such as type and stage of blood cancer, age, weight, gender, and medical history, multiple treatment methods are used often cooperatively to treat blood cancer. Clinical treatments includes surgery, chemotherapy, radiotherapy, bone marrow transplant and also emerging therapeutic methods such as targeted therapy and im- munotherapy. However, specificity and drug resistance remain the most significant hurdles in successful treat- ment of blood cancer. Therefore, extensive research is required to develop targeted and personalised medicine to effectively treat blood cancer.
KEYWORDS: cancer. blood cancer, diagnosis, treatment
I. INTRODUCTION
Cancer is a genetic disease characterised by uncontrolled cell division. Accumulation of mutations gives rise to abnormal expression of critical genes via substitution, insertion, deletion, inversion and duplication. This ulti- mately leads to over-expression of oncogenes, under-expression of tumour suppressor genes, null mutations, and ectopic expression of other key genes. The extent of the impact of mutation on protein function depends on how the resultant protein differs from its original conformation. The mutated proteins respond to signals differ- ently, fostering multiple hallmark cancer characteristics including sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating in- vasion and metastasis, reprogramming energy metabolism and evading immune destruction (Figure 1) (Hanahan and Weinberg, 2000). Some emerging hallmarks include deregulating cellular energetics, genome instability and mutation, tumour promoting inflammation, and avoiding immune destruction (Hanahan and Weinberg, 2011).
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Evading Sustaining immune proliferative destruc- signalling tion Reprogram- Evading ming energy growth sup- metabolism pressors Hallmarks of cancer Activating Resisting invasion cell death and metas- tasis Enabling rep- Inducing licative im- angiogenesis mortality
Figure 1. A summary of hallmark characteristics of cancer cells
Blood cancer is a term referred to cancers occurring in blood cells such as leukaemia, lymphoma and myeloma (Table 1.). Blood cancer is quite common with an incidence of 13.4% among all cancer types in the USA, with the 5-year mortality rate being 8.6% (Cancer Today, 2019).
Table 1. Different types of blood cancer and brief characteristics Leukemia A type of cancer found in blood and bone marrow, which is caused by the rapid production of abnormal white blood cells. With spurt in the multiplicity of cancerous cells affecting either the marrow or the blood, the ability of the circulatory system to produce blood is severely im- paired. Lymphoma A type of blood cancer that affects the lymphatic system. Cancer cells multiply and collect in the lymph nodes and other tissues. Over time, these cancerous cells impair the immune system.
Myeloma Cancer of the plasma cells. Myeloma cells prevent the normal production of antibodies, leaving the body's immune system weakened and susceptible to infection.
Furthermore, blood cancer is divided into multiple different families with distinct characteristics (Figure 2).
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Figure 2. Different families of blood cancers.
Molecular mechanism of cancer formation In order to obtain cancer hallmarks as illustrated in Figure 1, cancer cells require to adapt certain transfor- mations. Incipient cancer cells display growth factor independence by autocrine proliferative stimulation, or recruiting growth factors from normal cells in the tumour-associated stroma (Bhowmick et al., 2004; Cheng et al., 2008). Alternatively, cancer cells can render themselves hyper-responsive to otherwise limiting amounts of growth factors by increasing the level of expression of receptors to growth factors, or altering the structure of receptor molecules that enhance the binding of the ligand (Giancotti, 2014). Thereby, cancer cells acquire ad- vantages over normal cells by competing them out for growth factors. Cancer cells may also become constitu- tively active, rendering checkpoints in the cell cycle defective and hence promote uncontrolled cell proliferation.
Meanwhile, cancer cells evade growth suppressors by disrupting negative feedback mechanism that attenuates growth signalling. Cancer cells promote telomerase activity, allowing the escape of induction of cell senescence and apoptosis, resulting in replicative immortality. Germline TP53 mutations cause Li-Fraumeni syndrome (LFS), a rare disorder that predisposes patients to different types of cancer, including leukemias and lymphomas (Srivastava et al., 1990). B cells are particularly more susceptible to malignant transformation because the ma- chinery used for chromosome rearrangement and antibody diversification can cause chromosomal translocations and oncogenes mutations. Thereby, cancer cells pass on the growth advantages to their offspring and crowd out normal cells by depriving them of nutrients and space. Cancer cells display loss of contact inhibition resulting in excessive cell growth to form layers of cells and thus neoplasm. The neoplasm promotes angiogenesis, the for- -Favera, 2001).
Leukaemias are inherently metastatic as leukocytes move throughout the vascular system, suggesting that no mutations are required for anchorage independent growth. Metastatic cancers are difficult to treat because delo- calised cancer cells are gaining progressively more energy from all parts of the body and also cannot be re- moved via surgery. The challenge of the current treatment of cancer is late diagnosis as the symptoms usually only show in the late stage (Chakraborty and Rahman, 2012).
Cancer cells evade immune destruction as well as reprogramming of cell metabolism. Most abnormal cells can be detected by the immune system which signals exit from the cell cycle and recruits enzymes to correct the mistakes in the DNA sequence. Alternatively, the immune system signals apoptosis or autophagy by releasing enzymes from lysosome to digest the cell or by activating cytochrome c in mitochondria to activate caspase (Garrido, et al., 2006). However, cancer cells may down-regulating the signalling pathway (Levine and Kroemer, 2008; Mathew et al., 2007; Sinha and Levine, 2008).
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ISSN- 2394-5125 VOL 7, ISSUE 11, 2020 Risk factors in blood cancer formation There are several risk factors which can affect incidence and prevalence of blood cancer. Gender is a significant risk factor for blood cancer. The World Health Organization (WHO) reported that of all incidents of blood can- cer in 2018 in the USA alone, 58% were males and 42% were females. Across the world, males generally have higher incidence of blood cancer than female (Figure 3).
Figure 3. Estimated age-standardised incident rates (ASR) (world) of blood cancer in 2018. Data is ob- tained from GLOBOCAN (2018).
Besides, Caucasians have a higher incidence of blood cancer. ASR of leukaemia is highest among non-Hispanic whites (15.0 per 100,000 population) and lowest among Asian and Pacific Islander populations (7.8 per 100,000 population) and American Indian and Alaska Native populations (8.3 per 100,000 population) (U.S. Cancer Sta- tistics, 2017). Age is another risk factor in blood cancer formation. Generally, incidence of blood cancer increases significant- ly with increase in age, with the exception that acute lymphoblastic leukaemia has the highest incidence at age 1-4 (National Cancer Institute, 2018). This is because with increase in age, people are exposed to carcinogens for a longer time, which causes accumulation of mutations and, therefore, higher incidence of developing can- cerous haematological cells. However, while it is true that most blood cancers have the highest incidence in adulthood, leukaemia has the highest child to adult ratio (Siegel et al., 2014). The main contributor to this is the characteristic feature of leukocytes that leukocytes are inherently capable of circulating the vasculature and amoeboid migration (Ebnet and Vestweber, 1999; Patel et al., 2002), where fewer mutations are required for malignancy (Trendowski, 2015).
Meanwhile, there is positive correlation between incidence of blood cancer and living standards, as shown in Figure 4 (Cancer Today, 2018). As people in developed world have longer life expectancy, there is a higher chance of developing cancer due to accumulation of mutations.
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Figure 4. incidence/ASR(world) of blood cancer against Human Development Index in 2018. Data is ob- tained from GLOBOCAN (2018)
Other risk factors associated with blood cancer are shown in Figure 5:
Figure 5. Other risk factors associated with blood cancers
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ISSN- 2394-5125 VOL 7, ISSUE 11, 2020 The effect of blood cancer on patients’ life quality The general findings show that the haematological diseases negatively affect overall quality of life (Allart- V ., 2015). M ’ c c and increased susceptibility to fatigue (Courneya et al., 2009). Besides, haematological diseases destroys occu- pational and financial quality of life (Mols et al., 2007). Furthermore, haematological diseases devastate psycho- logical and social quality of life as intensified interpersonal relationships amplify the feelings of ambiguity or fear (Heinonen et al., 2001). Most findings show that chemotherapy improves pa ’ sical health but may ’ c Z t al, 1999).
II. DISCUSSION
Patients with blood cancer generally displays multiple symptoms illustrated in Figure 6: Figure 6. Symptoms of blood cancers
Symptoms are only visible in the late stage of cancer, which increases the difficulty for early diagnosis. Also, therapeutic outcomes heavily depend on the time of diagnosis (Singal et al., 2013). Many factors can contribute , c ’ ck k c c , ck i- ty of the symptoms, psychological fear of cancer, and also socioeconomic status (Tsai et al., 2018). Therefore, late diagnosis is the main obstacle for effective treatment of cancer.
Common diagnostic tools for cancer include radiological, cytological, and histological diagnosis (Table 2).
Table 2. Cancer diagnosis methods, advantages and limitations. CT: Computerized Tomography; MRI: Magnetic Resonance Imaging; FNAC: Fine Needle Aspiration Cytology; Data in the table were obtained from Hillman (2000); Uganda Ministry of Gender Labor and Social Development (2020). Cancer diagno- Radiological diagnosis Cytological diagnosis Histological diagnosis sis
• General X-ray • FNAC • Endoscopy • CT Scan • Test on body fluid • Needle biopsy • MRI • Scrape or Brush Cytolo- • Surgical biopsy Methods • Ultrasound gy • Incisional biopsy
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• Non-invasive • Easy to obtain • Accurate • It assists in making a di- • Cost-effective • It can identify the nature of agnosis and further man- • It causes less discomfort abnormally and guide future agement of body conditions to patients treatment, including types of • Interventional radiology, • It is Less likely to result cancer and responsiveness to which involves treatment as in complications certain treatments. Advantages well as diagnosis, has less • It assists in making a • Crucial in diagnosis of ad- risk, a shorter recovery time diagnosis and further man- vanced cancers to see the extent and less time in hospital than agement of body conditions of metastasis or whether the open surgery or key-hole tumour has been cleared (laparoscopic) surgery
Radiology may be subjective Cytological diagnosis is It is difficult to pinpoint the and less accurate as different less accurate than biopsy as microscopic lesion by looking pathologists may draw dif- it provides less information at the gross appearance. ferent conclusions from the of the cancer site. Different histologists are sub- Limitations same image. jective about such parameters Radiology processes less as the extent of the lesion, the information about the cancer. malignancy of a cancer, the nomenclature, etc.
With absence of solid tumour, blood cancer diagnosis however, cannot rely on common cancer diagnostic tools. As the primary site of blood cancer is in the bone marrow, the major diagnostic tool is based on blood tests or bone marrow (Table 3).
Table 3. Different methods used in diagnosis of blood cancer. CT: Computerised Tomography; MRI: Magnetic Resonance Imaging; Data is obtained from Ali and Sultana (2012); Leukemia and Lymphoma Society (n.d.); Mayo Clinic (2020).
Diagnosis
• Upon observations of symptoms, repeated complete blood counts and a bone marrow examina- tion are performed. However, in rare cases blood tests may not show leukaemia because the leu- kaemia is in the early stages or has entered the remission stage. • A lymph node biopsy can be performed if metastasis is suspected. • Following diagnosis, blood chemistry tests can be used to determine the degree of liver and Leukaemia kidney damage or the effects of chemotherapy on the patient. • leukaemia's visible damage on body parts can be detected, such as bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver (ultrasound). • CT scans are rarely used to check lymph nodes in the chest. • Mutation in SPRED1 gene has been associated with a predisposition to childhood leukaemia. SPRED1 gene mutations can be identified with genetic sequencing.
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• A physical exam on lymph nodes is performed to check for pain and swelling. • A biopsy of the lymph tissue is performed if lymphoma is suspected. • Certain blood tests are done, including complete blood count and testing for protein, urea, kid- ney function etc. • CT scan of chest, abdomen and pelvis may be done. • PET scan and Gallium scan (in case of non Hodgkin lymphoma) are done. • Bone marrow biopsy is done to determine staging of lymphoma (Figure 7).
Lympho- ma
• A number of blood tests are performed to determine complete blood count, level of albumin, calcium and total protein. • Blood and urine are tested to check for cancerous antibodies and proteins. Myeloma • Tests are made for hypercalcemia, anemia, renal failure and bone lesions to confirm the diagno- sis. • Bone marrow biopsy and bone x rays are performed to detect the disease. • Bone density testing is done to monitor the bone loss.
Figure 7. Bone marrow biopsy. Source: Mayo Foundation for Medical Education and Research (2020).
Treatments of blood cancer Treatment is dependent on the nature of the cancer as well as the stage of malignancy. In the advanced stage of cancer, cancer cells undergo metastasis and develop into clones via further accumulation of mutations. Distinct cancer cell clones show cooperative behaviour of promoting mutual survival (Cleary et al., 2014), which further increases the difficulty of successful cancer treatment. Common treatment methods for cancer include surgery, radiotherapy, chemotherapy, as well as emerging treatment tools such as targeted therapy and immunotherapy (Table 4). A combination of approach is common in cancer treatment.
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ISSN- 2394-5125 VOL 7, ISSUE 11, 2020 Table 4. Common treatment methods for different cancers. Data are obtained from Ali and Sultana (2012); Cancer Research Institute (n.d.); Mayo Clinic (2020).
Treatment Description
Removal of solid tumour, usually performed in the early stage of cancer. Higher risk is Surgery involved if the cancer site resides in critical locations. It is usually followed by other treatments.
Induce apoptosis in cancer cells or slow cancer growth by damaging the DNA through Radiotherapy high energy radiation. However, radiotherapy may cause side effects as it damages normal cells also.
A drug treatment to eliminate fast-growing cells. Chemotherapy can be used for ad- vanced cancer as it eliminates cancer cells around the body by halting the cell cycle and Chemotherapy inducing apoptosis. Chemotherapy is commonly used for bone marrow transplant. However, chemotherapy also causes nausea, hair loss, fatigue as it kills normal fast growing cells including hair cells and intestine cells.
Also known as personalised medicine, targeted therapy works by tar c c ’ specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. Targeted therapy can involve monoclonal antibodies, which consists of a lipo- Targeted therapy some of phospholipids and embedded antibodies that serve to specifically target cancer cells and remove off-target effect. It can also use small-molecule drugs for intracellular targets.
Immunotherapy boosts the immune system to slow or stop growth of cancer cells, pre- venting metastasis, and eliciting immune response to destroy cancer cells. Common Immunotherapy approach includes monoclonal antibodies and tumour-agnostic therapies, non-specific immunotherapies, T-cell therapy, and cancer vaccines.
Treatment for Leukaemia High dose of direct radiation may also be used for treatment of leukaemia by aiming at the cancer cells to reduce remission. Radiation therapy eliminates cancer cells by either damaging their DNA directly or creating free rad- icals within the cells that can in turn damage the DNA. Cancer cells whose DNA is damaged beyond repair stop , k ’ c L c ., 2008). Chemotherapy can be used in concert with radiotherapy, including radiosensitizers, which render cancer cells more sensitive to radiotherapy (Wardman, 2007), and radioprotectors, which protect normal cells from radiation (Mun et al., 2018).
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ISSN- 2394-5125 VOL 7, ISSUE 11, 2020 Chemotherapy is the most commonly used method to treat leukaemia, which occurs in 3 stages (Table 5).
Table 5. 3 Stages for Chemotherapy. Data is obtained from Chemotherapy for Acute Myeloid Leukemia (AML) (2020). Stage 1 Induction where all abnormal cells are eliminated in the blood.
Stage 2 Consolidation where further damage is incurred to rare abnormal cells.
Stage 3 Maintenance where regrowth of any leukaemia cells is prevented.
If leukaemia spreads to the brain or spinal cord, intrathecal chemotherapy is used where drugs are directly in- jected into cerebrospinal fluid (CSF). However, treatment of ALL may result in increased risk of developing AML or less often non-Hodgkin Lymphoma. In patients who have large numbers of leukaemia cells in the body, Tumour Lysis Syndrome (TLS) is likely to occur, most often in the induction phase of treatment. TLS can result in hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, which may cause kidney injury and failure, abnormal heart rhythm and damage to the nervous system (Abu-Alfa and Younes, 2010; Cairo et al., 2010). This can often be prevented by giving extra fluids during treatment and by giving drugs such as bicar- bonate, allopurinol, and rasburicase to help the body get rid of these substances (Gertz, 2010).
Targeted therapy includes Imatinib, a small molecule that inhibits a specific receptor tyrosine kinase, which is effective in treatment of chronic myelogenous leukaemia (Druker et al., 1996), which is characterised by over- expression results from a chromosomal translocation (Rowley, 1973).
However, above treatment may be ineffective in treatment leukaemia. As chemotherapy acts primarily on pro- liferating cells, malignant stem cells are quiescent and therefore insensitive to therapy, allowing relapse of blood cancer (Dean, Fojo and Bates, 2005). Imatinib resistance also contributes to ineffectiveness of treatment signifi- cantly (Iqbal and Iqbal, 2014), Therefore, stem cell transplantation is carried out to completely eliminate blood cancer for patients who are insensitive to chemotherapy (Copelan, 2006). Stem cell transplantation may be car- ried out in 2 ways (Table 6).
Table 6. Stem cell transplantation 1 Autologous bone marrow or stem cell transplantation is the process that uses the patient's own stem cells.
2 Allogenic bone marrow transplant is that where stem cells from a donor is used.
For allogenic bone marrow transplant, there is effective treatment but also higher risk of complications due to problem of histocompatibility (Ali and Sultana, 2012).
Traditional medicine like acupressure may be used to drain the lymph nodes. Fucoidan found in seaweeds can hold a natural cure for lymphoma, and can also protect against toxicity associated with chemotherapeutic agents and radiation (Atashrazm et al., 2015).
III. CONCLUSION AND OUTLOOK
Blood cancer, as a genetic disorder, causes abnormal production of blood cells in bone marrow. Modern tech- nology has enabled more diverse and more effective means for treatment of blood cancer, including radiothera- py, chemotherapy, targeted therapy, immunotherapy as well as hematopoietic stem cell transplantation. Howev- er, major obstacles need to overcome with extensive research, including delayed cancer diagnosis, non- specificity of treatment, difficulty in targeting stem cells and drug resistance. More effective biomarkers are needed for early and accurate diagnosis. Considering the pressing need for efficient and safe medicinal re- sources, future efforts to develop radiosensitizers and radioprotectors remain extremely important. Embryonic stem cells and somatic stem cells may become a source of hematopoietic stem cells. Histocompatibility prob- lems may be solved by establishing comprehensive banks of embryonic stem-cell lines or by creating genetical- ly matched stem-cell lines individually.
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