Cervical+Cancer

= Cervical Cancer =

Meet the Patient
Mariana, a 44 year old Hispanic woman, is a regular smoker who lives with her husband, three children, and her older sister who was diagnosed with cervical cancer at age 49. They live in a small, one story house in Uptown Oakland area where poverty is highly concentrated. Recently, she contracted an HPV infection that started causing her pelvic pain so she visited the doctor’s office to get it checked out. To her surprise, the doctor informed her that the infection has spread and morphed into invasive cervical cancer.

What is Cervical Cancer?
Mariana has the more common form of cervical cancer, squamous cell carcinomas, which make up 80-90% of cervical cancers. Squamous cell carcinoma occurs when squamous cells in the cervix lining become abnormal and spread to surrounding areas such as the vagina. There are ten types of cervical cancer with squamous cell carcinomas and adenocarcinoma being the main types.



 Cervical cancer usually occurs during midlife with women aged 35 to 44 making up the highest percentage of new cases (24.9%) and is closely followed by women aged 45-54 who made up 24.2% of the new cases from 2007 to 2011. The same trend can be seen for mortality rate in which 24% of women aged 35-44 died from cervical cancer. [|Incidence rate and mortality rate]have declined over the years due to the increase in screening in which the Pap smear test detects signs of cervical cancer when it is in a benign state. Statistics has shown that from 1975 to 2011, the incidence rate decreased an average of 1.2% per year while mortality rate decreased by an average of 1.3% per year during 2002 to 2011 in the United States. It is estimated that in 2015, 12,900 cases will be diagnosed and 4,100 deaths will occur as a result of cervical cancer. The 5-year relative survival rate has also been increasing, although at a much slower rate. Based on SEER’s 2004-2010 data, there is a 67.9% of surviving 5 years or more after being diagnosed with cervical cancer. However, the 5-year relative survival rate depends on the stage in which the cancer is at. If squamous cell carcinomas are localized in the cervix lining, a woman has the highest probability of surviving cervical cancer with a 90.9% 5-year relative survival rate.

//__The Role of Race __//
 Race plays a role in determining a woman’s risk for developing cervical cancer; Hispanics have the greatest risk in the United States, “followed by African-Americans, Asians and Pacific Islanders,…” whites, and American Indians and Alaskan natives. Hispanic women had the highest incidence rate of 10.2 new cases per 100,000 persons based on the age-adjusted data gathered from 2007-2011. However, Hispanic women had a low mortality rate of 2.8 deaths per 100,000 persons compared to Black women who had the highest mortality rate of 4.1 deaths per 100,000 persons. The main reason for this cancer health disparity is the lack of screening produced by unequal access to health care among Hispanics and African Americans. It is also suggested that like many other health issues, low socioeconomic status (SES), income, and education is associated with a higher mortality risk.

__// Common Risk Factors //__
 Another risk factor is smoking which increases Mariana’s chances of getting cervical cancer by two-fold. Since women who smoke have tobacco by-products in their cervical mucus, researchers hypothesize that these by-products mutate cervix cells’ DNA thus bringing about cervical cancer. Furthermore, smoking reduces the immune system’s ability to fight off HPV infection. In a similar manner, human immunodeficiency virus (HIV) increases women’s risk for a human papillomavirus (HPV) infection, and therefore cervical cancer, due to the damages done to the immune system. In general, anything that inhibits the immune system’s ability to fight off foreign substances or remove cellular insults allow infections to spread, grow, and potentially transform into a malignant cancer. An additional risk factor for Mariana is a family history of cervical cancer; since her sister was diagnosed with cervical cancer, Mariana’s risk for developing it is two to three times higher than women with families that do not have cervical cancer. Although researchers are unsure of the genetic disposition for cervical cancer, some posit that women inherit an inability to fight HPV infection. Since HPV infection is the most well-known risk factor, it is essential to understand the biological mechanisms of how it causes cervical cancer.

Human Papillomavirus (HPV) and Its Molecular Machinery
The majority of adults contract or will contract HPV in their lives, but the body usually clears it out on its own; unfortunately for Mariana, HPV infections that are not cleared from the body are what cause cervical cancer in women. These infections are termed high-risk and become chronic usually after 10 years, forming warts and precancerous lesions on the surface of the cervix lining. During pre-cancerous stages when the cervical squamous cell carcinomas are localized in the cervix and tiny in size, symptoms are not usually present. However, once the cervical lesions spread to surrounding tissues, symptoms such as “abnormal vaginal bleeding, increased vaginal discharge, pelvic pain, or pain during sexual intercourse” become more evident. Like many other women, the origin of Mariana’s cervical cancer is the spread of a high-risk HPV infection. Of the various types of HPV, “HPV-16, -18, -31, -45 account for more than 90% of cervical carcinomas… [with HPV-16] accounting for about half of the cervical cancer cases in the United States and Europe.”

HPV is a tiny virus that has a genome divided into 3 parts: the noncoding upstream regulatory region (URR), the “early” region, and the “late” region.  The early region contains the E1 through E8 genes whose products can activate the HPV infection and determine whether or not the infection will become malignant.  HPV is usually transmitted by skin-to-skin contact. Once inside the body, it makes it way to the epithelium, breaks through the basal layer by creating a small abrasion on the epidermis, and begins its replication cycle by hijacking the host cell’s DNA replication machinery. <span style="font-family: Georgia,serif; line-height: 1.5;"> To become cancerous cells, HPV-DNA is first integrated into the host genome which deletes the E2 region, thus creating a loss-of-function in the E2 gene whose job is to down-regulate transcription of the E6 and E7 genes. Without the E2 gene, the E6 and E7 genes can be transcribed freely and produce products that “subvert the cell growth-regulatory pathways and modify the cellular environment in order to facilitate viral replication” in an active HPV infection. <span style="font-family: 'Times New Roman',serif; font-size: 13.3333330154419px; line-height: 1.5;"> <span style="font-family: Georgia,serif;"> They have a high affinity for the two most common tumor suppressor genes, p53 and retinoblastoma gene product (pRb), both which regulate cell growth; the E6 gene product specifically binds p53 and degrades it while the E7 gene product binds hypophosphorylated pRb. The E7-pRb complex prevents pRb from binding to transcription factor E2F-1, enabling the viral genome to undergo DNA synthesis. Therefore, the net result of the inactivation of p53 and pRb is sustained proliferative signaling, resistance to apoptosis, genomic instability, and evasion of growth suppressors as depicted in Figure 1. These alterations allow for the accumulation of mutations and DNA damage at a rate faster than the cell can repair, inevitably transforming the infected cells into cancerous ones.

<span style="font-family: Georgia,serif;"> Understanding the molecular machinery of HPV infection and how it leads to cervical cancer can design treatments that target specific biological pathways, especially the E6 and E7 genes since they are the key players in progression towards cervical cancer. The first method is to create a loss-of-function in both the E6 and E7 genes or in just one of the genes. The E6 gene can be blocked by using a peptide aptamer, “a distinct class of molecules that are selected for in vivo binding to a given target protein and can block its intracellular activity selectively.” A study done in 2000 showed that E61-1 and E61-17 peptide aptamers- isolated from yeast clones- inhibited HPV16-postive cancer cell growth; however, the study only confirmed that E61-1 induces apoptosis while E61-17 did not show binding to E6 in vivo under standard conditions but did in vivo in yeast and mammalian assays. By blocking the function of E6 gene products (p53 degradation), the concentration of p53 is elevated which stimulates apoptosis in HPV-infected cells, protecting the host from tumor cell proliferation, genetic instability and possibly replicative immortality. Interestingly, the study showed that 15 out of the 17 E6-binding peptide aptamers did not inhibit HPV16-positive cancer cell growth, meaning that extensive screening must be done in order to discover the small subset of peptide aptamers that have the specific and desired function. The inability to inhibit growth can be attributed to low binding affinity to HPV16-positive cancer cells so another experimental possibility to discovering a useful peptide aptamer is mutating the peptide in such a way to increase the binding affinity and observing whether or not that change induces growth inhibition. Another widely known method to prevent HPV-induced carcinogenesis is to reinsert or turn on the E2 gene in order to de-regulate the E6 and E7 genes. It has been shown that “the re-introduction of E2 into HPV-postive, but not HPV-negative cervical cancer cell lines results in a G1 cell cycle arrest.” However, to induce cell growth arrest, the E6/E7 promoter must also be repressed or else the coexpression of HPV16 E6 and E7 genes will override the E2 gene’s function. In order to do this, we can use the previous method of introducing the E61-1 peptide aptamer to repress the E6 gene then insert an E2 gene from another cell that is still intact. Another study done in 2000 showed that the E2 gene can also transform cancerous cells into senescence cells which exhibit features such as increased cellular size by about 20-50-fold and the presence of perinuclear beta-galactosidase, “a highly specific marker for senescence that is not present in either growth-arrested or differentiated cells in vitro or in vivo. Thus, the E2 gene is an essential inhibitor that can prevent HPV-induced carcinogenesis.While these two approaches are most commonly used to prevent cervical cancer caused by HPV infections, there are a host of other methods that have yet to be discovered.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Treatments
<span style="font-family: Georgia,serif; font-size: 10pt;">The most efficient method of avoiding cervical cancer is regular screening via the Pap smear test in which cervix cells are collected and examined for pre-cancerous lesions; the Pap smear test can also be combined with a HPV test. If the Pap test result is atypical, diagnostic tests for cervical cancer are prompted. Unfortunately for Mariana, her lack of preventative action has led to the development of invasive cervical cancer. Since the squamous cell carcinomas have spread to the upper part of the vagina, Mariana has been diagnosed with Stage IIA of invasive cervical cancer which has a 63% 5-year observed survival rate. Therefore, the recommended standard treatments are as followed with radical hysterectomy in conjunction with [|pelvic lymphadenectomy] and concurrent radiation and chemotherapy being the most commonly used treatments for stage IIA patients: surgery, radiation therapy, chemotherapy, and targeted therapy. <span style="font-family: Georgia,serif;"> <span style="font-family: Georgia,serif;">//__<span style="font-family: Georgia,serif;">Surgery __// <span style="font-family: Georgia,serif;"> There are multiple procedures that Mariana can choose from. The first is conization in which a cone-shaped piece of an abnormal cervix tissue or cancer is removed either by using a scalpel or by a procedure called [|loop electrosurgical excision procedure (LEEP)] or by laser surgery, depending on the type of cervical cancer and cancer cells’ location. The tissue is then examined under a microscope to see if any cancerous residues are still present; if so, additional treatment is required. Conization is typically used to remove localized precancerous cervical lesions since it would be unreasonable to remove each cancer tissue and examine it for leftover residues in invasive cancers. Because conization alone does not suffice as a treatment for stage IIA patients and is more of a diagnostic test, I would not recommend this surgery for Mariana since we know that her cancer has spread outside the cervix. A second possible procedure is total hysterectomy in which the uterus and cervix are removed either through the vagina or through the abdomen by making an incision. If the cervical cancer has spread to areas such as the vagina as in Mariana’s case, I would recommend radical hysterectomy in which the uterus and its surrounding tissues, the cervix, and part of the upper vagina are surgically removed, coupled with pelvic lymphadenectomy; unfortunately, that means Mariana can no longer bear children. In addition, the lack of lymph nodes may cause swellings in her leg due to fluid build-up, and the onset of menopause is immediate, causing “hot flashes, vaginal dryness, and night sweats… [from] the sudden loss of female hormones.” Although the symptoms are severe, a study on Italian women who received a radical hysterectomy, pelvic lymphadenectomy, and para-aortic lymph-node dissection had a 5-year overall survival rate of 83% with complications resulting mostly in women who received adjuvant radiation following surgery. If Mariana strongly wants to be able to continue to have children, she can choose radical trachelectomy. This procedure only removes the cervix and part of the upper vagina; the surgeon then places a band where the cervix used to be located to “act as an artificial opening of the cervix inside the uterine cavity.” A 2005 review reported that 70% of women who received a radical trachelectomy and tried to conceive following the surgery were successful; however, of these women, 29% of them had a miscarriage in either the first or second trimester of their pregnancy. In addition, the ideal candidates for radical trachelectomy are women younger than 40 years old and are at stage I, thus the risks of complications or infertility would be higher for Mariana if she chooses to go with this option. Besides individual concerns associated with each type of surgical procedure, we must consider the big picture which is that the removal of primary tumors can cause secondary tumors to proliferate and possibly metastasize since they can now utilize the nutrients and oxygen that were previously fueling the primary tumors.

//__<span style="font-family: Georgia,serif;">Radiation Therapy __//
<span style="font-family: Georgia,serif;">There are various types of radiation therapy which uses radiation such as x-rays to reduce growth of cancer cells or to kill them. External radiation therapy uses a machine to direct radiation at a woman’s pelvis and surrounding areas with cancer, usually for a few minutes a day for five days a week for a few weeks. Due to the lack of targeting, radiation can harm any part of the body it hits over a long period of time, potentially contributing to the acquisition of cancer hallmarks such as sustained proliferation signaling by turning off tumor suppressor genes or avoiding cell death by inhibiting TP53. Internal radiation therapy is much more invasive in that a cylinder loaded with a radioactive substance is inserted into the vagina for a few minutes before being removed. Although the latter therapy is considered painless, it has many side effects such as fatigue, nausea, loss of genital hair, and diarrhea that usually terminates after treatment is concluded. However, since the radioactive substance is in close proximity to the cancer cells, the radiation effect is confined to the cervix and vaginal walls. Another option for localized squamous cell carcinomas is intensity-modulated radiation therapy (IMRT) which uses a computer to create 3-D images of the tumor to help focus radiation beams at varying intensities and angles at the tumor, reducing the potential harm radiation can cause to healthy, nearby tissues. Since Mariana’s cervical cancer is not localized, external radiation therapy would be the best option in this category.

<span style="font-family: Georgia,serif;">__//<span style="font-family: Georgia,serif;">Chemotherapy //__ <span style="font-family: Georgia,serif;"> Chemotherapy is the use of drugs- taken orally or intravenously using a thin needle- to inhibit cancer cell division or to kill them. Oftentimes, it is given in conjunction with radiation therapy since it enhances the latter’s effect. One drug that is commonly used in treating cervical cancer is Cisplatin, an inorganic platinum drug that binds GC-rich sites and induces DNA and DNA-protein cross-links, causing cell growth inhibition and apoptosis. Cisplatin can be used to treat multiple cancers, but in regards to cervical cancer, it is usually applied when surgery or radiation therapy are not viable options. Even though cisplatin targeted therapy is perceived as a late-stage treatment for aggressive cervical cancer, it has a high success rate; randomized trials have shown that cisplatin-based [|chemoradiation] decreased mortality rate by 30-50% in patients with stage I through IIA. Although Cisplatin is very effective and considered the base cancer treatment, Mariana still needs to consider the drug’s severe side effects before jumping to conclusions: nephrotoxicity (kidney damage), neurotoxicity (nerve damage), ototoxicity (loss of hearing), alopecia (hair loss), and low blood cell levels particularly in the bone marrow. Because chemotherapy is not directed at the cancer cells only, healthy cells- particularly rapidly dividing cells- are damaged, resulting in various side effects similar to those of internal radiation therapy. Not only that, damaging healthy cells results in a lowered immune system response, making it harder to fight against other pathogens in general. The drug can also cause DNA damage in healthy cells and induce apoptosis or mutate genes in the cell to create genome instability, an enabling characteristic of cancer cells.

__//<span style="font-family: Georgia,serif;">Targeted Therapy //__
<span style="font-family: Georgia,serif;"> Targeted therapy is the same as chemotherapy except the drugs or substances used have a specific target they attack. One drug called Bevacizumab is used to treat cervical cancer that has metastasized by inhibiting angiogenesis, preventing cancer cells from receiving nutrients and oxygen needed for cell growth. “[Bevacizumab] is a monoclonal body (a man-made version of a specific immune system protein) that targets vascular endothelial growth factor (VEGF), a protein that helps new blood vessels to form” and is given through an intravenous infusion which then binds to any "soluble VEGF, preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation." This inhibition has a greater effect on tumor cells simply because they up-regulate VEGF and its target receptors unlike normal cells. Not only does the drug prevents new vessel formation, bevacizumab is thought to also prevent communication between tumor and nearly vessels so blood supply is limited, inhibiting tumor growth.

<span style="font-family: Georgia,serif;"> In August 2014, the FDA approved the use of bevacizumab in conjunction with chemotherapy to treat patients with aggressive, recurrent, or metastatic cervical cancer as is the case of Mariana. This decision was based on an international trial in which researchers compared chemotherapy alone (paclitaxel and cisplatin or paclitaxel and topotecan) with chemotherapy and bevacizumab. These treatments continued until the patients dropped out of the study, experienced cancer advancement, or the toxicity level of the treatment became too high and fatal to patients. At the conclusion of the trial, results showed that patients who received chemo with bevacizumab had a median survival of 3.9 months longer than those who received chemo alone. Bevacizumab can be used alone if it succeeds in inhibiting cell growth; however, once cancer cells start growing again, the drug has to be used concurrently with chemotherapy. Although the trial shows an increased median survival rate in patients using bevacizumab with chemotherapy, the increase is minimal so Mariana must assess other aspects of the drug. Regrettably, the side effects of bevacizumab are more harmful than using chemoradiation so much that it can interfere with wound healing or blood clotting and rarely does it create a [|fistula] between the vagina and part of the colon or intestine. Furthermore, a 2011 meta-analysis of 16 clinical trials on cancer patients who were treated with both chemotherapy and targeted therapy bevacizumab had a higher probability of dying from the severity of the drug’s side effects. The introduction of bevacizumab in cancer treatments has also led some tumors to develop resistance. Therefore, researchers must now design a new drug that targets another angiogenesis signaling pathway such as platelet-derived growth factor-C (PDGF-C). With that being said, Mariana should only choose targeted therapy if no other treatments are available, or they have failed in controlling or eliminating her squamous cell carcinomas.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; line-height: 1.5;">Recommendations
<span style="font-family: Georgia,serif; font-size: 10pt; line-height: 1.5;">When comparing therapy treatments, “[a] Cochrane meta-analysis of all randomized trials comparing RT to chemoradiotherapy found a 6% survival advantage in favor of the latter.” Also, since radiation therapy by itself was originally used for removing localized or massive tumors, it is not the best treatment for Mariana whose squamous cells carcinomas have spread elsewhere. With only chemoradiation and radical hysterectomy in conjunction with pelvic lymphadenectomy as the most feasible options, I highly recommend radical hysterectomy with pelvic lymphadenectomy. For all three therapy treatments, prolonged exposure to radiation or chemo can cause cancer cells to eventually develop resistance to the drugs used and essentially become immortal. One way this can occur is if the cancer cells can mutate the gene in a way to turn transcription of telomerase on. By doing so, telomerase can continuously produce telomeres to protect the ends of the chromosomes so that they will never shorten to the point of crisis where cells die or enter senescence. Of the three therapies available, only two are applicable to Mariana: chemoradiation and targeted therapy with the drug bevacizumab; when we compare the results from the international trial and the Cochrane meta-analysis as well as the potential harm caused by each treatment, I would suggest that Mariana use targeted therapy with bevacizumab as a last option, especially since her cancer is only at stage IIA. By removing the cancer cells from the body via radical hysterectomy and pelvic lymphadenectomy, the chances of cancer cells developing resistance, becoming immortal, or metastasizing- all which are high when using chemical poisons- are minimized; thus, I recommend this treatment as Mariana's best bet for surviving and preventing recurrent cervical cancer from transpiring.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Conclusion
<span style="font-family: Georgia,serif;">Mariana has squamous cell carcinoma which accounts for the majority of cervical cancer. There are many risk factors associated with this cancer such as smoking, racial identity, having HIV, having a family history of cervical cancer, and most commonly, having an HPV infection. A well-known approach to developing cervical cancer is unresolved high-risk HPV infection which can lead to carcinogenesis through multiple pathways. Luckily, public health advocacy for screening, specifically for Pap smear tests for cervical cancer, has helped prevent numerous cases of advanced stage cervical cancer by detecting it in its benign state and greatly increased 5-year survival rates over the years. However, if cervical cancer has developed, various methods such as surgery, chemotherapy, targeted therapy using bevacizumab, radiation, or a combination of these methods are available and has been shown to be effective. Since cancer is an evolving “organism,” researchers are continuously trying to find new treatments or prevention methods. A new treatment that is currently being tested in clinical trials is sentinel lymph node biopsy, a procedure that allows surgeons to target specific cancerous lymph nodes by using a radioactive tracer embedded in a blue dye. New vaccines that target other types of HPV besides the most common ones (HPV 16 and 18) are being developed that have functions that ranges from prevention to assisting a woman’s immune system fight the HPV infections. With the flourishing of technology, the possibility of eradicating cervical cancer can be considered within the next decade or so.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 13.3000001907349px;">Aperçu
<span style="font-family: Georgia,serif;">To the women of the world: <span style="font-family: Georgia,serif;"> With cervical cancer being a preventable disease through regular screening coupled with the flourishing of technology, the possibility of eradicating this cancer is in the near future. Until then, prevention is key!