Introduction


Mila is a seventy-six year old woman who has recently been diagnosed with stage III, epithelial ovarian cancer. A retired teacher and a loving mother and grandmother, she enjoys art and being outdoors. She is a generally active and healthy woman who goes on walks every day. She has no known family history of cancer and had not suspected anything was wrong prior to seeing her doctor. Following a routine physical examination, her doctor became worried upon detecting a possible enlarged ovary during her pelvic exam. Upon discussion with the patient, it came to the doctor’s attention that she had recently been feeling bloated and slightly fatigued, but had felt no reason to be worried, unaware that such feelings could be symptomatic of cancer. Following the pelvic exam, Mila’s doctor ordered tests to be run, including an ultrasound, and determined that she does indeed have cancer. She has since scheduled an appointment with a gynecological oncologist.


Part I - The Cancer


Ovarian cancer is fifth most common cause of cancer-related death in the United States.[1] It is estimated that there will be over 21,000 new cases of ovarian cancer diagnosed, leading to over 14,000 deaths this year.[2] Incidence of ovarian cancer has been slowly decreasing since the 1980s, while the number of deaths has been increasing.[3] The current overall five-year survival rate is 45%, but survival rates vary greatly depending on the stage of diagnosis. Patients diagnosed at the local stage, when the cancer is confined to the ovary, have a 92% five-year survival rate, but only 15% of patients are diagnosed this early. Slightly more patients, 18%, are diagnosed at the regional stage in which the cancer has spread to nearby lymph nodes. These patients have a 71% five-year survival rate. The vast majority of cases, 61%, are not diagnosed until the cancer has spread to other areas of the body, constituting the distant stage. The five-year survival rate for these patients is only 27%.[4]
Mila sadly falls into this last category.
The Stages of Ovarian Cancer
The Stages of Ovarian Cancer
Late stage diagnosis is most common for ovarian cancer, because no sufficiently accurate early detection mechanism exists and women are unlikely to notice any obvious symptoms until the cancer is severe. Doctors are typically only able to detect the disease during pelvic exams when the cancer is already advanced.[5] Furthermore, the most common symptoms include bloating, abdominal pain, increased urinary frequency, loss of appetite, and fatigue, which are commonly experienced in women without cancer, and are not likely to cause concern unless persistent for quite some time. Mila had experienced a few of these symptoms, but like most women, did not suspect anything was really wrong. While each of these symptoms can have a host of causes, in ovarian cancer they are likely caused by pressure of the cancerous growths on neighboring organs in the abdominal cavity and an accumulation of fluid. The enlarged ovary itself would not be likely to cause the pressure, as there is a significant amount of space surrounding each ovary, but the growth would cause an accumulation of fluid and cancer metastasis to nearby organs would lead to the pressure, fluid buildup, and swelling.

Major risk factors of ovarian cancer include a strong family history of breast or ovarian cancer and a previous instance of breast cancer, because these both indicate a likelihood of BRCA1 or BRCA2 mutations. Women who fall into this category may be able to reduce their cancer risk by having their ovaries and fallopian tubes removed. Since she has no family history of cancer, it is unlikely that Mila falls into this category, so there was need for her to be taking any extraordinary preventative measures.[6] Additionally, pelvic inflammatory disease and Lynch Syndrome, a genetic disorder that increases risk for colorectal and certain other cancers, are linked to increased ovarian cancer risk.[7] Heavier and taller women are also more like to suffer from ovarian cancer and incidence is greatest for white women compared to other races.[8] The median age of diagnosis is sixty-three and about seventeen percent of patients are diagnosed, like Mila, between the ages of seventy-five and eighty-four. This age group has the highest mortality rate from ovarian cancer, making up over twenty-five percent of total ovarian cancer deaths.[9]

Mila is pretty typical of patients diagnosed with ovarian cancer as a tall, older, white woman. There is no way she could have expected to get this cancer, as she has led a healthy life, making this diagnosis even more unfortunate. Her age along with the advanced stage of the disease sadly make long-term survival very unlikely. Knowing her personality, she will definitely fight the disease as best she can, but it is probable that she will succumb to it in the end. Having her family around her will hopefully bring her some comfort in this time of need as she begins the standard treatment process.


Part II - The Treatment

Treatment of ovarian cancer depends on a variety of patient specific factors, but typically involves both surgery and one ore more forms of chemotherapy. The first step following diagnosis in almost all cases is surgery. Following surgery, a drug treatment plan will be created based on the stage of the disease and the overall health of the patient among other things.

The primary surgical step of ovarian cancer treatment serves multiple purposes and should be performed by a gynecological oncologist if possible. These doctors are trained in the specifics of cancers of the female reproductive system and are more knowledgeable of the intricacies of these diseases than a more general oncologist or surgeon. Unless the cancer is diagnosed at a very early stage, open surgery must be performed and laparoscopy is not possible. The first goal of surgery is the determination of the more specific stage of the cancer. While preliminary staging of advanced stage ovarian cancer can be done using ultrasound and MRI, the full extent of the disease’s spread can only be determined through surgery. Samples of various abdominal tissues and fluid are taken for microscopic evaluation to look for the presence of cancerous cells.[10] Based on ultrasound imaging, Mila’s cancer has been denoted as stage III due to possible cancerous growths in her abdomen. Depending on the location and size of these growths, it will be more specifically staged as IIIB or IIIC. Stage IIIB consists of growths of 2 cm or smaller, while stage IIIC growths are larger than 2 cm. In both cases, growths are confined to the abdomen and may be on the surface of the liver or spleen, but not inside either organ.[11]
Female Abdominal Anatomy
Female Abdominal Anatomy
The second goal of surgery is the removal of as much of the cancerous tissue as possible, which is known cytoreduction or debulking. While it is nearly impossible to remove all of the cancer from the abdomen once it has spread from the primary tissue, a vast reduction in size increases the effectiveness of chemotherapy following surgery. Typically, the surgeon will remove the uterus along with both ovaries and fallopian tubes. In young patients with stage I cancer, unilateral ovary and fallopian tube removal may be possible if the patient wants to retain the ability to have children, but this does not apply in Mila’s case. In addition to the reproductive organs, other organs suspected to be invaded by cancerous cells, such as the appendix, bowel, spleen, liver, pancreas, or stomach, may be totally or partially removed. Extensive resection of upper abdominal metastases will only be performed if the patient is determined to be able to tolerate such an invasive surgery. Since Mila is in good health and can thus handle such a surgery, her surgeon will remove all metastases possible. The overall goal of debulking is to reduce the cancer as much as possible by removing all visible cancer and reducing all growths to less than 1 cm in size.[12] The fewer cancerous cells that remain in the abdomen following surgery, the more likely it is for all of the cells to be killed by cancer drugs.

Following surgical reduction of the cancer, patients typically undergo adjuvant chemotherapy to kill the remaining cells and prevent further growth. In addition to intravenous chemotherapy, patients may also be prescribed intraperitoneal (IP) chemotherapy. IP chemotherapy, which is injected via catheter into the abdomen, is recommended for stage III patents whose cancer has been reduced to less than 1 cm, but the increased concentration of drugs in the abdomen causes significantly more severe side effects.[13] In someone of Mila’s age, this form of treatment would not be recommended due to the excessive stress it would put on her body. Two classes of drugs are typically prescribed for the treatment of ovarian cancer, taxanes and platinum-based drugs. Taxanes are microtubule inhibitors and act by preventing the proper formation of the mitotic spindle, by inhibiting microtubule assembly or disassembly. Platinum-based drugs cause DNA crosslinking, inhibiting the cancer cell’s ability to repair or synthesize DNA. These drug types work together to disrupt the cell cycle and prevent proper division, ultimately leading to cell death. This damage cannot be confined to cancerous cells however and patients will likely experience negative side effects, including nausea, vomiting, loss of appetite, hair loss, and hand, foot, and mouth sores.[14] Additionally, these drugs may damage peripheral nerve cells, leading to neuropathy, which has a combination of symptoms, such as tingling, burning, pain, numbness, and muscle weakness.[15] Chemotherapy also brings the risk of severe allergic reactions, including death. The patient’s doctor will determine the specific drugs, dosing, and number of cycles. The most recommended regimens consist of a combination of carboplatin and either paclitaxel or docetaxel.[16] A randomized clinical trial found that while patients given either of these two taxanes had similar progression-free survival, objective tumor response, and 2-year survival rates, overall side-effects and toxicity were worse for paclitaxel.[17] Thus, Mila would benefit from a regimen including docetaxel as it is advantageous to reduce the potential adverse effects of chemotherapy as much as possible, especially at her age. Patients over the age of 65 are unable to complete their prescribed number of chemotherapy cycles more often than younger patients. Older patients also experience increased cancer drug toxicity, because their bodies are generally weaker.[18] Although Mila is in overall good health, her age will likely contribute somewhat to the severity of her chemotherapy side effects. Following chemotherapy, patients will undergo clinical reevaluation to look for cancer recurrence and cancer antigen levels in their blood may be monitored for an extended period of time. If the cancer does return, patients may be treated with lower dose chemotherapy to control symptoms and increase their length or quality of life.


Part III - The Molecular Basis

Like all cancers, ovarian cancer develops as a result of various somatic mutations that lead to uncontrolled cell growth. The most commonly mutated genes in the ovarian cancer genome include several known to act as oncogenes or tumor suppressor genes in a variety of cancer types. The gene implicated in the greatest number of cases is TP53. 46% of ovarian cancers involve a mutation in this gene.[19] TP53 is considered a tumor suppressor gene, because normal function of the protein it encodes keeps cell growth in check and loss of gene function leads to tumor development. The encoded protein contains transcriptional activation and DNA binding domains. As a transcription factor, it regulates more than 100 genes associated with the cell cycle. These genes can in turn induce senescence, cell cycle arrest, apoptosis, or DNA repair in response to stress.[20] Mutations in TP53 help cancers to evade of cell death. The next most prevalently mutated gene in ovarian cancer is FOXL2, which is involved in 18% of cases.[21] The product of this gene is also a transcriptional regulator. Instead of being implicated in a variety of cancers, it is more specific to ovarian cancer, because the protein is only found in the ovaries. It is implicated in ovary cell differentiation and maintenance and also can induce apoptosis in these cells.[22] Thus, the gene acts as a tumor suppressor gene in ovarian cancer, helping cells evade death. A mutation in the FOXL2 gene will prevent apoptosis in mutated cells, leading to the uncontrolled growth characteristic of ovarian cancer. Another gene that is involved in multiple cancer types is KRAS, which is mutated in 12% of ovarian cancer cases.[23] KRAS is an oncogene involved with tissue signaling at the cell membrane and signal transduction pathways via its GTPase activity.[24] In the absence of normal tissue signaling, cells can proliferate uncontrollably, causing cancer. Another oncogene, which presents mutations in 9% of ovarian cancer patients, is PIK3CA.[25] In addition to cellular signaling, as is typical for oncogenes, PIK3CA is also involved with vasculogenesis through a not yet determined pathway.[26] In addition to the uncontrolled growth of cancer cells, this mutation also induces angiogenesis, the growth of vasculature needed to supply oxygen to the tumor. Continued expression of the gene allows the tumor to produce more and more blood vessels to sustain its continued growth. Mutations in each of these genes alter cells in a specific way, but the common thread is that they all help the cancerous cells to live and proliferate. Accordingly, knowledge of the genetic basis of the cancer can promote the development of different treatments.

Recent developments in the treatment of cancer revolve round so-called targeted therapies. These drugs target specific molecules that are involved with cancer progression. They interact with these molecules to prevent new cancer cells from forming and tend to be specific to a single cancer type. Using cancer genotyping data, therapies are designed to target the products of the most commonly mutated genes or to otherwise affect the involved pathways. There are currently no targeted therapies for the treatment of ovarian cancer. As members of signal transduction pathways, however, the KRAS and PIK3CA gene products could provide an opportunity for the development of such a therapy that would be effective in a number of ovarian cancer cases. If a drug were to be developed that could turn off KRAS or PIK3CA, it would stop the uncontrolled proliferation of the cancerous cells. Inhibition of either of these growth-signaling pathways would represent a breakthrough in ovarian cancer treatment, but at this point systemic chemotherapy is the only drug treatment option.

The two chemotherapy drugs most commonly prescribed together for ovarian cancer are docetaxel and carboplatin, which work together to prevent proper cell division and induce cell death. Docetaxel is a member of the class of drugs called taxanes, which act as microtubule inhibitors and prevent the proper formation of the mitotic spindle, by inhibiting microtubule assembly or disassembly. Docetaxel inhibits microtubule disassembly by binding to β-tubulin and stabilizing the microtubules. In addition to preventing their disassembly, docetaxel inhibits the lengthening and shortening of microtubules that is necessary for intracellular transport. The excess microtubules bundle and accumulate, which triggers apoptosis of the cells.[27] In addition to directly inducing apoptosis, the inhibition of microtubule disassembly prevents proper mitotic spindle formation. Without the spindle, these cells cannot divide correctly and the cell cycle comes to a halt. This again leads to cell death. Carboplatin, on the other hand, is a platinum-based drug, which inhibit the cancer cell’s ability to repair or synthesize DNA. Carboplatin acts as an alkylating agent, adding alkyl groups to various electronegative groups within the cell.[28] Alkylated DNA bases recruit repair enzymes, which break up the DNA as they try to replace the affected bases. This segmentation prevents transcription from occurring. Additionally, carboplatin forms cross-links between guanines in double-stranded DNA, which inhibits the uncoiling of the DNA, preventing replication and transcription. It also induces nucleotide mispairing leading to mutations that prevent the cell from carrying on its life cycle.[29] By targeting both the DNA and the cancer cells as a whole, this combination of chemotherapy drugs ensures cancer cell death. It is impossible to target only the cancer cells however. Other dividing cells, such as epithelial cells, white blood cells, and those of the hair follicles are killed off as well. This results in the common chemotherapy side effects of nausea, from gut epithelial lining disruption, weakened immune function, from a decrease in white blood cells, and hair loss, from hair follicle cell death.


Conclusion

The lack of targeted therapy and difficulties in early detection make epithelial ovarian cancer very deadly. Especially in Mila’s case, as an older woman, the chances of extended survival are very low. Following staging and debulking surgery, Mila should discuss a chemotherapy regimen with her doctor. Because there are increased side effects and such a high mortality rate for older patients, she should also discuss palliative care options. Since she is a strong and otherwise healthy woman, she should undertake chemotherapy, but also realize that it may be an extremely uncomfortable process. If the side effects become too great to handle or force her to deviate too much from her typical way of life, she may want to discontinue treatment. Foregoing chemotherapy, while it would definitely shorten her life, could increase the quality of the time she has left.


Metastatic ovarian cancer is the toughest of opponents and how long you decide to fight is up to you, but stay strong and keep your loved ones close.


In loving memory of Emilie Ludmila Marchand
IMG_5228.jpg
My grandma, Mila, with my two younger brothers and I circa 1999

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