The case of Delbert Pyle

Delbert Pyle, known to his family and friends as Grandpa Dell, was diagnosed with non-small cell adenocarcinoma, a kind of lung cancer, at the age of 70, a typical age of diagnosis for this specific lung cancer. He works for an oil company called Union Oil, traveling the world with his wife and two sons wherever his work takes him; he and his family lived in Australia for seven years after finding oil and have moved all around the United States. Dell and his wife have smoked cigarettes the majority of their lives, and his wife has been recently diagnosed with emphysema. Dell and his family are upset about his diagnosis, but they are hopeful for a positive prognosis.

Non-small cell adenocarcinoma is a specific type of lung cancer. It does not run in Dell’s family, so is therefore an isolated case. This cancer is not particularly aggressive, as it takes years of build up and several events for it to even be detected by an imaging scan. However, lung cancer causes more deaths per year than does several other types of cancer combined, including colon, breast, and prostate cancers[1] . Since the cancer takes such a long time to be detected, it is able to grow or metastasize to other parts of the body before the patient is diagnosed. The risk of developing non-small cell adenocarcinoma is higher in men than in women, with a one in thirteen chance of being diagnosed1. Race is also a risk factor of this disease, with the risk of a black male developing this disease being 20 percent more likely than a white male developing the disease. The reason for race being a factor is still unclear, but black males are more likely to be diagnosed with this disease along with other various illnesses around the same time[2] . Adenocarcinoma is also usually found to be more common in males than in females. Since Dell is a white male and has smoked for the majority of his life, it can be assumed that the smoking is the main reason for Dell developing this disease. Unfortunately, because of the amount of cigarettes Dell has smoked, it creates a more negative prognosis than if the cancer had developed with an absence of smoking. Luckily for Dell, despite the smoking, he is in relatively good health; he remains active and enjoys watching and playing football with his family. His active lifestyle will have to be lessened and account for the fact that he will be unable to be as active as he has been in the past, due to probable symptoms of bone pain, joint point, and weakness from the lung cancer.

Dell was diagnosed with stage IIA lung cancer. Using the TNM staging system, which measures the size of the tumor, how it has spread to nearby lymph nodes, and whether the cancer has metastasized, Dell’s cancer is reported to be T1a/T1b, N1, M0. This stage determines: “the cancer is no larger than 3 cm across, has not grown into the membranes that surround the lungs, and does not affect the main branches of the bronchi. It has spread to lymph nodes…on the same side as the cancer”[3] . At this stage, the prognosis of Dell surviving for five years is at 30%[4] . This is not an ideal prognosis, and Dell and his family are becoming increasingly worried as they realize the amount of time they have left with Dell could be cut short. The family wishes to pursue any treatment option, but realizes that because of Dell’s age, it is likely that some treatments might not be possible or beneficial to his case.

Dell and his family are curious to find out more about adenocarcinoma compared to other types of lung cancer. Non-small cell adenocarcinoma can be compared to non-small cell squamous carcinoma, a similar kind of lung cancer. Squamous cell carcinomas are usually found towards the center of the lungs, close to a bronchus, beginning in flat cells lining the inside of the airways in the lungs called squamous cells.. One of the main risk factors that lead to the diagnosis of these carcinomas is smoking, similar to adenocarcinomas[5] . Adenocarcinomas, on the other hand, are mostly found along the outside of the lung and are usually be detected later than other lung cancers as it grows much slower than squamous cell carcinomas. The prognosis for adenocarcinoma is much more positive than the prognosis for squamous cell carcinoma, therefore Dell and his family are remaining positive, despite the 5-year survival rate for his particular case.

Dell and his family have come to realize and accept the prognosis, and want to work toward any possible treatments that could extend Dell’s life for any period of time. This diagnosis has brought this family closer together, as they want to make the last years of Dell’s life as enjoyable as they possibly can be. His two sons, who have since moved away and started families of their own have decided to live closer to Dell and spend as much time with him as possible. Dell’s grandchildren are young, with the oldest being 6 years old, and are very excited to be able to spend more time with their grandpa. Dell has decided to quit smoking and work towards a healthier lifestyle in attempts to extend the amount of time he has left with his family. He understands that the prognosis is not great, but still has high hopes that treatment will help and he will be able to live a longer life. It is very tough on the family to have one parent diagnosed with non-small cell adenocarcinoma and the other diagnosed with emphysema, but the family remains strong and unified.

Treatment Options

Dell and his family are still grasping the idea that he has been diagnosed with non-small cell adenocarcinoma. As he is 70 years old and the family understands that the prognosis is not great, they want to make sure that he has a comfortable, family filled end of his life. They would like to pursue possible treatment options, but not if it involves an intense recovery process.

According to the National Comprehensive Cancer Network, or NCCN, the preliminary screening for Dell’s type of cancer involves pulmonary function tests, a bronchoscopy, a pathological mediastinal lymph node evaluation, and PET or CT scan, and a brain MRI[6] . Mediastinal lymph nodes are found in the area between the chest and the lungs, surrounded by the breastbone, spine, and lungs[7] . The cancer is then officially diagnosed using the TNM staging system; Dell has already been informed of his diagnosis of stage IIA adenocarcinoma, or T1a/T1b, N1, M0. Unfortunately at this stage in non-small cell lung cancer, surgery is not a possible option, as the cancer has partially spread to surrounding lymph nodes. Therefore, the doctor suggests treatment by radiation therapy due to Dell’s age and preferences of living out the rest of his life with minimal pain and with his family. Radiation therapy is a less non-aggressive treatment than chemotherapy and surgery, and is standard for a person who cannot be operated on, which coincides with Dell’s situation. Dell also would prefer not to have surgery or chemotherapy, as he wants to enjoy the last years of his life as best as he can. According to the American College of Radiology, radiation can replace surgery as the primary treatment and is used as a potential cure or relief of specific symptoms caused by the primary tumor.[8]

There are four newer techniques of radiation therapy that are possible with lung cancer that the doctor recommends for Dell. The first, called three-dimensional conformal radiation therapy, or 3D-CRT, locates the placement of the tumors and uses radiation beams aimed at the tumor from several directions in order to avoid tissue damage. This is one of the more basic treatments, with slightly lessened radiation side effects such as such as skin problems, fatigue, and nausea[9] .

The second type of therapy is called Intensity modulated radiation therapy, or IMRT. This radiation therapy uses movement of radiation beams aimed at the tumor, adjusting the strength of the beams throughout the time of treatment in order to avoid harming normal tissue. IMRT usually consists of a longer treatment time, due to its complex planning and safety checks[10] . However, due to the amount of planning done before treatment, the radiation beam is very focused on the tumor and leads to less of a possibility for side effects from the radiation. This is beneficial to Dell due to the lessened risk of side effects, but he does not want a treatment that is going to take him away from his family for long periods of time. Also, with the longer treatment, the side effects are most likely going to last longer, making Dell’s ability to enjoy time with his family much harder.

Stereotactic body radiation therapy, or SBRT, is the treatment the doctor highly recommends for Dell. This therapy uses large doses of radiation in focused beams for one to five treatments. The radiation beams are aimed at the tumor from several different angles to avoid healthy tissue and to attempt to lessen tumor movement while breathing. SBRT uses a very complex setup in order to reduce risk of side effects and tissue damage. Unfortunately, due to the complex set up, it takes a significant amount of time before treatment can be done, which could possibly lead to an increase of the severity of the disease[11] . However, this type of therapy seems to have the best results with the least amount of symptoms and the least amount of treatment time, which is ideal for Dell’s desires of a simple treatment with the least amount of effects, allowing him to enjoy time with his family.

The final option for Dell in radiation therapy is stereotactic radiosurgery, or SRS. This therapy is one session uses an extremely high-powered radiation beam for one treatment that can last anywhere between a few minutes or several hours. However, SRS is mainly used for tumors that have spread to the brain, which does not coincide with Dell’s symptoms. Naturally, radiation therapy will have a couple of side effects, such as fatigue, nausea, weight loss, and hair loss, but most of them should go away after treatment. Since Dell’s preferred method of radiation therapy, SBRT, has a short treatment time, however, the side effects should not last too long and Dell can return to living out the rest of his life in peace with his family[12] .

Curious about other methods of treatment for Dell’s cancer, his family has found that many doctors recommend that Dell look at clinical trials to attempt to cure his cancer. One of the ideal possible clinical trials is called Intensity-Modulated Scanning Beam Proton Therapy With Simultaneous Integrated Boost (SIB). Dell fits all of the criteria and is an ideal candidate for this trial. This trial uses either intensity-modulated photon therapy (IMRT) or intensity-modulated proton beam therapy (IMPT) to target the tumor and attempt to avoid surrounding tissue. Intensity-modulated photon therapy, otherwise known as intensity-modulated radiation therapy, and intensity-modulated proton beam therapy are very similar. Both send radiation inside of the body to the tumor, and attempt to lessen the effects of surrounding tissue. However, IMRT uses photon particles, like an x-ray, to send in radiation and IMPT uses proton particles to send in radiation[13] . IMRT radiation intensity can be altered during treatment “to achieve a higher degree of spatial agreement (‘conformality’) of the resulting dose distribution with the tumour target volume”[14] and uses more
Comparison_of_dose_distributions_between_IMPT_(right)_and_IMRT_(left).jpg
Comparison of Photon therapy (left) versus Proton beam therapy (right)
beams than IMPT.As seen in the image, due to IMRT’s (left side of image) use of a large amount of beams to surround the tumor, it is able to reach more of the tumor, but unfortunately more outside tissue is also affected, compared to IMPT which effects less of the outside tissue (right side of image)[15] . This treatment lasts up to six weeks, with a daily 20-30 minute daily treatment and occasionally chemotherapy, depending on what the doctor in charge of the study decides. Patients are randomly assigned to the IMRT group or the IMPT group, using a flip of a coin to determine which group they are placed in. The first step in this process includes a PET/CT or MRI of the lung and then placement into a cradle position, which will be used to hold Dell in the desired treatment position. Dosage of radiation therapy is determined by when the patient enters the trial, with the first group of participants receiving the lowest dose, continuing until the highest tolerable dosage is reached. During the trial, the patient must complete a symptom questionnaire and physical exams at least once a week. One of the major downfalls of this clinical trial is that it is only administered in Massachusetts and Texas, which would separate Dell from his family for an extended period of time. This is a very decent clinical trial, but the doctor encourages Dell to consider SBRT radiation therapy as the main option. The doctor believes that, although this clinical trial may improve Dell’s condition, it is not in his best interest to endure the long process and symptoms that follow chemotherapy and clinical trial procedure.

Adenocarcinoma at a Molecular Level

Dell understands a little bit of molecular biology, and wants to know about non-small cell lung cancer adenocarcinoma in a little more detail before he decides on a treatment. The doctor explains that there are many different types of genes and proteins that can be mutated to cause adenocarcinoma. There is a litany of mutations in proteins and other factors that can lead to adenocarcinoma, but some of the most common critical mutations are found in TP53, KRAS, KEAP1, and EGFR proteins. About 51% of people with adenocarcinoma have TP53 mutations, 26% have KRAS mutations, 14% have KEAP1 mutations, and 10% have EGFR mutations.[16] TP53, KRAS, and KEAP1 are different types of proteins that have specific functions throughout the body. TP53 is involved in the cell cycle and determines whether or not a cell can continue to divide through various checkpoints throughout the cycle. KRAS encodes a GTPase and helps to control cell growth, apoptosis, and differentiating between cells using many different effectors,[17] and KEAP1 is a protein-coding gene that can suppress transcriptional activity and target specific proteins for degradation.[18] EGFR, found upstream of KRAS, is an epidermal growth factor receptor protein that leads to cell proliferation by dimerization and phosphorylation.[19] Even though these are the most commonly mutated proteins, there is still a low percentage of patients that have these mutations, showing that each individual person has their own combination of mutations that result in adenocarcinoma.

KRAS is unique in the sense that it is mostly found in adenocarcinoma and rarely found in squamous cell carcinoma, a very similar subset of non-small cell lung cancer. KRAS is activated by point mutations in DNA, specifically amino acid substitutions on positions 12, 13, or 61.[20] These missense mutations activate the KRAS pathway, which can form RAS proteins with impaired GTPase activity. The mutated RAS proteins proceed to sustain proliferative growth signaling and evade apoptosis.2 Unfortunately, KRAS is found mainly in patients who smoke or chew tobacco, and treatments are currently in the clinical trial stages, meaning that if Dell is found to have this mutation, his chances for five year survival are lessened.[21] However, there is work being done on drugs targeting downstream pathways to inhibit KRAS. Current studies of phase I and II trials have shown that an inhibitor of MEK, one of the pathways associated with KRAS, such as selumetinib or trametinib, in combination with the drug docetaxel, can target these KRAS mutations to inhibit cell growth. Results are inconclusive as of now, but there is hope that continuing trials will lead to subsequent phase III trials determining the best combination of drugs to prevent proliferative signaling of KRAS.[22]

EGFR, although only present in 10-15% of non-small cell lung cancers, is also more unique to adenocarcinoma than to squamous cell carcinoma. Mutations of EGFR make it much more sensitive to tyrosine kinase inhibitors such as gefitinib and erlotinib, which interrupts EGFR signaling. Therefore, patients who have tumors with EGFR mutations have a longer survival rate than those with KRAS mutations, as the more sensitized the mutation in EGFR, the easier the tyrosine kinase inhibitors can take action.6 MET, a mesenchymal epithelial transition factor, encodes HGFR, heypatocyte growth factor receptor, which is involved in regulating cell growth and signal transduction. In non-small cell lung cancer, MET is usually amplified, which helps cells to induce proliferative growth and evade growth suppressors. Although normally found before targeted therapies, MET can be found to arise as a resistance to EGFR tyrosine kinase inhibitors, suggesting that targeted therapy can lead to cells containing resistance factors. Two of the most common drugs that are used block the signal of EGFR to proliferate cell growth are called Erlotinib and Afatinib. These drugs attempt to stop growth factors from binding to the EGFR proteins, therefore preventing cancer cells from sustaining proliferative signaling. However, as with all drugs come several possible side effects such as skin problems, diarrhea, mouth sores, and loss of appetite.[23]

One of the most common mutations, found in many cancers, is that of TP53. In a study taken to determine gene expression in adenocarcinoma and squamous cell carcinoma, it was found that p53 was generally under-expressed, meaning that the p53 pathway could be disrupted due to a loss-of-function mutation or deletion.[24] As a tumor suppressor gene, when TP53 is mutated, cancer cells are able to grow and proliferate uncontrollably. The most frequent mutations are normal C to T nucleotide transitions changing to C to A transitions. TP53 is mainly involved in the two main hallmarks of cancer, sustaining proliferative signaling and evading growth suppressors. Sustaining proliferative signaling is one of the most important and therapeutically targetable hallmarks, with many cancer cells inducing amplification of proliferative signaling genes, such as EGFR.[25] As you can see from the image below, the suspected percentage of mutations of genes involved in adenocarcinoma cancer growth is displayed by each hallmark of cancer, as well as by the emerging hallmarks, enabling characteristics, and a suggested new hallmark. This shows how many different possibilities and pathways there are for cancer to form, and how unique each individual cancer can be. Dell is excited to have learned more about his disease on a molecular level, and hopes to find out what specific mutations occurred to cause his cancer.
Non-small cell adenocarcinoma associated genes.
Non-small cell adenocarcinoma associated genes.


The Final Stages

Dell has learned a lot about non-small cell adenocarcinoma of the lung. He has found that there are many possible gene mutations, such as KRAS, EGFR, and TP53, that could have occurred to cause his cancer, and that there are specific drugs that could interfere with the pathways of the mutated genes and attempt to stop any future cancer growth. He has learned about the possible radiation therapies, specifically Stereotactic Body Radiation therapy, as well as the possible clinical trials, such as the option comparing the effects of proton beam therapy versus photon therapy, while also realizing that there are several side effects with every treatment option. Weighing his options, Dell and his family decide to choose the Stereotactic body radiation therapy option, as it allows Dell to remain close to his family and live out the rest of his life with hopefully minimal pain and symptoms.

Aperçu Non-small cell adenocarcinoma of the lung is a cruel cancer, which does not give Dell a very long life expectancy. KRAS and EGFR mutations in this cancer, which proliferate cell growth, are tough to treat. Dell should take the treatment with the least amount of side effects to be able to spend time with his family, and you should learn from his mistakes by not smoking and treating your body well.
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