Bursley,+Rachel

= Stage IV Squamous Cell Lung Cancer =

Although I did not know it at the time, July 4th, 2008, was the last time I would ever see my Uncle Fred again. Three months later, a middle-aged man who had appeared healthy just weeks before was whisked away in the blink of an eye by one of the most brutal and relentless killers: lung cancer. Though his death was quick, it was in no way merciful or painless. From the time he was formally diagnosed in September, to his death only a month later, he fought a valiant yet fruitless battle that left our family broken and in denial. How could someone be ripped so unexpectedly from our lives? Above all, it just did not seem fair. What good could possibly come of this?

** The Diagnosis **
I remember the initial words of the diagnosis ringing through my ears- “stage IV squamous cell lung carcinoma.” Squamous cell lung carcinoma is a subtype of one of the two main categories of lung cancer: non-small cell lung cancer. Lung cancers are divided into two main groups, non-small cell and small cell, based on their size and treatment approaches. A large percentage of all lung cancers, about 25 to 30 percent, are squamous cell carcinomas. Lung cancers are given names based on the tissues they affect, with squamous cell lung carcinomas growing near the bronchial tubes. The bronchial tubes are the two main tubes that lead from the trachea, where air enters after being inhaled, into each lung (Figure 1). The cancer’s stage of growth is determined by which areas of the body it has spread to, with Stage I indicating its presence only in the lungs, Stage II being growth in the lungs and surrounding lymph nodes, Stage III describing cancer of the lungs and lymph nodes throughout the chest, and Stage IV for cancer that has spread beyond the lungs and lymph nodes, into surrounding fluid or other organs.

Lung cancer is typically very difficult to treat, and the further it spreads, the worse the prognosis is. Apparently, there has been some slight advantage noted for females and those of Asian descent due to the types of mutations that these groups tend to acquire. These mutations may make lung cancer more responsive to treatment than others. Caught in its earliest stage, however, the five-year survival rate for non-small cell lung cancers is about 50 percent at best. By stage IV, this already marginal outlook shrinks down to virtually nothing, with the survival rate equaling only about one percent. Unfortunately, my uncle was not an anomaly. Because the lungs are so large, tumors can grow significantly before any symptoms arise, and consequently most lung cancers are detected when they have already reached stage III or IV. My uncle’s was only found after an MRI was performed after he got into a severe motorcycle accident. The scan lit up, revealing tumors all over his body including in his lungs, adrenal glands, brain and spine. Although he never mentioned anything, he did not seem to be quite himself the last year or so of his life, and looking back my family believes he may have suspected that something was not right. Still, as mentioned above, because the lungs are so large, the cancer can become invasive and spread to other areas of the body before the tumors are large enough to cause serious discomfort.

While the elusiveness of lung cancer partially explained its sudden onset, our family was still in shock as to how such a young and apparently healthy man could become so sick, so seemingly fast. With no family history of lung cancer, we felt as though we had lost a very cruel and unfair game of Russian roulette. We had heard that smoking increases your risk of developing lung cancer, by a whopping 90 percent, but it had been over twenty years since my uncle had taken his last draw. Yet his particular type of cancer, squamous cell lung carcinoma, has been highly linked to smoking. Known to be extremely slow growing, the cancer could have began to brew years before, just now appearing and proving that his quitting was too little, too late.

Other factors could have also promoted mutations leading to the cancer, or making it more aggressive. For instance, being exposed to various compounds such as asbestos, chromium, and nickel can increase your risk. My uncle likely ran into a number these on many occasions not only because some of these compounds were frequently used in homes and buildings as he was growing up, but also due to his budding interest in science, particularly chemistry, which led him to handle many chemicals now known to be carcinogenic. He also held a life-long passion for photography and handled many chemicals and solvents. In addition, a glass of wine or two quite frequently accompanied his dinner, which may have exacerbated the problem. It has been noted that consuming at least 30 grams of alcohol per day, the equivalent of about two glasses of wine, slightly increases your risk of developing lung cancer. Curiously, but tragically as well, some of these risk factors also seem to be not only additive, but multiplicative in nature, so that having exposure to more than one increases your risk more than the independent risks combined.

There had also been signs, though the doctors had not seen them, or at least had not connected the dots and attributed them to lung cancer. My uncle had gone to the doctor a few times months prior for unexplained weight loss, and had a periodic cough for as long as I can remember. These are not surprising symptoms of lung cancer- as the tumors obstruct and irritate breathing pathways, coughing becomes one of the first symptoms of the disease, though doctors rarely look to lung cancer as the culprit. As cancer cells rapidly divide, they also require an increase in fuel, and thus an increase and alteration to normal cellular metabolism that frequently causes unexplained weight loss in patients. As these symptoms are also shared with a host of different diseases ailments, it would seem to make lung cancer exceedingly difficult detect, and in many cases when it is detected, despite treatment, it is too late.

Treatment Options for My Uncle Fred and Others with Stage IV Non-Small Cell Lung Cancer
The standard of care for stage IV, non-small cell lung cancer depends on the location and size of tumors, as well as the patient’s overall health. A wide variety of treatment options may be implemented including chemotherapy, radiation therapy, or targeted therapy. The healthier the patient, the more options the patient has for treatment, and the more aggressive the treatment can be. Even when stage IV patients are otherwise healthy and stable enough for the most rigorous treatment plans, cancer at this stage has by definition spread to other areas of the body, making the main goals of treatment to slow the cancer’s progression and relieve symptoms, rather than cure the disease.

Because the risks often outweigh the benefits, screening is rarely performed for lung cancer. Screening is only recommended for a very small group of people and is generally performed using a low-dose CT scan. One of the main drawbacks of low-dose CT scans is their potential to subject patients to unnecessary and sometimes life-threatening procedures. In one clinical trial, about 25 percent of participants initially screened as a false negative. Because of their low specificity, low-dose CT scans are not often employed, and the cancer is generally found when the patient is very sick and finally showing symptoms, making treatment options limited. Unfortunately, my uncle was not an exception to this rule. He entered the operating room the day he was diagnosed and had several tumors removed from his spine. The plan was to then prolong his life with chemotherapy, and help him to regain some mobility by undergoing physical therapy. Still, while chemotherapy is generally the first tactic used for these patients, and 70 percent of non-small cell lung cancer patients respond to it, response is only defined as relief from cancer-related symptoms, rather than the possibility of being cured of the disease. In addition, actual tumor shrinkage occurs in only about 1/3 of patients.

The surgery left my uncle weak and the cancer was spreading rapidly. Because chemotherapy works by attacking rapidly dividing cells, it not only damages cancer cells, but also healthy cells in the patient’s body. Consequently, the patient must be fairly stable to receive such a harsh treatment. The doctors concluded that the cancer had progressed too far and my uncle had been left too debilitated to undergo such a radical treatment. He received radiation; a very common second-line defense for patients with his type and stage of cancer who cannot receive chemotherapy, to hopefully shrink the tumors temporarily. Still the clock was ticking to seek out other possibilities for a man that was not only dying, but needlessly suffering as well.

Another common therapy that can be used for late-stage non-small cell lung cancer is known as targeted therapy. A targeted therapy, as the name suggests, works by targeting specific proteins that are the result of genetic mutations, which have the potential to aid in the success of the cancer. Bevacizumab, known by its commercial name Avastin, is one targeted therapy that can serve as a potential treatment option for non-small cell lung cancer patients in late stages, however it is not usually given to non-small cell lung cancer patients like my uncle, who have squamous cell carcinoma. Avastin works by essentially depleting the tumor of nutrients and slowing its growth by binding to a protein called vascular endothelial growth factor, also known as VEGF, which when activated allows the tumor to maintain a blood supply, feeding it and allowing it to grow (Figure 2). Because Avastin works by manipulating vasculature, it can increase the risk of bleeding in patients. This can be especially problematic for patients with squamous cell carcinoma who, because of the location of the cancer, frequently have tumors near large blood vessels. Consequently, Avastin was not a viable treatment option for my uncle, and the search continued for something that could ease his symptoms and lengthen his life.

Another common targeted therapy targets the products of a mutated ALK gene. The ALK gene codes for a protein known as the anaplastic lymphoma receptor tyrosine kinase. Receptor tyrosine kinases are signaling molecules, which can send important messages to the cell, commanding it to perform a variety of functions when the receptor is turned on. When activated, the ALK receptor tyrosine kinase tells the cell to grow and divide. Receptor tyrosine kinases such as ALK are turned on when they bump into another receptor tyrosine kinase that is an appropriate partner. However, some patients with non-small cell lung cancer have a mutation in their ALK gene caused by a breakage and re-fusing of the chromosome where the ALK gene is located, causing faulty ALK to be produced. These ALK genes have characteristics of both themselves and their partner so that they can always be turned on, causing the cell to continue to proliferate out of control.

If a patient with non-small cell lung cancer has a mutation in the ALK gene, they may be treated with crizontinib, known as Xalkori, and later ceritinib, commercially known as Zykadia. These drugs work to block the mutant ALK protein from sending a proliferative signal. While more than half of patients with an ALK gene mutation respond to these drugs, studies generally find that the patient is only able to live longer without an increase in symptoms, known as an increase in progression-free survival rate. This is significant because it means these drugs have the potential to lead to a better quality of life, but it has not yet been adequately documented to suggest that ALK gene therapy could extend the patient’s life overall, although this may be a possibility. In addition, only about 5 percent of patients with non-small cell lung cancer have a mutation in the ALK gene, and these are generally patients who have a history of minimal or no smoking. Consequently, with no time to sequence his genome any treatments given would be based on probability alone. It was unlikely that a mutated ALK gene caused my uncle’s cancer, and ALK therapy was not an option for him.

A final common gene therapy targets mutations in the EGFR gene. The EGFR gene codes for a protein known as the epithelial growth factor receptor, which is also responsible for telling cells to grow and divide. Some non-small cell lung cancers are caused by the mutation in the EGFR gene, causing hyper-expression of the receptors on the surface of cells. This increases the likelihood that a receptor will be turned on, and thus that the cell will grow and divide uncontrollably. EGFR mutations can be targeted by a drug known as erlotinib, more commonly known as Tarceva, as well as afatinib, known by its brand name Gilotrif. These drugs also work by blocking the protein, in this case EGFR, thus stopping the proliferative signal at its crux. Unfortunately, non-small cell lung cancers caused by EGFR gene mutations are also most frequently seen in those without a history of smoking. In addition, the patients are frequently female. Thus EGFR gene targeted therapy would also likely prove useless for my uncle.

One of the last options for my uncle was to enroll in a clinical trial. Clinical trials are highly recommended for individuals with late-stage non-small cell lung cancer because the prognosis with current treatments is so poor. Anyone who has ever looked into a clinical trial, however, knows how narrow the selection criteria can be. Although there were many clinical trials available, and still are today, my uncle unfortunately did not qualify for any of them. About a month after his diagnosis, he was gone.

** A Closer Look at ALK-Targeted Therapies **
Although treatment options are in large part dictated by the staging of the cancer, even in the final stages of non-small cell lung cancer, prognosis can look dramatically different from individual to individual. As mentioned several times before, unfortunately my uncle’s cancer was so far along by the time that it was found that eradicating it completely was not an option, and his team of oncologists decided it was better to not waste time screening his cancer for genetic abnormalities that were unlikely in his particular case. However, this tragic outlook is not the same for all non-small cell lung cancer patients, or even all individuals whose cancer has reached stage IV. While a stage IV non-small cell lung cancer diagnosis is not ideal to say the least, and the aims of treatment almost always are to alleviate symptoms and slow the growth of the cancer, many promising therapies are available to greatly extend not only the quality of life, but possibly life expectancy as well. Because cancers even of the same type can arise through such drastically different pathways, the treatment regimen for one patient with stage IV non-small cell lung cancer may be completely different than another, and consequently may have an entirely different prognosis. Due to these vast and important distinctions, I want to highlight a promising treatment for four to seven percent of patients with non-small cell lung cancer: ALK-targeted therapies.

As briefly mentioned above, this small, yet significant percentage of patients, have cancer whose origins can be traced back to the translocation of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene. Typically, these patients have a type of non-small cell lung cancer other than squamous cell carcinoma. Translocation of the ALK gene is caused by a breakage of chromosome 2 at two sites, followed by a reversal and re-insertion of the DNA. This translocation causes the ALK gene to fuse with a new gene, and in most cases for non-small cell lung cancer patients, this gene is the echninoderm microtubule-associated protein-like 4 (EML4) gene. While all of its pathways are not known in detail, the ALK gene is thought to code for a protein known as a receptor tyrosine kinase, that when activated by a signaling molecule, sends a message to allow for proliferation of normal nerve cells (Figure 3). It does this by binding to a partner, each triggering the addition of phosphate groups onto the other using ATP molecules. Like a light switch, this addition of phosphate groups turns on a pathway that relays the message for the cell to grow and divide. However, translocation of the ALK gene allows for mutant receptor tyrosine kinases to be transcribed in which the protein is always activated, and thus always allows for the proliferation of the cell. The ALK receptor tyrosine kinase also acts upstream of various other pathways which are thought to suppress cell death, and promote cell growth. While normal receptor tyrosine kinases must find a partner in order to be turned on, mutant ALK receptor tyrosine kinases can become phosphorylated without a partner. As a result, they are always on, even in cells where their expression is uncommon. For instance, the ALK gene is almost never expressed in lung tissue. However, if the mutant ALK gene is expressed as a result of this mutation, cells can not only grow and divide uncontrollably, but mutant cells which would otherwise be told to stop growing and die may evade cell death. These characteristics lead to the manifestation of two important hallmarks of cancer; sustaining proliferative growth signaling, and evading cell death.

The upshot of having a non-small cell lung cancer caused by this mutation as opposed to others, is that there are multiple targeted therapies that have proven effective and will predominantly only attack the cells producing the ALK gene. Although these targeted therapies have the potential to also work on some other receptors, and thus impact normal cells, they are for the most part effective only on ALK receptors, most likely to be found in the cancerous cells. Indeed, studies show that these drugs usually produce minimal side effects for patients, indicating their specificity. In addition, it has been noted that late-stage non-small cell lung cancers that have a mutation in the ALK gene are very sensitive to ALK-targeted treatments, frequently making these treatments very effective. The two targeted drugs used today for non-small cell lung cancers caused by ALK gene mutations are crizontinib (Xalkori) and ceritinib (Zykadia). Critzontinib is typically the first line of defense, and can be followed up by ceritnib if the patient does not tolerate crizontinib or stops responding to it.

Crizontinib is known as a small molecule inhibitor, and is a competitive inhibitor of ATP. Recall that the signal was constitutively transduced in ALK mutated cancer cells because the receptor tyrosine kinase can add phosphate groups onto itself from ATP molecules. Crizontinib works by binding to these receptor tyrosine kinases so that even if they want to add phosphate groups on, they cannot because crizontinib is instead bound. As a result, the signal is not transduced, and it is as if the ALK gene was not expressed to begin with (Figure 4). In a comparison of patients treated with crizontinib versus chemotherapy, progression-free survival, response rate, and quality of life increased with treatment of the targeted inhibitor. Progression-free survival for those treated with crizontinib was over twice as long as those who were treated with chemotherapy; with the progression-free survival at 7.7 months for those treated with the targeted inhibitor and 3 months for those treated with the standard chemotherapy. The targeted therapy also elicited a response from patients in about half of the time it took for a response to be elicited by chemotherapy. The median response time for chemotherapy was 12.6 weeks, and the median response time for crizontinib was shown to be 6.3 weeks. Overall life expectancy could not be accurately compared as those who began to progress on chemotherapy were given the option to begin crizontinib treatment.

Unfortunately, crizontinib resistance is common in patients within the first few years of treatment. One study showed that a third of patients treated with crizontinib showed cancer that had acquired new mutations that would allow for a faulty ALK gene, while other individuals cancers began producing more of the ALK gene to compensate for the decreased activity caused by the inhibitor (Figure 4). Still other cancers found ways to circumvent the drug by coming up with mutations in unrelated pathways that also promote cell growth and division (Figure 4). As the population of cancer cells evolves with the new selection pressure that the targeted inhibitor poses, new treatments must be sought. Most patients will follow up with another small molecule inhibitor known as ceritinib, a drug twenty times more potent than crizontinib, which works in a similar fashion but in one study showed a decrease in the cancer of 55 percent of patients who had previously been treated with crizontinib. Most likely because of its high potency, ceritinib is only approved by the Food and Drug Administration for use in patients that have already tried crizontinib and either cannot tolerate it or have stopped responding to treatment.

Although a cure cannot yet be promised by these targeted therapies, what they can promise are potentially less side effects, a reliable response rate, and if nothing else, a couple more lines of defense before resorting to chemotherapy or palliative care. While my uncle did not have much of a fighting chance against //his// stage IV non-small cell lung cancer, the key word here is //his//. Cancer is very much a disease specific to the person, and the prognosis can vary greatly from individual to individual. As researchers increasingly use this more personalized approach, hopefully even more promising treatments will be on the horizon.

Conclusion
The loss of my Uncle Fred to stage IV, squamous cell lung carcinoma was sudden and unexpected for my family. However, after my research of this disease I have realized that his story is not so unique after all. Many lung cancers are detected in their later stages, and even for those that are not, treatment options are often limited in their success. If anything good at all can come from the loss of my uncle, it is that my family and I can take on the responsibility to share with others not only the dangers of smoking, but also the importance of being checked at the very first signs and symptoms of this deadly disease, especially if you have been exposed to factors that are known to contribute to its development. They tell you that as the years go by since you have quit smoking, your risk of developing lung cancer drops dramatically. While a very important and motivational message to get across to smokers who have given up trying to quit and think that the damage has already been done, it leaves those who have quit with an unrealistic sense of relief that they are out of the woods. It gives you the idea that a cough or weight loss could not possibly be attributed to something that you have given up years before. What they do not always tell you is that these cancers are frequently slow growing and difficult to detect, and that unfortunately, it may already be too late to prevent the disease. However, it may not be too late to improve your prognosis. Time, however, appears to be rare but crucial in these diagnoses.

Aperçu : Although the statistics for survival rates of non-small cell lung cancer are daunting, early stages of lung cancer that are localized or have only metastasized to one area of the body are sometimes curable, further emphasizing the importance of screening for high-risk patients. If you have a history of smoking or lung cancer in your family, make sure to be proactive with your preventative medicine and inform your doctor of your concerns for developing lung cancer.

//In loving memory of Fred Meyer; a man of endless compassion and generosity. You are deeply missed.//