There are many chronic medical disorders that cause pain and disability in patients. Cancer patients are no different; however, at times our treatments incite chronic symptoms that affect our patients negatively. We must all be committed to finding more effective and less toxic therapies for patients diagnosed with cancer. It is a noble and always worthwhile mission.
Personalized cancer therapy – What’s all the buzz about?
We live in a remarkable time of advances in science and medicine. The human genome has been sequenced and mapped. Materials and drugs on a nanoscale are being designed and developed to treat cancer, infectious diseases, and other human medical conditions. The usually numerous genetic abnormalities present in the cancer from any given patient can now be measured and described, and at times, even acted upon if a specific genetic or cellular pathway abnormality is present matching a drug known to improve killing of cancer cells with that specific mutation or aberration.
Until recently, biopsies of tumors were a process involving surgery or needles placed under ultrasound or some other type of radiologic guidance; we are now entering an era of “liquid biopsies”. Cancer cells shed from solid tumors at a variety of locations in the body can be detected in the blood, collected, and studied. Snippets of DNA circulating in the blood released from cancer cells can also be measured, and may serve as easier and more rapid ways to make a diagnosis of a specific type of cancer, to determine appropriate treatments, and to follow patients who have completed treatment to monitor for recurrence of malignant disease.
Personalized (also called precision) cancer therapy is currently a popular buzz phrase in the oncology community. Unfortunately, personalized therapy has not been adequately characterized or defined. Most patients want this phrase to imply they will receive a truly unique treatment for their particular malignant disease. This represents disreality and sometimes, disinformation. The average cancer, despite the organ of origin, contains dozens of mutations, deletions, or alterations in the genes. This does not account for the many other variations occurring in epigenetics, which are changes caused by modifications in expression or activity in other genes rather than abnormalities in the genes themselves. Cancer represents a cascade of genetic and molecular events that conspire to produce an autonomous collection of cells, out of control and able to reproduce and spread to other areas.
If you take one hundred patients with a given specific cancer diagnosis, say stage III colon adenocarcinoma, meaning a malignant tumor in the colon spread to lymph nodes near the tumor, the majority will get identical treatment involving surgical removal of the affected section of colon including the regional lymph nodes, followed by six months of standard adjuvant chemotherapy. Certainly, major advances have been made in understanding whether or not a colon cancer has a finding called microsatellite instability or not, and it is possible to perform other basic studies which may be useful in predicting response to chemotherapy drugs or prognosis. Some patients may have a “targeted” agent added to the chemotherapy agents based on the presence or absence of a few specific genetic findings. These targeted agents are stunningly expensive and are not without risks or side effects. Nonetheless, here we are almost twenty years into the new millennium and most patients are not candidates for novel or targeted approaches to treat their cancer.
Grade III and IV toxicities
I do not bemoan the state of modern multidisciplinary cancer therapy. I am exhilarated by the potential over the next several decades to move finally toward more individualized treatment options. We are simply not there yet. For the time being we still perform a logical series of investigative steps for new drugs leading to the holy grail of the academic investigator; the randomized controlled clinical trial. This produces so called level I evidence indicating a new drug or combination of drugs improves the survival probability of patients by some usually small, single digit percentage. Home runs, represented by a major (20% or more) improvement in long-term survival probability of patients receiving a novel therapeutic approach are rare. A multitude of cancer drugs have been approved by the Food and Drug Administration when clinical trials of hundreds or thousands of patients demonstrated an only 2-5% increase in survival probability. Usually at a cost of short- and long-term side effects, and occasionally even a few patient deaths caused by the treatment itself.
I am disturbed when I attend oncology meetings and hear physicians speaking dispassionately about the grade III or IV toxicity rates associated with a particular study drug. Grade III and IV toxicities are troubling, potentially dangerous, and more severe side effects with significant impact on patients’ daily quality of life. I was at a multidisciplinary oncology meeting recently where three consecutive speakers spoke about novel cytotoxic or immunotherapies which produced grade III or IV toxicities in “only” about 20% of patients treated. They were seemingly pleased with what they considered to be a low rate of severe problems, and quickly moved to point out the drugs increased survival time by almost six months. I wonder how the one out of every five patients who suffered those temporary or permanent life-altering side effects felt about the “low toxicity rate”? We are all intent on ridding the patient of their malignant disease and pulling out all the stops to extend survival, but I fear we not infrequently forget the impact of our therapies.
Return of a former patient
I saw a patient in clinic last month who is an interesting and strange combination of a cancer treatment success story but also a cautionary tale. I recognized the name when I saw it on my clinic list, but couldn’t immediately place a face or a story to him. He was coming to see me as a new patient. He was referred to me with a diagnosis simply stated as “liver cancer”. I walked into the examination room, and a slightly built, thin gentleman in his late 60s rose slowly from the chair. He smiled and greeted me, asking, “Do you remember me, Doc?” He certainly looked familiar and as I swept the dusty corridors of my memory files, I suddenly realized I did know this man. However, he had aged markedly since I had last seen him. I grasped his shoulder with my left hand and enthusiastically pumped his right hand. I asked him to take a seat and I opened with a very general question, “What is going on?”
He spoke for the next ten minutes and laid out the amazing and harrowing medical journey he had traveled since I last saw him. My history with this gentleman began over twenty-five years ago when he was diagnosed with a malignant tumor in the right side of his colon. I removed the tumor-bearing section of colon and because it had spread to two of the lymph nodes near the primary cancer, he received six months of the standard adjuvant chemotherapy at the time; two drugs called 5-Fluorouracil (5-FU) and Leucovorin. This man worked in machine shops and around oil drilling rigs throughout Texas and offshore in the Gulf Coast so he was outdoors in the sun frequently. He developed significant blistering of his exposed skin from enhanced sun sensitivity related to the 5-FU treatments. Nonetheless, he endured the treatments and returned to his normal life and duties.
I lost track of him after the colon operation until 2001. He didn’t want to take time off from work to travel to the big city. He had gone almost nine years without any evidence of cancer until his medical oncologist noted a slight rise in a serum tumor blood test; carcinoembryonic antigen (CEA). A perfunctory CT scan revealed a solitary metastasis at the edge of the right lobe of the liver. He was referred to return back to see me for surgical treatment. After we completed a thorough diagnostic evaluation, I performed a segmental resection to remove the single tumor which required removing less than 10% of his normal liver volume. At the time I noted his liver was quite normal in appearance. This gentleman was a smoker, admitting he smoked at least two packs of cigarettes a day while on the job, but he was not a heavy drinker. As he put it to me, he enjoyed an occasional glass of wine when he took his wife out for dinner or a beer at a ball game. He certainly had no evidence of any liver damage or abnormalities other than the single liver metastasis.
“I’m still around, Doc!”
This gentleman returned to his hometown in central West Texas and received an additional six months of chemotherapy with his local medical oncologist. This included a drug relatively new at the time. We have subsequently learned this drug can produce damage to the liver by inducing a condition called steatohepatitis, literally fatty inflammation of the liver. Any drug or agent causing damage and inflammation to the liver can produce cirrhosis of the liver. Excess alcohol intake inflames the liver leading to cirrhosis, certain chemicals can cause liver damage, and worldwide chronic infection with hepatitis B or C virus causes liver inflammation, damage, cirrhosis, and an increased risk to develop primary hepatocellular cancer.
I am foreshadowing here. This gentleman had never returned to see me after his operation in 2001. He explained when he returned recently he was too busy working rigs offshore and throughout different areas of Texas. I had not seen him in over fifteen years. He had aged dramatically during those years and was diagnosed with three new different cancers. First, in 2004 he developed a cough and a chest X-ray revealed a tumor in his upper right lung. A biopsy confirmed primary lung cancer so he underwent surgical removal of the upper lobe followed by six months of another chemotherapy cocktail. Sadly, despite developing a cigarette-induced cancer, he did not stop smoking. In 2010 his wife, also a smoker, developed an aggressive lung cancer and rapidly succumbed. Before she passed away, she mentioned to him, “Your voice is hoarse and scratchy, what is wrong with you?”
After burying his wife, he went to see his oncologist who referred him to a head and neck surgical specialist. A squamous cancer of the vocal cords was diagnosed. He underwent more chemotherapy and radiation therapy. When I saw him last month he had a voice that sounded like Joe Cocker after smoking several packs of cigarettes. This was his new normal. He reported his mouth was constantly dry from radiation therapy. He had difficulty swallowing and he always had the worst case of “cotton mouth” he could imagine. I recalled he was always a wiry gentleman, but he was now emaciated related to his difficulties with dry mouth and swallowing.
Dutifully, this gentleman went to see his medical oncologist and he performed various screening studies. One of these included measurement of tumor marker for prostate cancer called a prostate specific antigen, or PSA. In 2014 this blood value was significantly elevated. Further diagnostics studies and biopsies revealed prostate cancer. The patient underwent more radiation therapy to the prostate gland and the serum PSA value returned to normal. However, as a side effect of the radiation therapy he developed significant radiation proctitis, meaning inflammation of the lining of the rectum, manifest as frequent bleeding with bowel movements and severe pain upon defecation.
As he recounted all of these events and interventions, I sat quietly, occasionally shaking my head in disbelief and incredulity at what he had endured. I tried to put a positive spin on things when I told him, “You are a remarkable guy. Here you are alive and kicking over 25 years after your original cancer diagnosis.”
He rapidly and quietly deflated my congratulatory attempt when he stated, “You guys keep trying to poison me with drugs and radiation, but I’m still around, Doc.”
Can chemotherapy drugs cause liver damage?
A clear understanding was reached without further comment from either of us. He is alive, but he paid a high price because of his personal choices and addiction to cigarettes causing lung and vocal cord cancer, and because of the numerous cancer treatments to control and eradicate his malignant tumors while damaging normal tissues and organs. I proceeded to ask about his current situation. He reported he developed right upper abdominal pain just before the new year and his oncologist had obtained a CT scan. Two new tumors were present in his liver, and his oncologist was surprised to discover he had clear evidence of cirrhosis of the liver. The patient’s liver was shrunken in size and had a crenelated appearance consistent with the usual cobblestone scarring of a damaged liver. He also had dilated venous blood vessels, called varices, denoting increased pressure in the portal venous system of the liver. A biopsy of one of the tumors revealed hepatocellular cancer. This gentleman had no evidence of hepatitis of B or C virus infection on additional blood tests, and was not a heavy alcohol drinker. When I pressed him for additional information, he readily admitted he worked around numerous types of toxic chemicals during his long career, but he asked an incisive question, “Could the chemotherapy drugs have caused damage to my liver?”
A reasonable question for which I had no definitive answer, but I did inform him it was possible. The liver is the organ that breaks down or metabolizes all drugs and medications we deliver to patients either as tablets or through intravenous drips. Chemotherapy drugs by definition are toxic compounds and injury and inflammation to the liver is a potential outcome. This man had also spent a career working with industrial solvents and chemicals known to produce liver damage. The liver damage leading to cirrhosis in my patient was not from the common causes of hepatitis B or C virus infection or alcohol abuse, but was likely multifactorial in nature. Chemotherapy drugs are one of those factors.
Microwave thermal ablation
The malignant tumors in this man were in the right lobe of his liver. Based on location within the right lobe, I knew it would require removal of over 65% of his liver. I was aware such a significant resection of volume in this man with relatively advanced cirrhosis would produce lethal liver failure. Fortunately, a complete workup to detect any evidence of metastasis of the liver cancer to other areas in the body was negative. Therefore, I performed a less invasive operation using two small incisions each 1cm in size. Through one incision just above the belly button I placed an operating laparoscope which provides magnified images of all of the organs in the peritoneal cavity. Through the second incision I placed a laparoscopic ultrasound probe to identify and locate the malignant tumors. I was then able to pierce the skin with a microwave ablation needle and use the ultrasound probe to guide placement of the needle into each tumor. The microwave equipment was activated and at the completion of this treatment, both tumors and a surrounding zone of the liver had been destroyed. He tolerated this operation without any complications or difficulty and was discharged home two days later.
One of his tumors was at the surface of the far right lobe stretching the liver capsule. This was likely the cause of his initial pain and discomfort leading him to seek attention with his local physician. Happily, after the microwave thermal ablation, the pain related to the liver tumor abated within a few days.
I saw this man back in my clinic recently for his first post-operative checkup. When I asked him how he was feeling, he replied with a smile and a wink, “I feel all stretched out.” Prior to the operation I had described the technique of a laparoscopic surgical procedure, which includes distending the abdominal cavity with carbon dioxide gas to permit better visualization of all of the organs and structures. It does stretch the abdominal wall a bit, and most patients have some soreness of their abdominal wall for a few days. This man entered dangerous territory when he looked at the female medical assistant with me in the room and told her, “Now I know what pregnancy feels like.”
The medical assistant has been through two pregnancies and full term deliveries of healthy babies. With what can only be described as a sneer and a look of pure disgust, she retorted, “I don’t think so.” I quickly suggested to my patient he refrain from comparing a brief laparoscopic operation to a nine-month pregnancy or be faced with open derision and possible physical harm. He laughed, the medical assistant shook her head, rolled her eyes, and uttered a single word, “Men!”
More effective and less toxic therapies
Over a quarter of a century this man has developed, and so far survived, five different distinct types of cancer. He has now lived over fifteen years after being diagnosed with stage IV colon cancer. He developed colon cancer at a relatively young age, and with his panoply of cancers he deserves a thorough genetic evaluation. He is directly responsible for at least two of his cancers, lung and the vocal cord, thanks to decades of smoking cigarettes. All of his cancers may be related to environmental factors and exposure to potentially toxic substances. I cannot exclude chemotherapy as at least a partial cause of his liver injury and resultant cirrhosis. Hepatocellular cancer can be very aggressive and has a high rate of recurrence. This man has survived four previous cancers, only time will tell how he does following treatment of the fifth. Importantly, this patient accepts full responsibility for behaviors causing some of his malignant disease, but he is openly disheartened and adversely impacted by chronic side effects related to his cancer therapies. He has chemotherapy-induced hearing loss requiring high decibel conversations and numbness in his hands and feet that prevent him from doing the woodworking he once loved as a hobby. He has dry mouth, difficulty swallowing, rectal pain, and bleeding because of damage caused by ionizing radiation treatments. He looks much older than his chronologic age, and he walks stooped and slowly like someone worn out by a hard life.
There are many chronic medical disorders that cause pain and disability in patients. Cancer patients are no different; however, at times our treatments incite chronic symptoms that affect our patients negatively. We must all be committed to finding more effective and less toxic therapies for patients diagnosed with cancer, and we must emphasize and support research to prevent the development of malignant disease. It is a noble and always worthwhile mission.
If we are not willing to make some tough decisions personally and publicly and do the right things to promote healthier lifestyles, we will falter in our battles with cancer. The consequences to individuals who develop cancer, and to all of us as a society, are too great and too dire to ignore and deflect any longer.