While this paper was very important in establishing the treatment of colorectal-cancer liver metastases, it was also responsible for creating surgical dogma. The authors reported that patients who had four or more liver metastases were less likely to derive a survival benefit from surgical treatment and, therefore, surgical treatment was relatively contraindicated. Because patients with four or more metastases had a relatively poor prognosis compared to those patients with three or fewer metastases, surgery was considered too high a risk for too small a gain.
Relatively is relatively open to interpretation, but when I was a surgical oncology fellow, this alpha dogma ruled. I saw several patients in the clinic who had four or more liver metastases that were technically resectable, meaning they all could be removed while leaving a volume of normal liver adequate for the patient to survive. However, we referred them to our medical oncology colleagues for chemotherapy treatment because they had “too many tumors,” which was dogmatically believed to represent more aggressive, nonsurgically treatable cancer.
I think it is critical that we practitioners examine our patterns of behavior and our methods on a regular basis to stay on the cutting edge of treatment and to consider whether we can safely push the envelope to help our patients. As my fellowship in surgical oncology progressed, I went back and carefully reread the 1988 paper. In the discussion section, I was surprised to see that patients who had four or more liver metastases had a five-year survival rate of 17 percent, which was indeed inferior to the 33 percent reported for all patients in the series. This is what led the authors to recommend that patients with four or more lesions not be considered for surgical treatment. This confounded me because a 17 percent five-year survival rate was still better than the essentially 0 percent five-year survival rate in patients who did not undergo surgical treatment.
After completing my fellowship training, I decided that adhering to this dogma did not make sense to me. I knew my team and I could perform major liver operations with a low risk of life-threatening complications for our patients. I initiated a prospective hepatobiliary-tumor surgery database and carefully followed everyone we treated. For patients with stage IV colorectal cancer confined to the liver, I would consider surgical treatment that included removal of all tumors when possible. Or a combination of removal and killing additional small tumors with radiofrequency ablation (a technique that heats the tumors) when complete surgical removal was not feasible. These patients, like all our cancer patients, were then followed routinely over the course of their lives.
I tell medical students, residents, and fellows who work with me to question dogmatic practices and beliefs regularly. Challenging dogma certainly led to a difference in the lives of some of the patients I treated early in my career. In 2006 my partners and I published a paper reporting on 151 patients with more than four colorectal-cancer liver metastases that were treated surgically.5 We found that 51 percent of our patients were still alive five years after their surgical treatment, with just 22 percent staying disease-free. The remaining 29 percent who survived five years after surgical treatment had developed recurrence of their cancer but were still alive and receiving additional care. We learned the probability of long-term survival was improved using active chemotherapy agents before surgical treatment.
Importantly, my team and I are not alone. There are many surgeons and physicians worldwide who constantly investigate and look for better options to treat our patients. Around the time of our report in 2006, numerous surgical groups described their experience and confirmed almost simultaneously that surgical treatment of four or more colorectal-cancer liver metastases could improve the survival rate of patients. This goes to show that critical thinking and asking questions is in our professional DNA. We independently questioned Hughes’s 1988 report, as all of us cancer clinicians want better results for our patients!
We can never predict exactly what will happen with any specific patient. Take two examples from my group of 151 patients. Both patients were treated in 1995 and both were successful professional men in their mid-fifties. One man had seven colorectal-cancer liver metastases, all in the right lobe of his liver. I cannot speculate why his tumors grew only in the right lobe, but that is what presented itself to me when I first viewed his CT scans. I removed the right lobe of his liver, which comprised about two-thirds of his total liver volume, and he recovered from the operation uneventfully. At the time of surgery he told me his goal was to see his three children graduate from high school and college. I diligently informed him that I could offer no guarantees and assured him I would follow him closely and intercede should his cancer recur. This year he became a twenty-two-year survivor with no recurrence of the disease. He attended his three children’s high school and college graduations, and has gone on to see all three of his children married. He is now enjoying retirement, spending time with his wife, and spoiling his grandchildren.
The second gentleman’s story does not have a similar happy ending. He had five colon-cancer liver metastases located in both lobes of his liver. I removed the tumors with a combination of wedge and segmental resections. During his operation, as I do in all liver surgeries, I performed an intraoperative ultrasound on his liver. This is the ultimate diagnostic tool for hepatobiliary surgical oncologists because it allows us to lay a probe directly on the liver and detect additional tumors that are too small to be seen on CT or MRI scans. In about 6 percent of our patients, we find one or two additional small tumors with the ultrasound that we did not previously see on preoperative imaging studies. But in this man, I found only the five tumors viewed on his preoperative CT scan. Like the previous patient, he was in the hospital for only six days and recovered uneventfully. Also like my first patient, pathology confirmed that all tumors had been completely removed with a good margin of normal tissue. This patient, however, represents one of the more frightening phenomena we sometimes encounter in surgical oncology. Unlike my twenty-two-year survivor who has never had recurrence of his cancer, I was shocked when I looked at my second patient’s three-month postoperative images. He had six new liver metastases between one and one and a half centimeters in diameter. I was flummoxed because I had just evaluated his liver three months earlier with the best diagnostic tool available. While intraoperative ultrasound can detect small tumors, there is no device that reveals microscopic nests of cancer cells in the liver or in other organs. Clearly, the new tumors had been present in microscopic size when I performed his surgical procedure; I simply could not detect them. Unfortunately, his cancer grew at a meteoric pace, and he survived only another seven months while being treated with chemotherapy.
I say it to every patient: I cannot predict your future. Obviously, stories like my twenty-two-year survivor after surgical treatment of stage IV colorectal cancer are invigorating. The disappointment and angst represented by my second patient’s story underscores the importance of continuing to push for more basic and clinical research, and better therapeutic combinations to improve the outcomes of our cancer patients.
Dogma can be comfortable and can lull us into a sense of security. We may invoke dogma to support decisions that keep us inside our comfort zone. However, I believe dogma should be questioned continually and comfort zones should be abandoned and demolished on a regular basis.
Probe. Inquire. Cogitate. Imagine. Dream. Attempt. Experiment. Push. Question. Always question.
“I thought you said your dogma does not bite?”
“That is not my dogma.”
7
A Roll of the Genes
“Learning is not attained by chance; it must be sought for with ardor and diligence.”
Abigail Adams
Diligence: Careful and persistent work or effort
Every week I have patients who will ask me about sequencing the genes of their malignant tumors. Or they will ask if their cancer is an inherited type because they are worried about their children and family members. Because there has been so much information published or discussed
in the media, people are aware some cancers are hereditary. Other patients recognize that they may have specific genetic defects that can be targeted with a drug that normally wouldn’t be used for treating their particular type of cancer. Scientists and geneticists have now reached a point where they can sequence the entire genome of a tumor, perform complete or targeted exome sequencing, or study a specific set of genes known to have a high probability of abnormality in given types of cancer. However, they generally find numerous mutations, deletions, or overexpression of an entire series of genes in most cancers, and these make it impossible (currently) to address all of the issues in any given patient’s cancer.
Identification of specific genetic defects has produced major changes in the management of patients with cancer. A diagnosis of gastrointestinal stromal tumors proved uniformly fatal before it was discovered that there was a specific cancer-related mutation in the c-kit gene. A drug called imatinib was developed that targeted the tyrosine kinase molecule encoded by the mutated gene. Now patients with this cancer can live for many years, frequently more than five years, even with metastatic disease. The same drug has been used to completely change the management—and improve the survival rate—of patients with Philadelphia chromosome–positive chronic myeloid leukemia. The publicized decisions of movie stars and other high-profile figures to undergo prophylactic bilateral mastectomy, because of mutations in their BRCA genes that portend an extremely high risk of breast and ovarian cancer, has produced more public awareness of the importance of cancer genetics. In gastrointestinal cancers, we carefully follow patients and their families who have specific mutations in the APC gene—which leads them to produce numerous polyps in the colon and, ultimately, to colorectal cancer. As with the BRCA mutation, when patients with these APC mutations are identified before they have developed cancer, we will recommend removal of the entire colon and rectum to prevent the occurrence of cancer.
I learned the importance of cancer genetics early in my career. A surgical colleague of mine from another city in Texas called to tell me he had a young patient in her late twenties who initially sought care for recurrent abdominal discomfort. On evaluation she was found to have a large pancreatic tumor that was determined to be neuroendocrine cancer. He was not sure the tumor could be surgically resected so he referred her to me. Almost as an afterthought, he mentioned that the patient was also having vision problems. She had seen an ophthalmologist, who noted that she had a partial retinal detachment and some small angiomas (small, nonmalignant tumors consisting of abnormal nests of blood vessels) in the retinas of her eyes. The ophthalmologist had suggested that this unusual situation is known to occur in a condition called Von Hippel–Lindau disease (VHL). It had been over a decade since I thought about Von Hippel–Lindau disease, so I studied the syndrome. Patients with this disorder develop angiomas of the retina, which can bleed and cause blindness. Among other things, they can also develop hemangioblastomas (blood vessel tumors) of the central nervous system that can bleed, leading to stroke, death, or, if the lesion is in the spinal cord, to paralysis. I found some notations that a few rare patients with VHL will develop neuroendocrine tumors of the pancreas or pheochromocytomas of the adrenal gland. Pheochromocytomas are tumors that cause abnormal amounts of norepinephrine to be released into the blood. Norepinephrine is the substance that causes rapid heart and breathing rates when you are startled or frightened, the “fight or flight” response. Abnormally high levels of norepinephrine in the blood result in dangerously high blood pressure, potentially causing headaches, stroke, or death.
I met this young woman and, after talking with her, I examined her, including her eyes. Even I could see the retinal angiomas. We obtained a CT scan that revealed a ten-centimeter tumor of the head of her pancreas that was encasing the portal vein and superior mesenteric artery, which meant it could not be surgically removed. We also identified numerous small metastases in her liver. Arising from islet cells within the pancreas, pancreatic neuroendocrine tumors can sometimes release high levels of peptide hormones such as insulin, glucagon, somatostatin, and others. In this specific patient, however, there were normal levels of all pancreatic peptides in her blood tests, so she had what is called a nonfunctioning islet cell cancer.
I presented her findings at a multidisciplinary treatment planning conference. Because she had significant abdominal and back pain caused by the large tumor, we decided to try a nonstandard treatment. Radiation therapy is not commonly used in pancreatic neuroendocrine tumors, but we combined radiation with low-dose chemotherapy. At the end of a six-week course of treatment her pain had resolved. Because pancreatic neuroendocrine cancer is often slow-growing, I told her we would follow her closely and consider further chemotherapy only if her tumors began growing rapidly.
While my patient was receiving radiation therapy treatments I became a medical detective. During my undergraduate and medical school education I had seen family-history charts of individuals with a variety of genetic diseases. Depending on the type of inheritance pattern, the number of family members who are affected with a genetic disorder versus those who are not can vary. It’s a bit like gambling; the probability of rolling a specific numeric total with two dice can be calculated, but on any one roll the dice may or may not show that total. VHL disease arises from a mutation in the VHL tumor-suppressor gene located on the short arm of chromosome 3 at 3p25.3 (the chromosomal address for the gene). The disease is inherited as an autosomal dominant disorder meaning that both males and females have an equal chance of being affected if they receive a mutated gene from either parent who carries the disorder. Recognizing this, I asked my patient’s parents and her four siblings to come in for a complete evaluation that included MRI scans of their entire central nervous system and CT scans of their abdominal and pelvic regions. I was surprised by what I would soon learn.
The patient’s father had no symptoms or findings consistent with VHL. Her mother had suffered vision problems for more than a decade, and our ophthalmologist found that she had numerous angiomas of her retina. Her MRI scans revealed she also had several small asymptomatic hemangioblastomas in her brain. She had struggled for several years with poorly controlled high blood pressure and her CT scan revealed tumors in both of her adrenal glands consistent with pheochromocytoma. Blood and urine tests confirmed she had extremely high levels of catecholamines, substances that cause high blood pressure when released in excessive amounts. Three of the original patient’s four sisters were also affected by VHL, with all three having classic radiographic findings consistent with islet cell tumors of the pancreas. In two of the women, there was a solitary tumor with no evidence of spread to other areas; and only one had retinal angiomas. In the third, as in her sister undergoing radiation treatments, there was a large unresectable pancreatic head mass with numerous small liver metastases. None of the sisters had evidence of renal cell carcinoma (more common in VHL), although two did have simple kidney cysts. And only the mother of these girls had pheochromocytoma.
I dug deeper into the past and asked about any other family members who had vision or other medical problems. The mother of my patient informed me that her mother had lost her eyesight when she was thirty-one years old and had been completely blind until she died from a stroke at age fifty-two. This piqued my interest and I asked if there had been any tests done. Almost unbelievably, I was informed that an autopsy had been performed. I contacted the hospital in the small town where the maternal grandmother of my patient had lived and died, and after several weeks of phone calls and written requests, I received an autopsy report. Among other things, the autopsy described hemorrhage into a large hemangioblastoma in her brain that had caused this woman’s fatal “stroke,” and the report revealed that her blindness was caused by retinal hemorrhage and detachment. The mother of my first patient had only a single sibling and testing of this individual and her children showed no evidence of VHL disease.
After treating the malignant pancreatic neuroendocrine tumors in the origina
l patient’s sister, I performed a resection on the smaller pancreatic tumors in the remaining two sisters. Both recovered from their respective operations uneventfully, and during their operations we found no evidence of spread to lymph nodes or the liver. After treating the mother of these girls with the appropriate preoperative medical therapy for the pheochromocytomas, I proceeded to remove both of her adrenal glands, sparing the outer cortex of the left gland in an attempt to prevent her from requiring steroid-replacement therapy for the remainder of her life. Fortunately, the operation was successful, she never required steroid replacement, and her blood pressure problems resolved. Of the four affected sisters, only one had a child, and we found that he also had VHL disease. On his initial evaluation as a teenager, however, he had no evidence of any tumors either in the central nervous system or in any other organ.
We continued our investigative work with chromosomal-banding analysis, and we observed that the four sisters all had deletion of a significant portion of the short arm of both copies of chromosome 3. In contrast, their mother had a deletion of the short arm of one of her chromosome 3 copies but had point mutations in the other VHL gene. I love working in research institutions and medical schools because there are bright people eager to collaborate and provide insight and feedback. When I mentioned this unusual chromosome pattern to one of my colleagues, who is, interestingly enough, an expert in chromosome 3p (I guess the long arm of chromosome 3 was just too boring for her), she was intrigued because she had not seen this high incidence of neuroendocrine tumors in VHL patients previously. We obtained tissue samples from more than a dozen patients who had spontaneously developed nonfunctioning malignant pancreatic neuroendocrine tumors. Interestingly, we found that all had significant areas of deletion of portions of chromosome 3p. As we winnowed the findings, we discovered a novel neuroendocrine tumor-suppressor gene at 3p21.1 that was abnormal in patients with VHL-related pancreatic neuroendocrine tumors and in the majority of patients with spontaneous development of these unusual pancreatic malignancies. Because of the loss of a piece of the short arm of their third chromosome, these four sisters had VHL and were predisposed to develop pancreatic neuroendocrine tumors. This is an example of what we now understand after studying the entire human genome; loss or alteration (mutation) in specific gene addresses in our DNA can increase the risk of developing different cancers related to the genetic changes.
In My Hands: Compelling Stories From a Surgeon and His Patients Fighting Cancer Page 5