When we doctors follow a patient, we watch specific organs or sites in the body, based on the specific type of cancer and where it originated, for any evidence of recurrence. Our knowledge regarding the particular metastatic patterns of different types of cancer was first described by Stephen Paget in the late 1800s. He recognized that cancers originating in different sites, such as the breast, lungs, colon, or prostate, tended to metastasize only to other specific organs or locations. This has been called the seed-and-soil hypothesis. Cancers that start in certain organs have a propensity to spread to other specific organs, much like seeds falling on suitable soil and growing successfully. For patients who have completed treatment for colorectal cancer, I tell them I will be closely watching the three Ls: the lymph nodes, liver, and lungs. Those are by far the three most common spots for colorectal cancer to metastasize, and microscopic nests of cancer cells that were resistant to chemotherapy can reside in those sites. Occasionally colorectal cancer spreads to the bone, but having it arise in other sites is rare.
Patients who have melanoma, lung cancer, or breast cancer will regularly have CT or MRI scans of their head because these cancers are known to metastasize to the brain. We do not normally perform such scans in patients with colorectal cancer because the brain is an unusual site for metastatic spread. However, as we have become more successful in our treatment of colorectal cancer at the primary site and in the three Ls, strange things have been happening. I have operated on more than 1,800 patients with colorectal cancer metastatic to the liver. Some of those patients are still alive and doing well with no evidence of recurrent malignant disease. Others have had metastasis recur in the liver or show up in the lungs or lymph nodes or occasionally as nodules in the peritoneal (belly) cavity. I also have an unusual, small group of nine patients who developed brain metastases seven to thirteen years after successful treatment of their colorectal cancer—after each of the patients had passed the mythical five-year cancer-free survival benchmark. Each of these patients was distraught and dismayed that the colorectal cancer had returned and all admitted they thought they’d been cured because their five-year anniversaries were behind them. The first few times this happened I was befuddled. I had not previously seen patients with colorectal cancer and brain metastases. In the past, patients with stage IV colorectal cancer had a low probability of five-year survival so the slow-growing cells that implanted in the brain didn’t get a chance to cause problems. Nine patients out of more than 1,800 is not a lot of folks or a high proportion, but it is not zero, either. It is also not enough to change practice patterns, meaning I don’t routinely order CT or MRI scans on the brain for my colorectal-cancer patients just because of these nine people. Sadly, none of the nine patients survived more than eighteen months after treatment of brain metastases.
This serves to emphasize the point I make to all patients; once you develop cancer you should be followed for the rest of your life to diagnose any evidence of cancer recurrence as soon as possible. Patients are the best judges of their own bodies and feelings, so I ask them to notify their primary-care physician or me for any new or subtle symptoms regardless of how long they have survived after their cancer diagnosis.
It may be time to set aside the five-year benchmark as a standard measurement of success in cancer care. With some cancers, including advanced pancreatic, lung, stomach, and esophagus cancer, it is rare for patients to survive more than a few years or even months. With many other cancers, however, it is now routine for patients to survive ten years or longer, occasionally requiring medical interventions such as surgery, chemotherapy, radiation treatments, or targeted therapies. Once diagnosed with cancer, patients and their physicians must remain ever vigilant because cancer could care less about statistics and probabilities. We must persevere and redouble research efforts to improve the survival time and quality of life of ever more of our cancer patients.
10
Opportunity Calling, Version 2.0
“It’s not what you look at that matters, it’s what you see.”
Henry David Thoreau
Wisdom: The quality of having experience, knowledge, and good judgment; the quality of being wise
Liver surgery has something in common with real estate: location is important. Some patients have several tumors all located in one lobe of the liver that I can remove with a right or left hepatectomy. Other patients have multiple tumors in both lobes that require a customized, tailor-made surgery combining segmental and wedge resections to remove the cancer while leaving enough liver for the patient to survive. Conversely, and to the extreme frustration of hepatobiliary surgical oncologists, some patients may have a single tumor in a critical location that makes it unresectable. For example, a tumor nestled up under all three of the hepatic veins flowing into the inferior vena cava is usually unresectable. When removing areas of the liver, it is possible to take two of the three veins but one must be left intact to drain blood out of the liver. It is also crucial not to leave tumor behind on one of the veins (a positive-margin resection), because the cancer will recur and the patient usually does not benefit from a major surgical procedure that failed to render him or her cancer-free.
Patients with malignant liver tumors, whether primary (meaning they started in the liver) or metastases (meaning they spread from another organ to the liver), are frequently assessed in a multidisciplinary liver-tumor conference. This gives the team of oncologists, along with radiologists, gastroenterologists, and pathologists a chance to review all of the information on a given patient. Not infrequently, patients who have malignant tumors confined to the liver are not considered candidates for surgical treatment because the number of liver tumors is too great, the tumors are too large, or the tumors are spread throughout the liver in such a pattern that an insufficient amount of liver would remain following surgical resection. Or the patient’s liver is cirrhotic, severely damaged, from causes that include chronic hepatitis B or C virus infection or alcohol abuse. Or the patient has the infuriating situation of a single tumor in a critical location where a negative-margin resection is not possible.
I was at a national surgical meeting in 1993 presenting the results from a phase I clinical trial using a novel approach to treat primary liver cancer. After my talk, two men wearing rumpled suits approached me. They explained they were engineers who had an idea for a new treatment for liver cancer. I believe I gave them a look akin to that of Mr. Spock from Star Trek with an arched eyebrow and an, “Oh, really?” They asked if they could buy me a cup of coffee. Since my serum caffeine levels were low at the moment, I agreed.
The engineers showed me a series of drawings of a type of needle electrode to be placed into a tumor that would kill it by heating it. They explained they had read my published studies about using new devices to treat malignant liver diseases and hoped I would work with them on their tool. I listened intently and then started firing questions at them. They were somewhat taken aback but quickly realized I was asking because I was interested. I inquired if they were ready to start human clinical trials using their ideas, but they explained they had only a prototype device.
This initiated a series of conversations between us over the ensuing months producing refinements in the radiofrequency generator and in the needle electrode. The design and composition of the needle changed multiple times as we explored metallurgy, tensile strength and insulation of metals, material malleability, and durability of the device. The final design was an eighteen-gauge insulated shaft with a series of sharp metal tines that could be made to protrude and retract from the end of the needle once it was placed into the liver tumor. When fully deployed it looked like the ribs of an umbrella. An electrical alternating current passed across the metal tines and resulted in ionic motion and frictional heating within the tumor environment. The goal was to produce heat sufficient to kill the tumor. This began my experience with radiofrequency ablation (RFA) of unresectable liver tumors.
After experimenting with different designs and materials,
we finally had a prototype that I used to treat malignant liver tumors in animals. The RFA treatment yielded very high levels of heat, temperatures in excess of one hundred degrees Celsius, the boiling point of water. In our initial experience with the RFA device, the heating was so rapid the tissue around the metal tines coagulated and became an excellent insulator but prevented killing of the entire tumor. Thus, we learned to ramp up the energy slowly, over several minutes, to allow thorough and reproducible dissipation of lethal temperatures throughout the tumor surrounding the RFA needle electrode. We also performed studies demonstrating that the treatment was safe and did not produce damage to other tissues or organs as long as they were not in contact with the area being heated. The procedure killed the tumor and a surrounding area of normal liver, which was planned and is similar to the way we include a margin of normal, nonmalignant tissue when we perform a surgical resection to assure no cancer cells are left behind.
Armed with preclinical and bench research data, I prepared a protocol to treat twenty patients who were undergoing surgery to remove malignant liver tumors. This is called a proof-of-principle study. In the protocol, I requested permission to treat one of the tumors intra-operatively with the RFA needle, and then proceed with removal of the area of liver that included any additional malignant tumors. Our pathologists confirmed that the tumor treated with RFA was completely killed as long as it was no bigger than 2.5 centimeters in diameter. Larger tumors required placement of the needle followed by RFA of overlapping areas of the tumor to destroy the malignant cells completely.
Confirmation of complete killing of resectable liver tumors in twenty patients led to a second protocol using RFA to destroy unresectable malignant liver tumors. The tumors were deemed unresectable either due to their location near critical blood vessels, which precluded obtaining a tumor-free surgical resection margin, or because of coexisting severe cirrhosis, which is associated with a high risk of postresection liver failure. Patients with primary or metastatic liver cancers were included in our study. The clinical research trials using RFA for unresectable liver tumors were performed in tandem at the G. Pascale Istituto Nazionale di Tumori in Naples, Italy, and in Houston.
In 1999, my colleagues and I reported our experience with RFA of otherwise-inoperable liver cancers in our first group of patients.6 We noted that the treatment was safe and produced no major side effects or toxicities in the patients. We also demonstrated that we completely killed the malignant tumors treated with RFA in more than 95 percent of the patients we selected. Select is a key word here as we were very careful to treat tumors that were not too large. We knew the zone of lethal temperature around the RFA needle was limited by the basic physics of heat dissipation in areas farther away from the electrode. This paper became one of the most frequently cited surgical publications in the world in 2000, 2001, and 2002.
During that time we continued to use RFA to treat tumors that could not be removed surgically. This included the use of RFA on small tumors in one lobe of the liver when we surgically removed larger tumors in the opposite lobe. We confirmed after treatment of hundreds of patients, even those with severe cirrhosis of the liver, that RFA could be performed safely with very low complication rates. A small percentage of patients did develop side effects such as infections, scarring around bile ducts, or injury to other organs if the practitioner using the RFA was not cautious in the placement of the needle. Based on our studies and those of other groups, RFA for unresectable liver tumors became an approved treatment by the U.S. Food and Drug Administration in 2001. RFA has become an important tool, used worldwide, to treat tumors that otherwise would continue to grow and lead to the death of the patient. I now have hundreds of patients who have undergone RFA of unresectable liver tumors who are still alive and doing well five, ten, or even fifteen years after their treatment.
I recently saw one of these patients. When I met her in 2002, she was frightened by a diagnosis of an unresectable intrahepatic cholangiocarcinoma. She was told by her medical oncologist she would probably not survive more than one year. She was forty-three years old and otherwise in excellent health, and she had gone to see her primary-care physician when she developed some vague discomfort in her upper abdomen. Assuming she might have a problem with gallstones the doctor ordered an ultrasound of the liver. It revealed her gallbladder was completely normal but showed a tumor high in the liver. A subsequent CT scan confirmed a single eight-centimeter tumor in the center of her liver that surrounded all three of her hepatic veins. After additional testing, including a biopsy, it was concluded she had a malignant biliary tumor. She had been seen by several surgeons, and, like them, I felt that this tumor was not resectable. However, there was no evidence of spread to any other site in the body.
She and I discussed treatment with chemotherapy, radiation therapy, or RFA—which I explained was a newer treatment but one I believed was feasible in her case, using an open surgical approach. She agreed and the next week I performed the RFA operation. Treating a tumor that large required careful planning and monitoring with an intraoperative ultrasound probe placed directly onto the liver during the operation. I had to move the needle several times and produce overlapping zones of thermal destruction of the tumor. The RFA treatment took almost two hours to complete.
After the operation, the patient was up walking the same afternoon. She was relieved that I had been able to treat the tumor and was very hopeful that the RFA procedure had been a success. I was guarded when we discussed her prognosis. I explained that while I was confident the entire tumor had been treated, I could not be absolutely certain that there was not some small area of tumor still left alive. And it was possible a tumor that large could have metastasized somewhere else in her body. She listened and then cheerfully explained to me, “I just know that everything is going to be fine.”
She was right. I saw her in my office a few weeks ago. It has been more than fifteen years since the RFA procedure. Her latest CT scan demonstrates a still-definable area where the tumor once was but where there is now scar tissue from the RFA destruction of her unresectable central liver tumor. She has never had recurrence or spread of her cancer. She is active, energetic, and, as she said, “living the hell out of life!” Hoorah!
A fortuitous meeting with two frumpy-looking engineers led to a remarkable opportunity. RFA has now been used on tens of thousands of patients worldwide to treat tumors in the liver and other organs. It is not a perfect treatment and it is not without risks or possible side effects to patients. Some tumors treated with RFA are not completely destroyed. Surgical resection and RFA of malignant liver tumors is a local treatment, which means it does not prevent cancer from recurring at another site where it is hiding. Regardless, RFA has allowed patients who otherwise would have succumbed to their malignant disease to live for longer periods, in some cases for many years.
Through all this, I learned a marvelous lesson: always listen to ideas; always look for new opportunities. The concepts may come from patients, family members, concerned citizens, inventors, research scientists, or medical colleagues. For me, when the concept came from a couple of engineers, something great happened!
11
Breathless
“A high station in life is earned by the gallantry with which appalling experiences are survived with grace.”
Tennessee Williams
Grace: A divinely given talent or blessing; the condition or fact of being favored by someone
Cancer sucks. You may have seen the buttons, T-shirts, signs, or even Twitter and other internet memes bearing this proclamation. I first saw it when a new patient, a young woman who is the subject of this chapter, handed me a button and emphatically ordered, “Put this on your coat, and don’t forget it!” Yes, Ma’am.
First, a warning: Do not read this story if you are looking for a happy ending. There isn’t one. This is about the ugly truth of what cancer does to some patients and their families. There can be humor and amazing character that shines through an agg
ressive and painful cancer. But this is the dark side. I wrote the outline for this piece several years ago, but I have been hesitant to publish it. Some people may be offended or upset when they read this story. In that case, stop here. The patient who is the focus of this account asked me to tell her tale. She wanted people to know that cancer can strike at any time, at any age, and in any person despite the absence of genetic or other risk factors.
After receiving my CANCER SUCKS button, I sat down and listened to her for the next thirty minutes. It was not necessary to ask many questions because my thirty-year-old petite, fit, one hundred–pound patient provided detailed information about her cancer and other areas of her life that were relevant at the moment. To describe her as talkative is an understatement. She informed me she was a single mother, very busy working full-time and raising a four-year-old son, and she had recently earned a black belt in karate. She mentioned this last accomplishment several times during our first meeting, and then added that I should consider myself adequately forewarned of her martial arts prowess. Laughing, she said she expected me to take very good care of her lest I get my butt kicked by a girl. Duly noted, and thanks for the warning.
This energetic young woman had been enjoying her independent life, caring for her son, and indulging in vigorous hour-long karate sessions daily. For three months she had noticed an intermittent, dull right upper abdomen pain and backache. The discomfort was more pronounced after a karate workout and she self-diagnosed a pulled muscle. Two weeks before I met her, the pain had intensified and become constant. She visited her primary-care physician who examined her and realized her liver was markedly enlarged and tender. A CT scan revealed a large melon-sized tumor occupying the entire right lobe of her liver. A biopsy indicated the tumor was a malignant adenocarcinoma. Adenocarcinoma in the liver usually represents metastasis from another organ, such as the esophagus, stomach, pancreas, colon, breast, or lungs. The CT scan did not reveal evidence of a primary cancer at any of these or other sites, and mammograms, an upper endoscopy, and colonoscopy did not detect any abnormalities. She had no elevation in any of the serum (blood) tumor markers we measured, and the presumed diagnosis was a large intrahepatic cholangiocarcinoma.