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After a Cancer Diagnosis, Reversing Roles With My Mother
Photo
Steven Petrow (left) with his siblings, Jay and Julie, and mother, Margot Petrow, on her 84th birthday in February.Credit Caroline Petrow-Cohen
If anything about my mother was conventional, it was the smoking. Like many of her generation she smoked early and often, and I swear she waited to light up until we were hermetically sealed in our family’s Ford Country Squire. My brother, sister and I hated it — we tried over and over to get her to quit. She made some attempts: Patches and gum, even hypnosis by a Russian. She had some short-term successes, but soon enough I could smell the smoke on her breath or see the burnt-out butts hidden in her desk drawer ashtray.
The last time I begged Mom to quit, she shot back with a stern rebuke: “I very much appreciate your concern,” followed by an expletive. The message was clear: Mind my own business. Indeed, Mom has always been “spirited.”
From both ends, ours was not an easy relationship.
Four years ago, at 80, Mom wound up in the emergency room after she passed out in bed; her carotid artery was 90 percent blocked. The doctor ordered a routine pre-op chest X-ray and found a mass that turned out to be lung cancer. “Did my smoking have anything to do with this?” Mom asked the handsome cancer surgeon, almost flirtatiously. “Yes,” he told her. “Then I’ll quit,” she said. And that, finally, made her stop, once and for all.
A few weeks later “Dr. Handsome,” as the family began referring to him, took out part of her left lung at the very same New York cancer hospital where I’d had cancer surgery three decades before. I’d wound up there only because Mom had insisted that I get a second opinion after my first operation, an orchiectomy to remove my cancerous testicle, at a hospital on the opposite coast. While I’d been overjoyed when the oncologist told me I was a candidate for “watchful waiting” and that he’d “never lost a patient,” Mom thought the latter comment quite odd for a doctor who treated cancer patients. I caved, flew east, and learned I needed more treatment, stat. Score one for Mom.
During Mom’s first hospitalization for her cancer our roles flipped. I became her caregiver, and she became my charge. With nurses busy elsewhere, I made sure her bedpan got changed, or contacted the surgeon to boost her pain medications when needed. On a no less important matter, I made sure she got a chocolate, not vanilla, milkshake daily. After my own stays in the hospital, I had learned how to “work” the hospital staff, using genuine praise, patience and small gifts of candy.
I also had that firsthand knowledge of what it meant to suddenly become a cancer patient, dependent on the kindness of strangers and family alike. I knew what it was like to face the mechanical roar of the CT scanners, not to mention the anxiety and fear that your book of life may be coming to an end sooner than you’d expected.
Some days I held Mom’s hand, her Jungle Red manicure always perfect, as the nurses pricked her repeatedly to get a good line. Other times I’d just sit with Mom and let her talk. About my father. My sibs. And herself.
Increasingly, she asked me about my cancer travails, which included multiple surgeries and four rounds of chemo. “I can’t believe you went through all this,” she said time and again. Still, I’d been in my 20s; mom was now in her 80s. As different as our cancers were, not to mention our ages, I’d become her travel guide in this new country of illness.
Then one day she piped up, her voice an octave or two higher than usual: “I’m afraid.”
“Afraid of what?” I asked.
“Of the pain of dying. And leaving you kids.”
I told her we’d make sure she didn’t suffer. And as for the three kids, I told her not to worry about us. “We’re all in our 50s now,” I reminded her.
As I had decades ago, Mom recovered from her first operation. And also like me, she moved into a netherworld I knew all too well: The “after” stage, during which you struggle to believe it’s over, all the while dreading its return.
Last year I moved her semi-annual scan from late December to mid-January. With bad news always a possibility, why risk ruining the holiday? I was glad I’d done that when the scan showed a new mass. Although the doctor was the official bearer of the bad news, it was left to my brother, sister and me to explain what that meant, all the while reassuring her we’d be there to help.
As it turned out, one of the most important decisions she’d have to make was what treatment, if any, she should soldier through to combat this new malignancy. Dr. Handsome recommended radiation, but he didn’t sound very optimistic. I decided Mom needed a second opinion, maybe even a third, and with some cajoling — just as she had urged me on so many years before — she sat down with a radiation oncologist. He was much more encouraging about what to expect, and she took his advice.
And so it was not too many months ago, after helping her back into her street clothes and into the Uber after her daily radiation, that we were headed home from the hospital. She grasped my hand tightly and told me how glad she was that I was with her. “Whatever our problems were,” she said, “I’m happy they’re behind us.” I squeezed her hand back.
Steven Petrow is a regular contributor to Well and lives in Hillsborough, NC. You can follow him on Twitter @stevenpetrow
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Friday, May 20, 2016
Newly Diagnosed? Key Steps for Success
These basic principles can help you navigate the journey no one plans to take.
By John Leifer
It takes just two words to shatter the predictable cadence of our lives and launch us on a journey of unknown length to an unforeseeable destination: It’s cancer.
Seconds after the words emerge from the mouths of our physicians, drawn out and hanging in the air as though spoken in slow motion, our bodies snap into action. Adrenaline courses through our veins as we struggle to size up the threat. Then waves of anxiety begin their relentless assault on our consciousness.
Our minds are reeling. We feel an overwhelming urge to shut down, to pretend that it is merely a bad dream or a mistaken lab result. But the reality is undeniable. Our lives will never be quite the same. We’ve joined the ranks of more than 1.65 million Americans who will be diagnosed with cancer this year. The question is, How will we respond to the challenge?
If you have been diagnosed with cancer, you don’t have to allow yourself to be passively relegated to the ranks of victim or statistic. You can become an active participant in navigating the journey. How you respond at this moment of crisis may have a tremendous bearing on the length, difficulty, and even outcome of your journey through cancer.
Successful navigation of the roads that will lead you through diagnosis, treatment, and recovery requires accurate, trustworthy information. Guidance through this space could easily fill the pages of a book (as I found out by writing one), but there are some essential steps that can steer you in the right direction from the beginning. Here, based on hard-won experience, is a summary of those key steps.
Step 1: Slow Down.
If you have been recently diagnosed, you may be among the large number of patients who feel a tremendous sense of urgency to deal with the invader—and deal with it now! While understandable, reacting in this way can prevent a more methodical, careful selection of a care team that will be the right choice for the long term, a thorough understanding of treatment options, and optimal decision-making for yourself and your family. The reality is that though cancers grow at varying rates, very few progress at a speed that would make it necessary to rush into treatment without obtaining the information necessary to make informed decisions.
Step 2: Identify Your Traveling Companions.
As a patient you will likely find that information doesn’t dribble in; it comes in a torrent. This information must be processed, saved, and acted on. All of this occurs at a time when the stress of the diagnosis means that you’re likely not thinking as clearly as you usually do and are thus less able to sort through the information you receive. That’s one of the prime reasons for identifying a caregiver who will be present for all interactions with the medical team. The caregiver—ideally a family member or close friend— can takes notes, record sessions for later review, ensure compliance with the doctors’ instructions, and share information with others as necessary.
But the role of caregiver goes far beyond that of secretary. Caregivers play an invaluable role in meeting the emotional, spiritual, social, and functional needs of their loved ones. Though rewarding it is not an easy job. Caregivers often ride the same emotional roller coaster as the cancer patient, and they struggle with anxiety, depression, and burnout as a result. It is important to select a caregiver whom you can count on consistently, even when the journey gets tough, and to remind the caregiver of the importance of self-care!
Step 3: Find The Best Care Team for You.
The medical profession has worked hard to perpetuate the myth that all physicians are created equal. If only this were true! Most people would be shocked if they understood the tremendous variation in physicians’ training, experience, knowledge, clinical skills, and compassion—all factors that could affect the quality of care you receive.
Your best chance of finding the right doctor is to do your homework. Begin by viewing your initial appointments with potential physicians as job interviews—they are interviewing for the job of caring for you. Your task is to find a physician who possesses the attributes that you deem most important.
And remember, depending on your diagnosis, this process is one you may go through several times as you build a care team that may include several specialists at various points along the course of your journey. Selecting individuals who meet your needs, and who can communicate effectively with the other professionals on your team, is essential.
Step 4: Choose A Care Facility Carefully.
Just as doctors vary in critical ways that can influence your care, so too do the facilities in which they practice. It is important to understand the differences between the treatment options and expertise available at various facilities. For instance, the care offered at a community cancer center and that provided by an NCI-Designated Cancer Center will likely be significantly different. While excellent care is available at a broad range of facilities, it is important to understand the treatment requirements associated with your unique diagnosis and to seek care at the place that will offer you the best possible outcome.
Step 5: Understand Your Treatment Options.
Cancer is not one, single disease, and there is often more than one option for treating a particular type of cancer. It is essential that you have a complete understanding of the treatment options, the risks and benefits of each, and the costs associated with different forms of treatment. Standard pathways or methods for treating the most common types of cancer are published by the National Comprehensive Cancer Network (nncn.org), and they are available in versions written for lay readers. If your physician appears to be deviating from a standard pathway, know that you have the right to inquire as to why.
Step 6: Seek A Second Opinion.
Virtually everyone can benefit from a second opinion, which is a valuable way to gather more information about your diagnosis and the options available to you. And yet many patients do not seek a second opinion—either out of fear of insulting their physician or the mistaken belief that all physicians will take a similar approach to treating the disease. Sometimes patients simply don’t want to go through the hassle when they are already struggling to cope.
But unless you have a very early-stage, easily managed tumor, chances are you will benefit from a second opinion. It may allow you to explore a broader range of treatment options, as well as gain additional information about the disease; if nothing else, it will simply confirm what you’ve been told and give you greater confidence moving forward with treatment.
Step 7: Actively Prepare for Treatment.
Now that you have settled on your doctors, the facility in which you will receive care, and a specific treatment plan, you are ready to prepare for active treatment.
First and foremost, talk with your care team about what to expect during active treatment. It is far better to anticipate potential side effects than be caught off-guard when they manifest.
Inquire about nutrition, exercise, pain management, and any other topic you believe is relevant to staying the course and successfully completing the journey. Do not expect your physicians to read your mind about issues that concern you.
Finally, understand the financial ramifications of treatment. If you have concerns, discuss them with the care team. A social worker may prove to be an invaluable resource in helping address these issues.
Moving Forward
Whether your initial treatment is successful or you move on to a different treatment strategy, hope and optimism will play an essential role on your journey. Hope is the energy that propels us forward despite the presence of obstacles; embracing hope and looking ahead toward optimal health can help immensely as you manage your daily life with cancer.
Regardless of your final destination, the journey through cancer will bring trials and tribulations. It will forever change you, and to the degree that you are able to embrace the struggle, it will strengthen your very soul.
John Leifer has spent more than 30 years immersed in the healthcare industry as a senior healthcare executive, consultant, academician, and writer. An outspoken advocate for patients’ rights, he has published widely on the need for patients to receive appropriate, safe, and effective care—including two recent books: The Myths of Modern Medicine: The Alarming Truth about American Health Care (Rowman & Littlefield, 2014) and After You Hear It’s Cancer: A Guide to Navigating the Difficult Journey Ahead (Rowman & Littlefield, 2015). To learn more visit afteryouhearitscancer.com or write to John at mailto:jleifer@leifer.com.
More than 100,000 American women undergo mastectomy and breast reconstruction every year. Thousands more are having double mastectomies to prevent it.
But despite widespread awareness of breast cancer, much less is known about the surgeries women have, particularly mastectomy and reconstruction, which may be time-consuming, a cause of chronic pain and traumatic, if unsuccessful. Most women do not emerge with new breasts and nipples in a single operation. Breast reconstruction takes months and even years. Some women never finish, living without nipples or with imperfect results. Others opt not to have reconstruction. Still others struggle with one of the biggest women’s health questions today: lumpectomy and radiation or mastectomy?
“Breast Cancer Surgery and Reconstruction: What’s Right for You” offers a glimpse into modern breast surgery and reconstruction with stories and photos of real women that provide a realistic and compelling look at what these procedures entail and the impact on womens’ lives. This is a book to help other women with issues surrounding their choices, with powerful insights from those who have been there.
Susan and one of her clients are featured in chapter 18. We're so excited. Susan.
Using chemicals found in sea snail eggs, researchers at the University of Wollongong in Australia have created a compound that's very effective at killing multi-drug resistant cancer cells.
Potential cancer treatments often come from unexpected sources, like plants, artificial sweeteners and industrial solvents. Now, tests have shown that a type of molecule originally derived from sea snail eggs has performed surprisingly well in destroying cancer cells, particularly those that have become resistant to other treatments.
A wide range of blood cancers and solid tumors, including breast, ovarian, pancreatic and lower gastrointestinal cancers, can develop a resistance to chemotherapy drugs over time. This multidrug-resistance can severely limit treatment options and increase the chances of relapse.
Researchers at the University of Wollongong, Australia, found a new classs of N-alkylisatin molecules were able to kill 100 percent of multidrug-resistant cancer cells within 48 hours. By comparison, a commonly used chemotherapy drug only managed to kill 10 percent of cells over the same period.
This was particularly surprising to the researchers, due to how similar N-alkylisatins are to existing, relatively ineffective drugs.
"Because of this similarity, we weren't expecting that they would have such an effect on cell lines that are normally resistant to these types of molecules," says lead researcher, Kara Perrow.
The anticancer potential of these chemicals, sourced from the egg clusters of a sea snail common to Australia and New Zealand coastlines, has been known since 2002, but developing the N-alkylisatins from them is a much newer process, which is said to make it 1,000 times more effective at killing cancer cells. They work, Perrow says, by targeting the microtubules, or the "skeleton", of the cells.
"Our compounds interfere with the assembly and disassembly of these structures – essentially disassociating them so that the cell cannot undergo any further division and at that point, it dies."
Making N-alkylisatins safe for human use is the next step, and if all goes to plan, the drug could be available in 5-10 years. Dr. Perrow explains her team's work in more detail in the video below.
Treating renal neoplasm with associated inferior vena cava (IVC) thrombus presents a challenging surgical endeavor. Manifestation of tumor thrombus within the renal vein or IVC occurs in 4 to 10 percent of patients with renal cell carcinoma (RCC), and traditionally these patients have been managed with open surgery due to the complex nature of the procedure.
Several staging systems exist to describe the extent of the IVC thrombus. Various series have described the management of patients with level I-II tumor thrombi via a laparoscopic approach. With surgeons’ growing experience using robotic techniques, renal tumors with associated tumor thrombi are increasingly managed with a robot-assisted approach at high-volume centers of excellence. Nonetheless, there is a paucity of literature describing robotic techniques for treatment of level III tumor thrombi.
Figure 1. Intracorporeal control of IVC with Rommel-style tourniquets.
The primary steps for right-sided radical nephrectomy and level III IVC thrombectomy include early ligation of the right renal artery in the intra-aortocaval space, circumferential control of the IVC above and below the tumor thrombus, control of the left renal vein, and use of intraoperative transesophageal and intraperitoneal ultrasound to delineate the extent of the tumor prior to IVC cross-clamping (Figure 1).
Case study
The patient is a 75-year-old Caucasian man with a medical history significant for chronic kidney disease stage 3 and prior right hip replacement. He initially presented with abdominal pain and gross hematuria. Cross-sectional imaging for hematuria workup revealed a central 9.8-cm right-sided renal mass with an associated suprarenal IVC tumor thrombus. MRI performed two weeks prior to surgery for staging of the thrombus showed a tumor thrombus extending into the retrohepatic IVC above the level of the short hepatic veins (Figures 2 and 3) and associated with retroperitoneal lymphadenopathy.
Figure 2. Axial MRI demonstrating cranial extent of the tumor thrombus.
Figure 3. Coronal MRI demonstrating cranial extension of the tumor thrombus.
The patient’s metastatic workup was negative. Preoperative creatinine and hemoglobin levels were 1.53 mg/dL and 11.3 g/dL, respectively. Consultation with medical oncology was obtained prior to surgery for consideration of preoperative neoadjuvant immune-modulation treatment. The consensus was to proceed with robotic radical right nephrectomy, retroperitoneal lymph node dissection and IVC tumor thrombectomy, with close observation of the pulmonary lesions.
It is generally recommended to repeat cross-sectional imaging for reassessment of the tumor thrombus within two weeks prior to surgery to determine if there has been any interval growth. In patients with level III thrombi, the central focus of the operation is meticulous dissection and control of the IVC in order to perform successful cavotomy, tumor thrombus extraction and caval reconstruction while minimizing bleeding. In our case, four short hepatic vessels required division (Figure 4). Total operative time was 353 minutes and estimated blood loss was 150 cc. No intraoperative or postoperative transfusions were required. Extended operative time was expected as this was the first robotic approach for a level III thrombus performed at our institution.
Figure 4. Control and ligation of short hepatic vessels for intrahepatic IVC control.
Uneventful recovery
Postoperatively, the patient was taken to the post-anesthesia care unit for anesthesia recovery, and was subsequently admitted to the regular nursing floor. The patient was ultimately found to have pT3bN1 disease, and final histological assessment revealed nuclear grade 3 collecting duct RCC.
The patient advanced to clear liquids several hours after surgery and was given a regular diet on postoperative day two. He was discharged on postoperative day three. The patient’s hemoglobin reached a nadir of 9.3 g/dL immediately after surgery and was 9.5 g/dL on the day of discharge. Hemoglobin and creatinine levels at one-week follow-up were 10.6 g/dL and 1.52 mg/dL, respectively. The patient received prophylactic low-molecular-weight heparin for 28 days after surgery.
Further experience needed
Robotic surgery for management of RCC and associated level III IVC thrombi is feasible in select patients. As with any novel technique, further experience with long-term followup is necessary. At high-volume institutions, this approach appears to be a viable option, with potential lower EBL and shorter convalescence compared with open surgery. Nevertheless, open surgery should currently remain the standard of care for patients with this complex condition, as the main goals for success remain safety and cancer control.
CreditIllustration by Cristiana Couceiro. Photograph by Ansel Adams, via the National Archives, College Park, Md.
THE IMPROVISATIONAL ONCOLOGIST
In an era of rapidly proliferating, precisely targeted
treatments, every cancer case has to be played by ear.
The bone-marrow biopsy took about 20 minutes. It was 10 o’clock on an unusually chilly morning in New York in April, and Donna M., a self-possessed 78-year-old woman, had flown in from Chicago to see me in my office at Columbia University Medical Center. She had treated herself to orchestra seats for “The Humans” the night before, and was now waiting in the room as no one should be asked to wait: pants down, spine curled, knees lifted to her chest — a grown woman curled like a fetus. I snapped on sterile gloves while the nurse pulled out a bar cart containing a steel needle the length of an index finger. The rim of Donna’s pelvic bone was numbed with a pulse of anesthetic, and I drove the needle, as gently as I could, into the outer furl of bone. A corkscrew of pain spiraled through her body as the marrow was pulled, and then a few milliliters of red, bone-flecked sludge filled the syringe. It was slightly viscous, halfway between liquid and gel, like the crushed pulp of an overripe strawberry.
I had been treating Donna in collaboration with my colleague Azra Raza for six years. Donna has a preleukemic syndrome called myelodysplastic syndrome, or MDS, which affects the bone marrow and blood. It is a mysterious disease with few known treatments. Human bone marrow is normally a site for the genesis of most of our blood cells — a white-walled nursery for young blood. In MDS, the bone-marrow cells acquire genetic mutations, which force them to grow uncontrollably — but the cells also fail to mature into blood, instead dying in droves. It is a dual curse. In most cancers, the main problem is cells that refuse to stop growing. In Donna’s marrow, this problem is compounded by cells that refuse to grow up.
Though there are commonalities among cancers, of course, every tumor behaves and moves — “thinks,” even — differently. Trying to find a drug that fits Donna’s cancer, Raza and I have administered a gamut of medicines. Throughout all this, Donna has been a formidable patient: perennially resourceful, optimistic and willing to try anything. (Every time I encounter her in the clinic, awaiting her biopsy with her characteristic fortitude, it is the doctor, not the patient, who feels curled and small.) She has moved nomadically from one trial to another, shuttling from city to city, and from one drug to the next, through a landscape more desolate and exhilarating than most of us can imagine; Donna calls it her “serial monogamy” with different medicines. Some of these drugs have worked for weeks, some for months — but the transient responses have given way to inevitable relapses. Donna is getting exhausted.
Her biopsy that morning was thus part routine and part experiment. Minutes after the marrow was drawn into the syringe, a technician rushed the specimen to the lab. There he extracted the cells from the mixture and pipetted them into tiny grain-size wells, 500 cells to a well. To each well — about 1,000 in total — he will add a tiny dab of an individual drug: prednisone, say, to one well, procarbazine to the next and so forth. The experiment will test about 300 medicines (many not even meant for cancer) at three different doses to assess the effects of the drugs on Donna’s cells.
Bathed in a nutrient-rich broth suffused with growth factors, the cells will double and redouble in an incubator over the course of the following two weeks, forming a lush outgrowth of malignant cells — cancer abstracted in a dish. A computer, taught to count and evaluate cells, will then determine whether any of the drugs killed the cancerous cells or forced them to mature into nearly normal blood. Far from relying on data from other trials, or patients, the experiment will test Donna’s own cancer for its reactivity against a panel of medicines. Cells, not bodies, entered this preclinical trial, and the results will guide her future treatment.
I explained all this to Donna. Still, she had a question: What would happen if the drug that appeared to be the most promising proved unsuccessful?
“Then we’ll try the next one,” I told her. “The experiment, hopefully, will yield more than one candidate, and we’ll go down the list.”
“Will the medicine be like chemotherapy?”
“It might, or it might not. The drug that we end up using might be borrowed from some other disease. It might be an anti-inflammatory pill, or an asthma drug. It might be aspirin, for all we know.”
My conversation with Donna reflected how much cancer treatment has changed in the last decade. I grew up as an oncologist in an era of standardized protocols. Cancers were lumped into categories based on their anatomical site of origin (breast cancer, lung cancer, lymphoma, leukemia), and chemotherapy treatment, often a combination of toxic drugs, was dictated by those anatomical classifications. The combinations — Adriamycin, bleomycin, vinblastine and dacarbazine, for instance, to treat Hodgkin’s disease — were rarely changed for individual patients. The prospect of personalizing therapy was frowned upon: The more you departed from the standard, the theory ran, the more likely the patient would end up being undertreated or improperly managed, risking recurrence. In hospitals and clinics, computerized systems were set up to monitor an oncologist’s compliance with standard therapy. If you chose to make an exception for a particular patient, you had to justify the choice with an adequate excuse. Big Chemo was watching you.
I memorized the abbreviated names of combination chemo — the first letter of each drug — for my board exams, and I spouted them back to my patients during my clinic hours. There was something magical and shamanic about the multiletter contractions. They were mantras imbued with promise and peril: A.B.V.D. for Hodgkin’s, C.M.F. for breast cancer, B.E.P. for testicular cancer. The lingo of chemotherapists was like a secret code or handshake; even the capacity to call such baleful poisons by name made me feel powerful. When my patients asked me for statistical data, I had numbers at my fingertips. I could summon the precise chance of survival, the probability of relapse, the chance that the chemo would make them infertile or cause them to lose their hair. I felt omniscient.
Yet as I spoke to Donna that morning, I realized how much that omniscience has begun to wane — unleashing a more experimental or even artisanal approach in oncology. Most cancer patients are still treated with those hoary standardized protocols, still governed by the anatomical lumping of cancer. But for patients like Donna, for whom the usual treatments fail to work, oncologists must use their knowledge, wit and imagination to devise individualized therapies. Increasingly, we are approaching each patient as a unique problem to solve. Toxic, indiscriminate, cell-killing drugs have given way to nimbler, finer-fingered molecules that can activate or deactivate complex pathways in cells, cut off growth factors, accelerate or decelerate the immune response or choke the supply of nutrients and oxygen. More and more, we must come up with ways to use drugs as precision tools to jam cogs and turn off selective switches in particular cancer cells. Trained to follow rules, oncologists are now being asked to reinvent them.
The thought that every individual cancer might require a specific individualized treatment can be profoundly unsettling. Michael Lerner, a writer who worked with cancer patients, once likened the experience of being diagnosed with cancer to being parachuted out of a plane without a map or compass; now it is the oncologist who feels parachuted onto a strange landscape, with no idea which way to go. There are often no previous probabilities, and even fewer certainties. The stakes feel higher, the successes more surprising and the failures more personal. Earlier, I could draw curtain upon curtain of blame around a patient. When she did not respond to chemotherapy, it was her fault: She failed. Now if I cannot find a tool in the growing kit of drugs to target a cancer’s vulnerabilities, the vector feels reversed: It is the doctor who has failed.
Yet the mapless moment that we are now in may also hold more promise for patients than any that has come before — even if we find the known world shifting under our feet. We no longer have to treat cancer only with the blunt response of standard protocols, in which the disease is imagined as a uniform, if faceless, opponent. Instead we are trying to assess the particular personality and temperament of an individual illness, so that we can tailor a response with extreme precision. It’s the idiosyncratic mind of each cancer that we are so desperately trying to capture.
THE THOUGHT THAT EVERY INDIVIDUAL CANCER MIGHT REQUIRE A SPECIFIC INDIVIDUALIZED TREATMENT CAN BE PROFOUNDLY UNSETTLING.
Cancer — and its treatment — once seemed simpler. In December 1969, a group of cancer advocates led by the philanthropist Mary Lasker splashed their demand for a national war on cancer in a full-page ad in The New York Times: “Mr. Nixon: You Can Cure Cancer.” This epitomized the fantasy of a single solution to a single monumental illness. For a while, the centerpiece of that solution was thought to be surgery, radiation and chemotherapy, a strategy colloquially known as “slash and burn.” Using combination chemotherapy, men and women were dragged to the very brink of physiological tolerability but then pulled back just in time to send the cancer, but not its host, careering off the edge.
Throughout the 1980s and 1990s, tens of thousands of people took part in clinical trials, which compared subjects on standard chemo combinations with others administered slightly different combinations of those drugs. Some responded well, but for many others, relapses and recurrences were routine — and gains were small and incremental for most cancers. Few efforts were made to distinguish the patients; instead, when the promised cures for most advanced malignancies failed to appear, the doses were intensified and doubled. In the Margaret Edson play “Wit,” an English professor who had ovarian cancer recalled the bewildering language of those trials by making up nonsensical names for chemotherapy drugs that had been pumped into her body: “I have survived eight treatments of hexamethophosphacil and vinplatin at the full dose, ladies and gentlemen. I have broken the record.”
To be fair, important lessons were garnered from the trials. Using combinations of chemotherapy, we learned to treat particular cancers: aggressive lymphomas and some variants of breast, testicular and colon cancers. But for most men and women with cancer, the clinical achievements were abysmal disappointments. Records were not broken — but patients were.
A breakthrough came in the 2000s, soon after the Human Genome Project, when scientists learned to sequence the genomes of cancer cells. Cancer is, of course, a genetic disease at its core. In cancer cells, mutated genes corrupt the normal physiology of growth and ultimately set loose malignant proliferation. This characteristic sits at the heart of all forms of cancer: Unlike normal cells, cancer cells have forgotten how to stop dividing (or occasionally, have forgotten how to die). But once we could sequence tens of thousands of genes in individual cancer specimens, it became clear that uniqueness dominates. Say two identical-looking breast cancers arise at the same moment in identical twins; are the mutations themselves in the two cancers identical? It’s unlikely: By sequencing the mutations in one twin’s breast cancer, we might find, say, 74 mutated genes (of the roughly 22,000 total genes in humans). In her sister’s, we might find 42 mutations, and if we looked at a third, unrelated woman with breast cancer, we might find 18. Among the three cases, there might be a mere five genes that overlap. The rest are mutations particular to each woman’s cancer.
Photo
Dr. Azra Raza, left, speaking to Donna M., a patient who travels from Chicago for treatment for myelodysplastic syndromes, in a waiting room at NewYork-Presbyterian/Columbia.CreditKirsten Luce for The New York Times
No other human disease is known to possess this degree of genetic heterogeneity. Adult-onset diabetes, for example, is a complex genetic disease, but it appears to be dominated by variations in only about a dozen genes. Cancer, by contrast, has potentially unlimited variations. Like faces, like fingerprints — like selves — every cancer is characterized by its distinctive marks: a set of individual scars stamped on an individual genome. The iconic illness of the 20th century seems to reflect our culture’s obsession with individuality.
If each individual cancer has an individual combination of gene mutations, perhaps this variability explains the extraordinary divergences in responses to treatment. Gene sequencing allows us to identify the genetic changes that are particular to a given cancer. We can use that information to guide cancer treatment — in effect, matching the treatment to an individual patient’s cancer.
Many of the remarkable successes of cancer treatments of the last decades are instances of drugs that were matched to the singular vulnerabilities of individual cancers. The drug Gleevec, for instance, can kill leukemia cells — but only if the patient’s cancer cells happen to carry a gene mutation called BCR-ABL. Tarceva, a targeted therapy for lung cancer, works powerfully if the patient’s cancer cells happen to possess a particular mutant form of a gene; for lung-cancer patients lacking that mutation, it may be no different from taking a placebo. Because the medicines target mutations or behaviors that are specific to cancer cells (but not normal cells), many of these drugs have surprisingly minimal toxicities — a far cry from combination chemotherapies of the past.
A few days after Donna’s visit to the clinic, I went to my weekly meeting with Raza on the ninth floor of the hospital. The patient that morning was K.C., a 79-year-old woman with blood cancer. Raza has been following her disease — and keeping her alive — for a decade.
THE LINGO OF CHEMOTHERAPISTS WAS LIKE A SECRET CODE OR HANDSHAKE; EVEN THE CAPACITY TO CALL SUCH BALEFUL POISONS BY NAME MADE ME FEEL POWERFUL.
“Her tumor is evolving into acute leukemia,” Raza said. This, too, is a distinctive behavior of some cancers that we can now witness using biopsies, CT scans and powerful new techniques like gene sequencing: We can see the cancers morphing from smoldering variants into more aggressive types before our eyes.
“Was the tumor sequenced?” I asked.
“Yes, there’s a sequence,” Raza said, as we leaned toward a screen to examine it. “P53, DNMT3a and Tet2,” she read from the list of mutant genes. “And a deletion in Chromosome 5.” In K.C.’s cancer, an entire segment of the genome had been lopped off and gone missing — one of the crudest mutations that a tumor can acquire.
“How about ATRA?” I asked. We had treated a few patients carrying some of K.C.’s mutations with this drug and noted a few striking responses.
“No. I’d rather try Revlimid, but at a higher dose. She’s responded to it in the past, and the mutations remain the same. I have a hunch that it might work.”
Researchers have discovered that cancers they once assumed were quite different might be similar genetically, which means a treatment that used to work for only a small group of patients now might help a much larger group. Mutations in the gene E2F3, for example, are found in breast, lung, bladder and prostate cancers, among others. Knowing this, it’s possible to develop similar drugs that target the gene across different cancers.
As Raza and I returned to K.C.’s room to inform her of the plan, I couldn’t help thinking that this is what it had come down to: inklings, observations, instincts. Medicine based on premonitions. Chemo by hunch. The discussion might have sounded ad hoc to an outsider, but there was nothing cavalier about it. We parsed these possibilities with utmost seriousness. We studied sequences, considered past responses, a patient’s recent history — and then charged forward with our best guess. Our decisions were spurred by science, yes, but also a sense for the art of medicine.
Oncologists are also practicing this art in areas that rely less on genes and mutations. A week after Donna’s biopsy, I went to see Owen O’Connor, an oncologist who directs Columbia’s lymphoma center. O’Connor, in his 50s, reminds me of an amphibious all-terrain vehicle — capable of navigating across any ground. We sat in his office, with large, sunlit windows overlooking Rockefeller Plaza. For decades, he explained, oncologists had treated relapsed Hodgkin’s lymphoma in a standard manner. “There were limited options,” O’Connor said. “We gave some patients more chemotherapy, with higher doses and more toxic drugs, hoping for a response. For some, we tried to cure the disease using bone-marrow transplantation.” But the failure rate was high: About 30 percent of patients didn’t respond, and half of them died.
Then a year or two ago, he tried something new. He began to use immunological therapy to treat relapsed, refractory Hodgkin’s lymphoma. Immunological therapies come in various forms. There are antibodies: missile-like proteins, made by our own immune systems, that are designed to attack and destroy foreign microbes (antibodies can also be made artificially through genetic engineering, armed with toxins and used as “drugs” to kill cancer cells). And there are drugs that incite a patient’s own immune system to recognize and kill tumor cells, a mode of treatment that lay fallow for decades before being revived. O’Connor used both therapies and found that they worked in patients with Hodgkin’s disease. “We began to see spectacular responses,” he said.
Yet even though many men and women with relapsed Hodgkin’s lymphoma responded to immunological treatments, there were some who remained deeply resistant. “These patients were the hardest to treat,” O’Connor continued. “Their tumors seemed to be unique — a category of their own.”
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Dr. Siddhartha Mukherjee, left, speaking to K.C., who has acute myeloid leukemia, at NewYork-Presbyterian/Columbia.CreditKirsten Luce for The New York Times
Lorenzo Falchi, a fellow training with O’Connor and me, was intrigued by these resistant patients. Falchi came to our hospital from Italy, where he specialized in treating leukemias and lymphomas; his particular skill, gleaned from his experience with thousands of patients, is to look for patterns behind seemingly random bits of data. Rooting about in Columbia’s medical databases, Falchi made an astonishing discovery: The men and women who responded most powerfully to the immune-boosting therapies had invariably been pretreated with another drug called azacitidine, rarely used in lymphoma patients. A 35-year-old woman from New York with relapsed lymphoma saw her bulky nodes melt away. She had received azacitidine as part of another trial before moving on to the immunotherapy. A man, with a similar stage of cancer, had not been pretreated. He had only a partial response, and his disease grew back shortly thereafter.
Falchi and O’Connor will use this small “training set” to begin a miniature trial of patients with relapsed Hodgkin’s disease. “We will try it on just two or three patients,” Falchi told me. “We’ll first use azacitidine — intentionally, this time — and then chase it with the immune activators. I suspect that we’ll reproduce the responses that we’ve seen in our retrospective studies.” In lung cancer too, doctors have noted that pretreating patients with azacitidine can make them more responsive to immunological therapy. Falchi and O’Connor are trying to figure out why patients respond if they are pretreated with a drug that seems, at face value, to have nothing to do with the immune system. Perhaps azacitidine makes the cancer cells more recognizably foreign, or perhaps it forces immune cells to become more aggressive hunters.
Falchi and O’Connor are mixing and matching unexpected combinations of medicines based on previous responses — departing from the known world of chemotherapy. Even with the new combination, Falchi suspects, there will be resistant patients, and so he will divide these into subsets, and root through their previous responses, to determine what might make these patients resistant — grinding the data into finer and finer grains until he’s down to individualized therapy for every variant of lymphoma.
Suppose every cancer is, indeed, unique, with its own permutation of genes and vulnerabilities — a sole, idiosyncratic “mind.” It’s obviously absurd to imagine that we’ll find an individual medicine to treat each one: There are 14 million new cases of cancer in the world every year, and several million of those patients will present with advanced disease, requiring more than local or surgical treatment. Trying to individualize treatment for those cases would shatter every ceiling of cost.
Cancer works the same way all life works, through the process of cell division and mutation. All living things grow and heal through cell division, and all living things evolve and change through the occasional mutations that occur as the cells divide. But some mutations can be deadly, leading to the unchecked growth that defines cancer. More than 14 million Americans have a history of cancer; it is expected to kill 600,000 Americans this year.
But while the medical costs of personalized therapy are being debated in national forums in Washington, the patients in my modest waiting room in New York are focused on its personal costs. Insurance will not pay for “off-label” uses of medicines: It isn’t easy to convince an insurance company that you intend to use Lipitor to treat a woman with pre-leukemia — not because she has high cholesterol but because the cancer cells depend on cholesterol metabolism for their growth (in one study of a leukemia subtype, the increasing cells were highly dependent on cholesterol, suggesting that high doses of Lipitor-like drugs might be an effective treatment).
In exceptional cases, doctors can requisition pharmaceutical companies to provide the medicines free — for “compassionate use,” to use the language of the pharma world — but this process is unpredictable and time-consuming. I used to fill out such requests once every few months. Now it seems I ask for such exceptions on a weekly basis. Some are approved. A majority, unfortunately, are denied.
So doctors like Falchi and O’Connor do what they can — using their wiles not just against cancer but against a system that can resist innovation. They create minuscule, original clinical trials involving just 10 or 20 patients, a far cry from the hundred-thousand-patient trials of the ’80s and ’90s. They study these patients with monastic concentration, drawing out a cosmos of precious data from just that small group. Occasionally, a patient may choose to pay for the drugs out of his or her own pockets — but it’s a rare patient who can afford the tens of thousands of dollars that the drugs cost.
But could there be some minimal number of treatments that could be deployed to treat a majority of these cancers effectively and less expensively? More than any other scientist, perhaps, Bert Vogelstein, a cancer geneticist at Johns Hopkins University, has tackled that conundrum. The combination of genetic mutations in any individual cancer is singular, Vogelstein acknowledges. But these genetic mutations can still act through common pathways. Targeting pathways, rather than individual genes, might reorganize the way we perceive and treat cancer.
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Deep freezers containing bone marrow, bone-marrow plasma and blood serum in Siddhartha Mukherjee’s research lab.CreditKirsten Luce for The New York Times
Imagine, again, the cell as a complex machine, with thousands of wheels, levers and pulleys organized into systems. The machine malfunctions in the cancer: Some set of levers and pulleys gets jammed or broken, resulting in a cell that continues to divide without control. If we focus on the individual parts that are jammed and snapped, the permutations are seemingly infinite: Every instance of a broken machine seems to have a distinct fingerprint of broken cogs. But if we focus, instead, on systems that malfunction, then the seeming diversity begins to collapse into patterns of unity. Ten components function, say, in an interconnected loop to keep the machine from tipping over on its side. Snap any part of this loop, and the end result is the same: a tipped-over machine. Another 20 components control the machine’s internal thermostat. Break any of these 20 components, and the system overheats. The number of components — 10 and 20 — are deceptive in their complexity, and can have endless permutations. But viewed from afar, only two systems in this machine are affected: stability and temperature.
Cancer, Vogelstein argues, is analogous. Most of the genes that are mutated in cancer also function in loops and circuits — pathways. Superficially, the permutations of genetic flaws might be boundless, but lumped into pathways, the complexity can be organized along the archetypal, core flaws. Perhaps these cancer pathways are like Hollywood movies; at first glance, there seems to be an infinite array of plot lines in an infinite array of settings — gold-rush California, the Upper West Side, a galaxy far, far away. But closer examination yields only a handful of archetypal narratives: boy meets girl, stranger comes to town, son searches for father.
How many such pathways, or systems, operate across a subtype of cancer? Looking at one cancer, pancreatic, and mapping the variations in mutated genes across hundreds of specimens, Vogelstein’s team proposed a staggeringly simple answer: 12. (One such “core pathway,” for instance, involves genes that enable cells to invade other tissues. These genes normally allow cells to migrate through parts of the body — but in cancer, migration becomes distorted into invasion.) If we could find medicines that could target these 12 core pathways, we might be able to attack most pancreatic cancers, despite their genetic diversity. But that means inventing 12 potential ways to block these core paths — an immense creative challenge for scientists, considering that they haven’t yet figured out how to target more than, at best, one or two.
Immunological therapies provide a second solution to the impasse of unlimited diversity. One advantage of deploying a patient’s own immune system against cancer is that immunological cells are generally agnostic to the mutations that cause a particular cancer’s growth. The immune system was designed to spot differences in the superficial features of a diseased or foreign cell, thereby identifying and killing it. It cares as little about genes as an intercontinental ballistic missile cares about the email addresses, or dietary preferences, of the population that it has been sent to destroy.
A few years ago, in writing a history of cancer, I interviewed Emil Freireich. Freireich, working with Emil Frei at the National Cancer Institute in the 1960s and ’70s, stumbled on the idea of deploying multiple toxic drugs simultaneously to treat cancer — combination chemotherapy. They devised one of the first standard protocols — vincristine, Adriamycin, methotrexate and prednisone, known as VAMP — to treat pediatric leukemias. Virtually nothing about the VAMP protocol was individualized (although doses could be reduced if needed). In fact, doctors were discouraged from trying alternatives to the formula.
Yet as Freireich recalled, long before they came up with the idea for a protocol, there were small, brave experiments; before trials, there was trial and error. VAMP was brought into existence through grit, instinct and inspired lunges into the unknown. Vincent T. DeVita Jr., who worked with Freireich in the 1960s, wrote a book, “The Death of Cancer,” with his daughter, Elizabeth DeVita-Raeburn. In it, he recalled a time when the leukemic children in Freireich’s trial were dying of bacterial meningitis during treatment. The deaths threatened the entire trial: If Freireich couldn’t keep the children alive during the therapy, there would be no possibility of remission. They had an antibiotic that could kill the microbe, but the medicine wouldn’t penetrate the blood-brain barrier. So Freireich decided to try something that pushed the bounds of standard practice. He ordered DeVita, his junior, to inject it directly into the spinal cords of his patients. It was an extreme example of off-label use of the drug: The medicine was not meant for use in the cord. DeVita writes:
“The first time Freireich told me to do it, I held up the vial and showed him the label, thinking that he’d possibly missed something. ‘It says right on there, “Do not use intrathecally,” ’ I said. Freireich glowered at me and pointed a long, bony finger in my face. ‘Do it!’ he barked. I did it, though I was terrified. But it worked every time.”
When I asked Freireich about that episode and about what he would change in the current landscape of cancer therapy, he pointed to its extreme cautiousness. “We would never have achieved anything in this atmosphere,” he said. The pioneer of protocols pined for a time before there were any protocols.
Medicine needs standards, of course, otherwise it can ramble into dangerous realms, compromising safety and reliability. But cancer medicine also needs a healthy dose of Freireich: the desire to read between the (guide)lines, to reimagine the outer boundaries, to perform the experiments that become the standards of the future. In January, President Obama introduced an enormous campaign for precision medicine. Cancer is its molten centerpiece: Using huge troves of data, including gene sequences of hundreds of thousands of specimens and experiments performed in laboratories nationwide, the project’s goal is to find individualized medicines for every patient’s cancer. But as we wait for that decades-long project to be completed, oncologists still have to treat patients now. To understand the minds of individual cancers, we are learning to mix and match these two kinds of learning — the standard and the idiosyncratic — in unusual and creative ways. It’s the kind of medicine that so many of us went to medical school to learn, the kind that we’d almost forgotten how to practice.
These basic principles can help you navigate the journey no one plans to take.
