by Azra Raza
As the internet dot-com bubble burst in the ’90s, the biotechnology industry was the big winner since some of the best minds in the country made lateral moves and began to invest their talents in this area. The striking changeabout since 2010 in the pharmaceutical industry has been its ability to attract and retain high-caliber academic scientists and clinical investigators. Even with this vital infusion, it takes a decade and a prohibitive billion dollars for a pharmaceutical company to get a new drug approved, most of the money having been raised from the private sector, which is clamoring all the while for a profit. Following the arduous R&D process and the tedious, time-consuming, and labor-intensive animal studies, by the time a clinical trial is undertaken in human subjects, the stakes are already too high and companies are struggling to demonstrate the tiniest statistical benefits over each other’s products.
Where drug development research is concerned, humans must remain the measure of all things. No model, whether it is in vitro cell lines or in vivo animal models or even freshly obtained cancer cells from patients, accurately predicts what will happen when a drug is actually administered to humans. So why not start with giving the agent of interest to humans directly, bypassing the misleading model systems altogether? It is possible to do this through the mechanism of phase 0 trials. The ideal manner to conduct clinical trials would be to take them through the traditional four phases as prescribed by the FDA but at each phase to examine as many biologic and clinical markers as possible in the subjects using the latest technology. If thirty participants in a phase 1 trial have their blood, bone marrow, microbiome, serum analytes, and all available tumor cells studied thoroughly using panomics, AI, imaging, and nanotechnology, then chances are high for identifying surrogate markers for positive and negative effects of the trial agent that may not yet translate into an actual clinical response. This information could help enrich recruitment of potential responders into the next phase of the trial by preselecting only those who show positive biomarkers of response. It is the best and only way to identify possible responders to a given strategy. It is so logical that you would be justified in wondering why this is not already happening.
The unfortunate reality is that not a single marker for response is examined in the majority of clinical trials being conducted even today. Why? Because this is how the system has evolved. The pharmaceutical industry sponsoring the trials is only interested in reaching a statistical end point to get their agent approved. The companies have usually invested almost a billion dollars already to bring an agent to the point of a phase 3 trial. It would add a staggering amount of money to their stretched budgets to perform such detailed biomarker analysis. I suggest saving all the money being squandered on testing the agents in pretherapy, preclinical models of cell lines, and mouse models and instead investing the resources in biomarker analysis. Some bold changes are needed at every level. To harness rapidly evolving fields like imaging, nanotechnology, proteomics, immunology, artificial intelligence, and bioinformatics, and focus them on serving the cause of the cancer patient, we must insist on collaboration between government institutions (NCI, FDA, CDC, DOD), American Society of Clinical Oncology, American Society of Hematology, funding agencies, academia, philanthropy, and industry. The success of many landmark projects of our time, such as the Human Genome Project, the Human Microbiome Project, and the Cancer Genome Atlas, are examples of collaboration between scientists around the world and can serve as a model for the First Cell Project aimed at developing the technology needed for early detection and prevention of cancer.
KITTY STARTED WITH the combination therapy, and once again, we fell into our weekly routine. She would come in and get the CBC done. We would meet and look at the hemoglobin level, white blood cells, and platelets together before I sent her to the infusion center for eight hours if she needed a blood transfusion, or she would make a return appointment for next week if the hemoglobin was acceptable. With Revlimid, her diarrhea returned. She restarted her old regimen of Lomotil and dietary restrictions. Six weeks into the combination therapy, her hemoglobin, instead of falling, had jumped up by a whole gram in one week. We thought there was a mistake and repeated the count. No mistake. Amazed, we did not want to overinterpret the results and decided to wait another week before opening champagne. The following week, her hemoglobin was even better. With this combination, Kitty did unexpectedly well. She required an occasional transfusion, the blasts did not decrease by much, a March 2014 bone marrow biopsy showed 22 percent, but at least they were not galloping out of control. We became cautiously optimistic. She continued this treatment with minor tweaking of Revlimid doses and varying intervals between Vidaza cycles.
Another year went by. Her nagging anxieties relieved, she resumed her activities. No, she did more—she extracted life out of life.
Thu 1/1/2015 3:20 PM
Dear Dr. Raza,
Well enough and happy enough, I got down to Lincoln Center on the A train last night to sing in the New Year, joining with a friend and few thousand other people in the audience as we sang “Auld Lang Syne” accompanied by the NY Philharmonic. Can’t think of a better way to celebrate and keep moving on. I never thought, expected to greet 2015!
Thanks. And my best wishes to you for all good things in 2015—love and health and delightful surprises.
A friend who lives in North Carolina called me to tell me that she had just received her invitation to the January 20 EVENT (She was a donor at the last fund raiser). Since I haven’t heard anything I thought I better say something. Should I contact someone?
All my best,
Kitty C.
The “event” was our next fund-raiser. This time, we had Paul Simon, James Taylor, Diana Reeves, and many other greats performing at Lincoln Center to benefit our research program. Kitty was excited to attend and to bring us sponsorship from friends. This interlude turned out to be full of enchanting activities for Kitty. She had learned to value each good day, and she was determined to make the most of it. She traveled, socialized with friends and family, attended performances at Lincoln Center, enjoyed her walks in the park and trips into the city to visit museums, attended lectures, saw movies, ate in Chinatown. And we talked. We talked all the time. We had our weekly routine in clinic, where we would dispense with the medical issues with alacrity and then relax and start comparing notes on our weekly activities. How privileged I have felt, meeting and befriending such remarkable souls. Work can really be more fun than fun.
Sat 2/21/2015 12:57 PM
Dear Dr. Raza,
Michelle Tapar interviewed me at home by telephone on Thursday. I told her “my story” including the significance of a center devoted to research and treatment of MDS and the depth and extent of the expertise brought to bear on each step of my treatment over the years.
She recorded my story but did explain that they have no plans to make any more films for the time being (They’ve completed the set that is currently being shown) and are now collecting stories for future filming. When and whether they do more will depend on a “number of factors.” In the event they resume filming, she said that they will contact me. And in that event, I’ll be ready and willing.
All my best,
Kitty C.
I repeated a bone marrow biopsy in August 2015. The aspirate was inadequate and blast percentage could not be accurately assessed. In fact, compared to the previous marrow test of March 2015, these results were no different. She had a 17 percent blast count in the aspirate and 15 percent in the biopsy back then. In addition, both marrows continued to show a small clone of del5q cells. My conclusion was that at least her disease was no worse.
Kitty’s blood counts slowly stabilized; the platelets were back in the 100,000 range, but it was clear that the treatment was proving to be too toxic to the bone marrow. I needed to do something different now. I suggested a short cycle of two to three days of Dacogen instead of Vidaza along with the Revlimid. She had not received Dacogen for more than five years by that point. She had
several cycles of this, and a repeat marrow check showed continued disease stabilization.
But right after the fifth cycle, she developed a high fever and was admitted to the hospital. She had a prolonged admission, diagnosed with pneumonia that did not respond to antibiotics but that eventually responded to antifungals. She had more than a liter of fluid removed from the lungs. Slowly, she improved and was discharged home after several weeks in the hospital.
In February and March of 2016, she only had 1 percent blasts circulating in the blood. By May, they were up to 10 percent. In June, they were in the 40 percent range. The increase could partly have been because of her infections. She had also received the white blood cell–stimulating growth factor Neupogen. We decided to wait it out. Leukemia has other ways of declaring itself. After she recovered from the pneumonia and was off both the growth factor and antifungal agents, her circulating blasts still continued to rise. She refused another bone marrow test.
In July 2016, Kitty turned eighty. She had not expected it. She was pleased. Although she didn’t want another bone marrow screening, she was still ready for more treatment. I started her now on a combination of Dacogen and another chemotherapy called 6-thioguanine (6-TG), using doses so small they were practically homeopathic because the treatment itself posed a serious risk of dangerously lowering the white blood cell count and suppressing the immune system further. It is a fine line between killing the leukemia cells and hurting the patient with aggressive, cytotoxic therapy. After this first course, in the third week of August 2016, she again presented with fever and a worsening pneumonia. She was hospitalized for three weeks that time, released on September 14, taking antifungals, antibiotics, antivirals, and Flagyl as an outpatient. They were brutal, wreaking havoc on every organ in her much-assaulted, enfeebled body. Suddenly, her sense of taste was gone. She said to me with wonder, “I had no idea until now how much of appetite is tied to taste.” She stopped eating, forcing down a few sips of those dreaded Ensure Plus shakes. She continued losing weight.
We repeated a bone marrow biopsy on October 12, 2016, and this showed 78 percent blasts. I treated her with Dacogen and 6-TG for three days from October 19 to 21. She tolerated the treatment well. Unfortunately, it wasn’t effective. The blood counts dropped dramatically. Time went on, and the counts failed to improve. Then, slowly, menacingly, the blast count started rising in her blood. When her white blood count started to increase rapidly, she was too frail for high-dose chemotherapy; I started her on oral hydroxyurea, another chemo, instead.
She refused admission to the hospital. Ever.
NOWHERE IS THE mind-body dualism more acute than in these final stages when the footsteps of approaching death become louder by the day. The protracted, harrowing, exhausting, tormented battle with MDS, and then AML, was finally coming to an excruciating finale. A part of Kitty had quietly gone missing. She was drained. She brought her sister and son for a valedictory meeting. We crowded into the little consultation room for one final meeting. Her beloved son sat silently, choking back tears. The scene seemed staged, contrived, our postures oddly stylized, as if we were all playing rehearsed parts in a play. She looked frail and emaciated. The chic outfit hung on her like a shroud, exaggerating her skeletal contours. She sat across from me, rallying whatever residual psychic resources she could from crevices unbeknownst even to her until just that moment, speaking slowly and deliberately, with an impossible dignity. She said, “I can’t eat, I can’t walk, I can’t read. I don’t want to. I have no desire to do anything anymore. All I feel like doing all day is sleep.” She took a deep breath. “I am dying.”
She requested hospice care.
Kitty died in the spring of 2017.
Death came by a thousand cuts.
In those twilight days, her son took tender care of her. In the beginning, we spoke on the phone every day. Then she became too weak to talk, and our long-distance conversations dwindled, became forced. Eventually, we ran out of things to say. One evening, I was in an Uber, caught in traffic on Fifth Avenue, late for a meeting on the Upper East Side, when my cell phone rang. It was her son. He swallowed before he could speak. “Dr. Raza, thank you for all you did.” He did not have to say more. I stared at the rushing pedestrians, the throng of cars, yellow cabs, buses, a lone policeman thrashing his arms, guiding the mad traffic. Everything around me was the same. My eyes had changed. A tristesse enveloped the tapestry of midtown Manhattan. I heard her voice from our first meeting eight years earlier.
We had met in a stuffy, airless, aseptic consultation room on the ninth floor of the Herbert Irving Pavilion. Kitty, with her dazzling smile, her fine features, clear blue eyes, her gorgeous halo of startling, salt-and-pepper curly hair, her slight frame, her stylish, loose linen top and baggy pants, book in hand. I noticed her unusual shoes with straps climbing up to mid-calf, brown leather, with comfortable-looking round toes punched with holes for air. “You like walking?” I asked.
“Love it,” she said. “And you?”
“I am a runner,” I said. “Three to five miles a day.”
She smiled. “Figures. You are just what I imagined. Someone who starts by racing the day. Exerting yourself to the full in whatever you do.”
A COUPLE OF months after Harvey died, little eight-year-old Sheherzad developed the flu. Any respiratory illness aggravated her chronic asthma, and for the next forty-eight hours, she struggled to breathe through nebulizers and inhalers, running high fevers and staying up nights with a hacking cough. It took a week for her to experience any relief. One early morning, I was working in the family room when she came out of her room crying inconsolably. I assumed she had a relapse and was worse. She was unable to answer for a few minutes as her little body shook with sobs. Finally, she was calm enough to explain. “Actually, Mom, I feel fine. But now I know how horrible it is to be sick and how good it feels to get better. My dad never got better,” she said, bursting into a fresh cycle of crying.
After Harvey died, I found myself feeling disconnected from the world, distanced, alienated almost. For almost five years, the focus had been entirely on his illness, every action, every thought related somehow to the lymphoma. Now, I suddenly had nothing to do, no frantic doctors’ appointments to keep, no overnight hospital stays, no need to coordinate consultations with ten experts, no anxiety to scan fifteen test results, make complicated decisions, face impossible choices, all the while arranging babysitters for Sheherzad, seeing my own patients in packed clinics, running a research lab. No more soul-wrenching pillow talks. More than the physical issues, it was the intellectual sterility I experienced that was entirely new and profoundly unsettling, a deep desolation oozing out of every sulcus and gyrus in my cerebrum, preventing me from thinking properly, making me unable to concentrate. I felt an indescribable hollowness. Like a dreamer who woke up, could not remember the dream, but remained stirred by the feelings, I drifted through the days listlessly, missing Harvey, and curiously enough, missing what I used to be like when I was with him. It was as if I had to reacquaint myself with a new post-Harvey me. I could not listen to music. Work remained the only distraction. Several months passed. I decided to do something about it. I ordered the hundred great books of the Western literary tradition (there are many such lists; I went for the fancy Easton Press ones, gorgeously bound, a delight to stare at, hold). For the next three years, I immersed myself in reading, starting with Euripides, Aeschylus, Homer, Plato, Augustine, all the way to Cervantes, Dostoevsky, and Rousseau to Elliott and Thackeray, Dickens and James, Wharton and Melville. It helped me orient myself back to being me, back to life, to grieve, to accept and eventually to move on. Fiction helped me mend, saved my sanity. Books seemed to bring time to a halt, the stories forcing me to pause and take stock of my own surroundings in the context of the unfolding fictitious dramas.
How do oncologists deal with dying patients day in and day out, caught in the amber of soul-destroying moments when people running out of time catalog their swelling regrets, their vanis
hing options, in a maelstrom of disorder and disease? And how do we deal with the grief once we lose them? Reading fiction, especially the classics of both Urdu and English, has helped me do both in a way that I could not have managed otherwise. By blurring the us-versus-them margins as I stood in the shoes of various characters and felt their joys and sorrows, fear and pain, it helped me appreciate the complexity of lives beyond the complacent, self-satisfied, simplistic Manichean duality of good and evil. My empathy for characters surged in direct proportion to the level of emotional engagement I experienced in a story. Fiction polished my cognitive and intellectual skills to read emotions in others, gauge anxiety levels, diagnose psychosocial fragility. Fiction gave me the equanimity and self-control to follow the advice of Emory Austin: “Some days there won’t be a song in your heart. Sing anyway.”
Obviously, no two patients are alike in how they face the end, and each one has individual needs. There is no algorithm to follow. The only practical approach is to let patients teach us what they need at any given moment, one at a time. The key is to listen when patients talk. To listen seriously. Listen more “hearingly,” the kind of listening that the blind develop naturally; listening for what is not said, listening to understand. Patients tend to hold back their tormenting concerns, the worries keeping them up at night. These require concentrated listening. Doctors are known to interrupt patients every eighteen seconds on an average.
Ultimately, nearer the end, nature itself quietly takes over, becomes the guide for patients, and patients in turn teach us what to do and how.
