by Azra Raza
Then, as suddenly as they had improved, Kitty’s blood counts tanked. After almost three years of a reasonable response, the benefits of Revlimid evaporated. I had anticipated this. She, too, knew what to expect because of our endless conversations, but even she was caught off guard when it actually happened. When I handed her the CBC report showing the return of her anemia, the blood drained from her face. She was genuinely taken by surprise. This issue of what the doctor says and what the patient hears remains baffling in general, but it is of special importance in oncology. Patients will concentrate on the positive, hopeful parts (some patients can respond to Revlimid for many years) and ignore the rest (others stop responding in months).
I was thinking about her disease, but Kitty was living through it. She was still feeling reasonably well; the worsening anemia was creeping so slowly that she had not felt any dramatic symptoms yet. Revlimid had stopped working, and we needed to come up with a new strategy to treat her worsening anemia. We repeated the blood counts weekly for the next month, and things continued to deteriorate. She started requiring blood transfusions once again. I decided to repeat the bone marrow biopsy and restage her disease. This came back showing evolution of her disease to a high-grade MDS with 13 percent blasts, or immature cells, in the marrow. A population of up to 5 percent falls within what’s considered the normal range for MDS, while the presence of 20 percent blasts changes the diagnosis from MDS to acute myeloid leukemia, or AML. Kitty had had less than 5 percent blasts since 2009. This time, the cytogenetics were normal, but a genetic profile of her abnormal cells showed the appearance of the dreaded mutation in p53 associated with a poor prognosis and shorter survival.
The next choices were either an experimental trial or Vidaza, which she had not received so far. Because Vidaza is a hypomethylating agent similar to Dacogen, which Kitty had not responded to, it was possible that she would not respond to Vidaza either. However, I hoped that as she had not received any hypomethylating agent since 2009, four years earlier, that evolution under selection by Revlimid treatment could have rendered the dominant clone of cells sensitive to Vidaza. We discussed the pros and cons of this approach at length and finally started her on the abbreviated five-day course a month instead of the typical seven days. She was nervous:
Wed 7/10/2013 3:25 PM
Dear Dr. Raza,
I’m set to begin the Vidaza treatment on Monday
Since I’m to see you the morning before I begin, here are a few questions that have occurred to me—some just wishful thinking or delaying:
Anything to be gained by waiting a few weeks? Or lost?
Any relationship at all between Vidaza (Dacogen, also?) and reversing or slowing the increase of blasts in my marrow? I’m sure I know the answer but need to understand again that this kind of a reversal would be the very cure you’re working for.
And is Vidaza my best chance (I understand 50 percent) to stave off dependence on transfusions and all that goes with that.
And (I know this is really magical thinking) would doing another bone marrow, biopsy possibly show a miraculous reversal in blasts?
I’ll bring this with me on Monday.
Thanks
Kitty C.
Despite her concerns, she started treatment. I began to see her every week again. Our conversations resumed. On the whole, she tolerated Vidaza well but had moments of awful nausea, fatigue, and listlessness while being treated. A week after the five-day course, she would begin to feel human again, and by the third week, she was herself. However, she continued to receive blood transfusions at the same frequency. After three months of Vidaza, I did another bone marrow examination. The blasts had increased to 25 percent; she now had AML. That transition is what we had sought to avoid at all costs, because AML is a universally fatal illness.
One depressing morning, I sat her down in clinic to review all the options. It was a choice between a rock and a hard place. Elderly patients such as Kitty are not good candidates for either a bone marrow transplant or 7+3 chemotherapy. The alternative treatment, if there was one, was an experimental trial. “Well,” said Kitty, “I am sure I don’t want chemo.” An experimental trial, with its possible toxicities and many more required bone marrow tests—“Ugh! I do hate them!” she said—held out only the possibility of questionable benefit. “To prolong my life by weeks? Maybe I will just get transfusions now and let nature take its course.” I could not argue with her. Before she left the clinic that October morning, she gave me a long hug, said thanks, and walked out with her head held high.
We met in clinic the following week. The cytogenetic results from her most recent bone marrow exam were available. To my surprise, there were two out of twenty cells showing del5q. A small “good” subclone was rearing its head again. Given that she had already received several years of treatment with Revlimid, these emerging cells would seem likely to be resistant to therapy with the drug again, almost by definition. But then, she had not received Revlimid in almost six months. I suggested we try Vidaza and Revlimid together. In our relationship, I provided the expert “how” of medical treatment, but the informed decision had to be hers. She decided that she did not want to give up. “Dr. Raza, I trust you. If you think I should try this, write the orders.”
THE WAR ON CANCER
In the late ’60s, chemotherapy was starting to produce remissions and even cures for some forms of childhood cancers. The picture for adults, however, still looked grim. President Nixon was ready to slash the budget for cancer research but for one woman, Mary Lasker.
Briefly, Mrs. Lasker, a wealthy businesswoman in her own right, married into more wealth, interested in the health care of Americans, was inspired and then obsessed with the problem of cancer. She consulted top oncologists and researchers about the best way to help. They unanimously agreed that meaningful impact on cancer would come through improved and expanded basic research. She decided to go after what she called “medicine for the people,” stating on television how shameful it was that “less is spent on cancer research in America than on chewing gum.” Mary recruited her friend Ann Landers to write a column appealing to the public to put pressure on President Nixon to increase funding for cancer research instead of cutting it. A quarter of a million devoted readers responded by contacting the White House, demanding the president’s attention for this pressing need. What eventually followed is summarized in these now famous one hundred words from President Richard M. Nixon’s 1971 State of the Union address.
I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal. America has long been the wealthiest nation in the world. Now it is time we became the healthiest nation in the world.
The media promptly dubbed it as Nixon’s war on cancer. Following the stupendous infusion of money and resources into cancer, expectation for a cure swung high, many serious investigators declaring an end in sight by 1976. The great bicentennial came and went and there was no cure. Ten more years passed and still there was no light at the end of the tunnel. Slash, poison, and burn (surgery, chemo, and radiation therapies) continued to be the prevalent strategies. A few types of cancers did benefit (testicular cancer, childhood malignancies, lymphomas) but mostly because of more informed use of the existing strategies rather than any dramatic novel ones. Important biologic insights emerged thanks to basic research but failed spectacularly to improve the outcome for patients suffering from common cancers who continued to die painful deaths at practically the same rate.
A breakthrough seemed to have surfaced in 1998 when cancer mortality began to decline, but it turned out that instead of President Nixon’s efforts to promote the war on cancer, credit for this long-awaited good news belon
ged to Dr. Terry Luther, the ninth surgeon general of the United States. Following the findings in the United Kingdom of a relationship between lung cancer and smoking, Luther had established the Surgeon General’s Advisory Committee, which released its report on January 11, 1964, concluding that lung cancer and chronic bronchitis are causally related to cigarette smoking. Efforts directed at cessation of smoking that were started in 1960s were finally starting to show results in 1990s. Screening for colorectal cancers saved more than twenty thousand lives, and it was clear that cervical cancer could be 100 percent treatable if detected early through Pap smears.
Eleven years later, in 2009, Gina Kolata reported in her New York Times column the jaw-dropping statistics that despite the infusion of more than $100 billion into cancer research, death rates for cancer had dropped by only 5 percent between 1950 and 2005 when adjusted for size and age of the population. The war on cancer was not going well. The question was why not. Were we not spending the funds well, or was cancer simply an impossible problem? Since 1984, my answer has been a resounding yes on both counts. As someone who has been directly involved in cancer research since 1977, and obsessed with it for longer, I am a firsthand witness to the recurring cycles of high expectation and deflating disappointments in the last several decades. Because the stakes are so high, both in terms of life-death issues as well as the staggering amount of money involved, emotions tend to run high on all sides.
Even though President Nixon and subsequent administrations have continued to invest heavily in cancer research—the dedicated budget for the National Cancer Institute alone rocketing up to more than $5 billion, with additional funding, thanks to the “cancer moonshot” backed by President Obama and Vice President Biden—the monies are not being spent as wisely as they could be. For example, the funding agencies continue to reward basic research in petri dishes and mouse models that bear little relevance for humans, with the majority of investigators using xenografts. A review of where the research funds go reveals the inherent biases perpetuated by the peer-review process as detailed by Clifton Leaf in his eye-opening book, The Truth in Small Doses: Why We’re Losing the War on Cancer and How to Win It. Enormous sums of money from the government continue to fund the same institutions and universities over and over. How seriously is one to take investigators from such institutions who author more than fifty abstracts for a single cancer meeting? Just look at the abstracts published by the American Society of Hematology meetings of the past couple of years and you will discover several such researchers, many authoring between fifty and more than one hundred abstracts each. If you consider the number of international meetings these researchers are rushing around to attend, I am confident you will find a minimum of 250 abstracts per year for each author. It is all a numbers game rather than thoughtful, quality research. The saddest part is that upon a serious examination of what is published, 70 percent of the basic research is not reproducible and 95 percent of clinical trials are unmitigated disasters.
Another problem in the funding crisis pointed out by Leaf, to which I am a witness, is that investigators are encouraged to ask small, highly esoteric, limited questions related to, say, a particular gene in a cancer cell. This results in thousands of publications on the same gene from multiple institutions involving a few dozen researchers without anyone examining the collective gain and making clinical sense of it all. Why?
Basic cancer research may one day be successful in identifying every signaling pathway that determines malignant transformation; however, it will be a long time before the entire process of cancer initiation, clonal expansion, invasion, and metastases is understood, especially in the context of the highly complex, poorly defined microenvironment in which the seed-soil interactions occur. Using this approach, an effective therapy for cancer can only be developed essentially after we understand how life works, how we age. Can our cancer patients afford to wait that long? Isn’t the history of medicine replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was fully understood (the most obvious being digitalis and aspirin)? The goal in cancer is not to understand it at its densest molecular level but to learn how to control it. Recognizing the complexity of cancer as a system, complete with emergent properties, isn’t it better to turn to strategies that actually deal with complex systems?
The art of medicine, once based purely on experience and observation, a hostage to tradition, gradually evolved into a practice increasingly driven by scientific evidence. More recently, it has undergone an unexpected transition by morphing into a monstrous business enterprise. For oncology, this milestone was reached in the 1990s when the pharmaceutical industry suddenly woke up to the realization that developing cancer treatments offers an untapped market of infinite monetary gains. The last thirty-five years saw a sweeping, radical change in oncology as drug development responsibilities shifted from academic and government-sponsored institutions to industry. Of course the ultimate aim for both is to bring relief to the cancer patient, but the latter added a profit motive as an attractive by-product. Under the control of companies whose investments easily reach into billions, far outweighing the paltry sums available before, each new drug was presented for clinical trials as the great, long-awaited panacea. Sadly, in a tragic anticlimax, the vast majority proved to be useless at the bedside, the remaining few painfully limping to meet the primary end point by improving survival measurable in weeks. Whose responsibility is it to reject such derisory, absurd end points? The FDA, the NCI, the institutional review boards, the patients, their advocacy groups, or the oncologists?
The problem is that we have all bought into this grotesque enterprise, cornering ourselves into an untenable situation, carelessly squandering precious resources and unwittingly harming lives, damaging the overall well-being of the community. A recent study titled, “Death or Debt? National Estimates of Financial Toxicity in Persons with Newly-Diagnosed Cancer,” published in the October 2018 issue of the American Journal of Medicine, tabulates the chilling economic burden borne by patients with newly diagnosed cancer. Using the Health and Retirement Study Data, this longitudinal study identified 9.5 million estimated new cases of cancer between 1998 and 2012 in the United States. Two years from diagnosis, 42.4 percent of individuals had depleted their entire life’s assets, and 38.2 percent incurred longer-term insolvency, cancer costs being highest during treatment and in the final months of life. The most vulnerable groups were those with worsening cancer, older age, females, retired individuals, and those suffering from comorbidities like diabetes, hypertension, lung and heart diseases, belonging to a lower socioeconomic group, or on Medicaid. Given the sensitive nature of discussions involving life-and-death issues, both oncologists and patients shy away from engaging in cost-related issues—oncologists for fear of introducing even the appearance of a bias in therapeutic choices.
Emotional and economic issues notwithstanding, yet another problem of handing over the task of drug development to industry is an indirect dampening of innovation and creativity. Pharmaceutical industry leaders anxious to maximize shareholder values see that the fastest route to making a buck in this rush-to-riches approach is one that builds on the success of others by producing biosimilar agents instead of investing in their own research and development efforts to identify radically different solutions. A glaring example of this approach is paclitaxel (Taxol), a drug that kills cells by inhibiting mitotic activity. Following its success, twenty-five drugs were developed by various companies aimed at the same target. Several billion dollars later, a response rate of 1 percent was seen in more than two thousand patients treated for a variety of solid tumors, establishing beyond a shadow of a doubt that mitosis is not the ideal target in cancer cells.
In an exceptionally candid, courageous summation of the John Conley Lecture, T. Fojo and colleagues come to several sobering conclusions:
The rapidly rising cost of cancer therapies, the regulations governing their adoption by public and private insurer
s, and the increasing economic risk of drug development have had the unintended consequence of stifling progress by diverting enormous amounts of time, money, and other resources toward therapeutic indications that are arguably marginal. Why else would we pursue gains of a few weeks to a few months with a new drug or as an expanded indication? And rapidly rising costs have also stifled innovation and creativity by promoting a me-too mentality. Why else would the portfolios of companies overlap so greatly with drugs so similar and with differences that either do not exist or that will only be discernible with trials that enroll hundreds if not thousands of patients, the numbers needed to establish statistical significance for nearly imperceptible differences?
A curious love-hate relationship has developed between academia and the pharmaceutical industry. On the one hand, major research findings in academia developed through NCI funds or the research and development efforts by industry, conducted under great secrecy, result in the identification of potentially useful novel strategies. To bring the discoveries to the bedside, clinical trials are conducted by academic oncologists but sponsored and funded by industry. This forces the industry and academia to become reluctant bedfellows. In order for a drug to show efficacy, the FDA demands that it be tested first in animal models. By now, every reader knows that such models are not relevant to humans. To make matters worse, when the drugs are approved for human trials, they can only be tested in patients who have been previously treated with some other established medication. Many agents that might have proved effective in earlier stages of the disease are therefore missed.
Finally, very few, if any, surrogate markers are used to gauge the biologic effects of drugs used in clinical trials. The surrogate or biomarkers include proteins produced by abnormal genes as well as processes that distinguish cancer cells from normal cells, such as formation of new blood vessels or angiogenesis. If a drug does not produce the desired clinical end point, it is then likely to be abandoned completely, even though its biologic activity could be harnessed for more effective use in combination with other agents.