It is a heartbreaking reality that diseases remain unavoidable despite significant medical achievements. In a way, diseases signify natural intervention, whether it is through selective pressure to promote healthier descendants or a method of population control. To alchemists’ dismay, a panacea does not exist, as diseases are simply too diverse. Some diseases, like the common cold, are slight nuisances that disappear within few weeks. Others, like Alzheimer’s disease, can lead to cognitive changes, coma or death.
Fortunately, treatment strategies can be provided efficiently by organizing diseases into a hierarchy. The bottom contains trivial diseases that can be treated with over-the-counter drugs, while the top consists of untreatable diseases.
This pyramidal disease scheme has an apex, which is context-dependent. By frequency, the deadliest disease is coronary artery disease, yet in developing countries, it is the human immunodeficiency virus.
Both diseases are excellent candidates, but the pyramidal apex is awarded to cancer. The key isn’t the fatality rate, but rather its resistance to treatment and detrimental effects on the patient’s quality of life. As such, Siddhartha Mukherjee rightfully deemed cancer as “The Emperor of All Maladies,” in a book of the same title.
Cancer refers to abnormal cells dividing uncontrollably before spreading and attacking other parts of the body. From the intestinal lining to the skin, cell division occurs normally, so these cells are susceptible to cancer formation. Only cells that are terminally differentiated, like neurons and muscle cells, do not divide.
Consequently, cancer is a heterogeneous group of diseases, which means there isn’t a single cure for cancer. Understandably, such a declaration is alarming to cancer patients and their families, but treatment strategies are offered on an individual basis.
However, Mukherjee must have a reason for depicting cancer as a single “emperor” despite its diversity. In order to overthrow the emperor, it is necessary to survey the empire, which means there should be some underlying similarities among all cancer types.
In a 2000 pivotal article published in Cell, Douglas Hanahan and Robert Weinberg outlined six key traits that depict how normal cells transform into cancerous cells. In essence, cancer cells want to grow and avoid dying.
Unlike normal cells, cancer cells are self-sufficient, as they don’t need growth signals to divide. To sustain growth and divide indefinitely, cancer cells require a constant blood supply. Conversely, cancer cells resist anti-growth signals and bypass cell death. Eventually, cancer invades other tissues through metastasis.
In a 2011 update, Hanahan and Weinberg delivered two additional hallmarks: altering the cellular metabolism and avoiding the immune system. They also isolated two enabling characteristics critical for transformation to happen: genomic instability through accumulation of random mutations and a tumor-promoting inflammatory environment.
This was thanks to countless years of cancer research, which was strongly promoted by Mary Lasker’s passionate activism and funded by the National Cancer Act of 1971. Historically, cancer research was improved by learning from previous mistakes.
The ancient Greek physicians Hippocrates and Galen were among the first to study cancer. They were aware that surgery was ineffective, as cancer would simply return. Based on their studies, they sadly dismissed the disease as incurable.
Challenging the ancient Greek opposition to surgical oncology, William Stewart Halsted developed radical mastectomy in 1882. He argued that cancer had spread outward, so curing breast cancer required removal of the affected breast and the underlying muscles.
Radical mastectomy was horrifying for women, since it left them badly disfigured. Tragically, Halsted firmly believed that larger surgical excisions would stop the metastatic spread. Since radical mastectomy yielded curative results, it remained a standard surgical procedure until mid-1970s.
Alternatives to surgery would soon be devised. In the 1900s, French doctors discovered that daily doses of radiation over several weeks significantly improved the cure rate for cancer patients. Yet, radiation was also the cause of cancer, so it was largely avoided until the 1970s, when radiation could be aimed precisely.
After World War I ended, scientists discovered that mustard gas reduced the white blood cells in poisoned soldiers. During World War II, an analog drug called nitrogen mustard was shown to reduce lymphomas. Soon after, Sidney Farber discovered that aminopterin, an analog of the vitamin folic acid, reduced pediatric acute leukemia.
With the success of aminopterin, Farber developed a closely related but less toxic compound called methotrexate. Like aminopterin, methotrexate reduced leukemia. More importantly, Jane Wright showed that methotrexate also triggered remissions in solid tumors, such as breast cancer.
In the mid-1970s, Bernard Fisher searched for minimally invasive alternatives to radical mastectomy. In a surgical procedure called lumpectomy, only the tumor and some surrounding tissue would be removed. Lumpectomy, in conjunction with radiation therapy or chemotherapy, improved breast cancer curative rates, thereby ousting radical mastectomy.
Undoubtedly, the war on cancer made significant strides in cancer treatment. The Wall Street Journal reported that from 2002 to 2011, mortality rate decreased by 1.5 percent annually on average for all cancers, while new cancer cases fell 0.5 percent annually.
In another Wall Street Journal article, Craig Thompson optimistically forecasts that within 10 years, the number of male and female cancer survivors will increase by 35 percent and 26 percent respectively. He attributes the survivorship increase to precision medicine.
Precision medicine focuses on prevention and treatment strategies that take into account of individual variability. In the 2015 State of the Union Address, President Barack Obama declared that he is “launching a new precision medicine initiative to bring us closer to curing diseases like cancer and diabetes.”
Rather than treating cancer based on the tissue it emerged from, precision medicine improves cancer therapy by targeting the precise mutations that an individual patient’s tumor has acquired. Hence, precision medicine effectively targets the hallmarks of cancer.
Traditional chemotherapy focuses on directly disrupting cell division, while targeted therapy attacks subtle nuances that distinguish cancer cells from normal cells. As such, targeted therapy is more selective for cancer and minimizes adverse effects.
Hormonal therapy and immunotherapy manipulate the endocrine and immune system respectively as additional ways to suppress cancer proliferation. Thompson also pinpoints that cancer cells can be eradicated by forcing them to differentiate.
Realistically, today’s cancer treatment strategies are too good to be true. Diagnosis and treatment for pancreatic and brain cancers remain poor, while treatment of seemingly manageable cancers remains inadequate.
Consider breast cancer. About 70 percent of women have breast cancers that test positive for the estrogen and progesterone receptors. Hormonal therapy, such as tamoxifen, is usually effective. About 20 percent of breast cancers test positive for a growth receptor called HER2, which is treated with an antibody called herceptin.
Yet, 10 percent of breast cancers lack the hormone receptors and HER2. This triple-negative breast cancer cannot be treated with conventional therapy. As such, it is similar to metastatic breast cancer, whereby a combination of chemotherapy and radiation therapy are necessary to hinder cancer progression.
Excess cancer therapies used to suppress metastatic cancer can lead to cancer resistance and relapse, both of which can be overcome. Cancer resistance can be blocked by interfering with drug-pumping proteins called ABC transporters. Relapse is averted by targeting cancer stem cells.
Such a rigorous treatment regimen required to control and eradicate metastatic cancer is incredibly expensive and harmful for the patient. Although cancer research is certainly advancing, cancer drugs are becoming increasingly costly. Adjusting for inflation, a new cancer drug cost about $100 in 1969: today, a new drug is worth roughly $10,000.
Combination therapies reflect the “more is better” principle endorsed by the Halsted radical mastectomy. From an economic and moral perspective, the principle doesn’t apply to medical treatments because of the overwhelming burden of adverse effects and the risk of cancer relapse.
Instead, treatments should aim to maximize the patient’s satisfaction, such that the side effects are minimized while cancer is being optimally treated. Further research must be devoted to understanding the central processes of metastasis and finding adequate therapies to suppress or even reverse tumor invasion.
Physicians must provide complete information regarding cancer prognosis, management and treatment strategies to patients and families, along with offering personalized care. As members of the civil society, we must devote our efforts to continue raising cancer awareness and support families afflicted with this dreaded disease.