Every student of Ethics 101 wrestles with the trolley problem. In this moral exercise of the imagination, you are standing by train tracks watching a runaway trolley race towards 5 people who are going to be crushed unless you intercede. If you pull a lever, the trolley will divert onto a different track, where it is bound to kill one person. In this situation, is it better to be passive or active? Should you pull the lever or not?
While not quite as dramatic a scenario, a similarly freighted decision between inaction and intervention plays out in oncology clinics multiple times every day as doctors weigh the risks & benefits of adjuvant chemotherapy for “cancer-free” patients.
In this context, the medical oncologist is asking themselves if it is worthwhile to administer potentially toxic treatment when there is no detectable cancer. The quandary arises because, despite confident pronouncements like “we got it all!” after a patient undergoes an operation to remove a tumor, remnant cells can still linger below the threshold of clinical detection, beyond the keen eyesight of the surgeon and even beyond the microscope of the pathologist. Even a single cell left behind can, given enough time to replicate, blossom into another tumor at the same site or, even worse, spread through the bloodstream to sow the seeds of metastases.
The medical oncologist is thus faced with a dilemma: in a patient with no current evidence of cancer, but at risk for future recurrence, can prescription of chemotherapy in the here & now be justified? And if the lever is pulled, and a patient is harmed by toxicity from treatment, is the oncologist culpable for that injury? After all, perhaps the most important guiding principle of medical ethics is primum non nocere – first, do no harm.
In truth, the oncologist’s predicament is different than the trolley problem because, without pulling the lever, there is still an outcome in which no harm is done, namely when adjuvant chemotherapy is omitted and the cancer never returns. The difficulty comes in predicting which patients will reach this ideal conclusion, where their original surgery ultimately proves sufficient to have rid them of cancer.
Stage II colon cancer is a prevalent example of when this therapeutic dilemma arises and when oncologists often wish for greater prescience before prescribing. Colorectal cancer is the fourth most commonly diagnosed cancer in the United States, with the National Institutes of Health’s Surveillance, Epidemiology, and End Results Program estimating 132,700 new cases in 2015 (http://seer.cancer.gov/statfacts/html/colorect.html), of which between a quarter and a third will be classified as stage II (meaning tumors that, at the very least, have invaded through the muscular layer of the colon wall but have not yet spread to lymph nodes or appreciably metastasized). Here, the oncologist can struggle to adhere to the precept of non-maleficence because, without adjuvant chemo, roughly 1 in 4 stage II colon cancer patients will have their cancer return within 5 years of “curative” surgery. So when, and for whom, should they pull the lever of chemotherapy?
Determining which of these patients ought to receive chemo (treatment which can, depending upon its exact composition, carry the risks of diarrhea, mouth sores, disabling rashes, a weakened immune system, and even permanent nerve damage) has oncologists walking a tightrope between under-treatment and over-treatment. Risk assessment for each patient has been aided by close study of their individual pathology, including whether their tumor has spread to the peritoneal surface or adjacent organs, was trying to invade blood vessels or nerves supplying the colon, and/or had blocked or perforated the colon at the time of diagnosis. But even these high-risk features are discerned from anatomic pathology, and not from a deeper molecular understanding of disease biology.
A recent revelation of the genetics driving colon cancer could allow for more savvy sorting of which stage II colon cancer patients will benefit from chemo, an insight that could spare thousands of people from recurrence-related deaths while also saving thousands more from receiving unnecessary treatment.
In the article by Dalerba et al. in the January 21st, 2016 edition of The New England Journal of Medicine, (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1506597) testing stage II colon cancers for expression of a gene called CDX2 allowed researchers to identify with greater precision those tumors which merited treatment with adjuvant chemotherapy. CDX2 is a marker for mature development of colon tissues, and its absence from tumors more than doubled the risk of recurrence and cancer-related death compared to cases when it was present. Among over 600 stage II colon cancer patients in this data set, treatment with adjuvant chemotherapy in the CDX2-negative subgroup was strongly associated with a higher rate of 5-year disease-free survival, whereas no benefit was seen in the CDX2-positive subgroup. I have already incorporated this seismic discovery into my own practice, where this prognostic biomarker contributes helpfully to existing clinical and pathologic data when I am balancing the costs & benefits of chemotherapy for my stage II colon cancer patients. I still can’t see the future, but my vision is slightly clearer: better living through chemistry, better fortune-telling through gene expression analysis.
Finally, I would be remiss not to mention, given that March is colon cancer awareness month, the importance of screening. The easiest way to avoid the oncologic dilemmas of stage II colon cancer is to prevent the disease from developing in the first place. Colonoscopies are both diagnostic and therapeutic insofar as the gastroenterologist can detect & simultaneously remove polyps before they have the chance to become invasive malignancies. All patients should get screened no later than the age of 50 and knowing your family history, i.e. if your relatives are prone to early-onset disease, may prompt screening at an even younger age.
Colonoscopy is a perfect example of an ounce of prevention being worth a pound of cure. A medical oncologist like myself is the last doctor who should be seeing a patient with colon cancer, not the first. As careful as I would like to be with those under my care, I am still learning when to pull the lever.
Dr. Mark A. Lewis is an assistant professor in general & gastrointestinal medical oncology at the MD Anderson Cancer Center in Houston, Texas. He is double-boarded in hematology/oncology after completing a fellowship at the Mayo Clinic in Rochester, Minnesota, where he was chief fellow in that training program. He has a passionate interest in patient-doctor communication, including online dialogue, and moderates a Facebook group for patients with multiple endocrine neoplasia, a rare tumor syndrome that personally affects him and his son. He is also active on Twitter as @marklewismd. He is co-chair of the Social Media Working Group for SWOG, one of the nation’s largest cancer research cooperative groups, and co-chairs their Adolescent & Young Adult Cancer committee as well.