What Is a Patient Who Refuses Chemotherapy Really Saying?

Maurie Markman, MD

There is probably no area of cancer medicine that has evolved more over the past 50 years than antineoplastic chemotherapy. In their early days, cytotoxic drugs, which initially evolved from wartime efforts to develop debilitating and deadly chemical weapons, were principally employed as last-ditch efforts in the management of metastatic cancers.

The drugs themselves were often quite toxic to the bone marrow, and emesis was a common and particularly devastating symptomatic side effect. As a result, a not insignificant percentage of individuals living today had observed someone who experienced “the horrors of chemotherapy” or at least heard such a strong second-hand story from a relative or friend.

Today, chemotherapy has become a component of standard-of-care cancer management, routinely utilized in patients in the metastatic, adjuvant, neoadjuvant, and maintenance settings. Further, antineoplastic drug therapy is recognized in multiple cancer arenas to improve existing symptoms, optimize quality of life, permit patients to continue with their normal daily activities, and prolong survival.

It is also increasingly the case that in certain situations multiple lines of therapy may be appropriately provided, potentially converting the malignancy in a given patient into more of a chronic disease process, where cure is unfortunately objectively unattainable but prolonged survival— measured in years rather than weeks or months of reasonable quality as defined by the individual patient—is a realistic goal of the treatment plan.

Ovarian Cancer Dilemma

Further, the adverse event profiles of such therapy have improved over time, resulting from experience with using an individual agent or regimen, development of less-toxic derivatives, and the concomitant use of highly effective supportive care products.Therefore, when a report appears entitled “Refusal of Recommended Chemotherapy for Ovarian Cancer”¹, a malignancy where chemotherapy is long known to be associated with a high objective response rate and relatively rapid and clinically meaningful palliation of symptoms (eg, abdominal pain and bloating, decreased appetite, fatigue), it is reasonable to inquire what exactly is being reported and what lessons might be learned to impact such refusal?

The specific study in question examined patients in the National Cancer Data Base who were diagnosed with ovarian cancer (n = 147,713) over a 14-year period (January 1998 to December 2011).¹ In this database, a total of 2707 patients were reported to have “refused chemotherapy.” This conclusion was apparently drawn from a response in the database which was based on documentation in the medical records that “chemotherapy was not administered. It was recommended by the patient’s physician, but this treatment was refused by the patient, a patient’s family member, or the patient’s guardian.”¹

Recognizing the limitations of an interpretation of information contained in any retrospective database, no matter how well the specific survey questions have been constructed and primary source material reviewed as well as the extended period of time included in this specific data repository, it is interesting to ponder the actual reasons for such refusal and how this experience may help inform discussions oncologists have with future patients in this clinical setting.

The investigators note that older-age patients, those with comorbidities, no medical insurance, higher stage, more recent year of cancer diagnosis, lower tumor grade, and treatment at a low-volume center were independently associated with chemotherapy refusal.¹ And, as expected, not receiving chemotherapy was associated with an inferior survival outcome.

It is important to acknowledge that, while the standard of care in the management of ovarian cancer treatment has rather substantially changed over the multiyear time period included in this database, platinum-based combination chemotherapy has remained the standard during this entire era.

Therefore, it is perhaps not surprising that many patients with certain clinical features such older age, comorbidities or advanced stage would not inappropriately question the benefits of treatment considering the anticipated side effects (ie, nausea, vomiting, fatigue, infection, required hospitalization, and certain hair loss).

Trying Other Options

And, although carboplatin is clearly established to be far less toxic than cisplatin, when one considers the impact of carboplatin-based combination chemotherapy on a patient’s quality of life, when the patient’s own baseline has declined perhaps substantially from “sometime in the relatively recent past,” an individual’s decision to forgo even an attempt at chemotherapy is not difficult to understand. But perhaps one solution to the dilemma facing oncologists in this specific setting is to fully acknowledge that, although the so-called standard of care of cytoreductive surgery followed by carboplatin-based combination chemotherapy may not be viewed as appropriate by a particular patient and her family at this point in her life, alternative and equally rational approaches may be acceptable.For example, the delivery of single-agent carboplatin is well recognized as producing a high objective response rate in advanced ovarian cancer, has even been suggested by some to be as clinically active as combination regimens², can be administered in the outpatient setting on an every 3- or 4-week schedule, and causes limited or no hair loss. Emesis can generally be reasonably well controlled with currently available pharmaceutical agents, and the drug is now generic.

In addition, a decision to administer a second cycle of single-agent carboplatin can be made after one determines how well the first course has been tolerated and can include an assessment of whether there has been any subjective or objective evidence of clinical benefit.

Such an approach would appear to be a rational strategy to possibly encourage a reluctant patient, who may truly benefit from chemotherapy, to “at least give it a try” with the very specific goal of improving the patient’s quality of life for what the patient would hopefully consider a meaningful period of time.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

References

1. Wallace SK, Lin JF, Cliby WA, et al. Refusal of recommended chemotherapy for ovarian cancer: risk factors and outcomes; a National Cancer Data Base study. J Natl Compr Canc Netw. 2016;14(5):539-550.
2. International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2002;360(9332):505-515.