By Richard T. Lee, MD, and Neal J. Meropol, MD, FASCO
- The term “palliative chemotherapy” is frequently used to signify chemotherapy given to patients with incurable disease.
- Many clinical studies have demonstrated the benefit of chemotherapy in patients with advanced cancer when compared to best supportive care, as it may provide a modest survival advantage over supportive care alone for these individuals. However, limited high-quality data exist about the effect on quality of life among patients with advanced cancer.
- In order to address the impact of new systemic treatments as palliative interventions, challenges must be addressed, such as the development and use of standardized supportive care interventions.
Although the field of palliative care initially focused on end-of-life care, it has evolved to become an integral part of cancer care from diagnosis through survivorship.1,2
The World Health Organization has published reports on palliative care in cancer, first in 1990, and later updated in 2002.3,4 The importance of palliative care has also been recognized by several national and international organizations (e.g., ASCO, the National Comprehensive Cancer Network, the National Quality Forum, and the National Institute for Health and Care Excellence). The Institute of Medicine also addressed the topic in its report Improving Palliative Care for Cancer.5-11
As the field of palliative care has evolved to incorporate a variety of disciplines that provide a more comprehensive approach to patient care, it is commonly referred to as “supportive care” to reflect this broadening inclusion of services. As defined by the World Health Organization, these therapies are aimed at improving the quality of life (QoL) of patients and their families in an integrated manner involving support teams and should address physical, psychological, spiritual, and social dimensions of care.3
When thinking about palliative interventions, oncologists have historically thought of chemotherapy quite differently than other interventions. The term “palliative chemotherapy” is frequently used to signify chemotherapy given to patients with incurable disease rather than for symptom management. In most cases, palliative chemotherapy is given primarily for disease control and to prolong survival.
In contrast, palliative radiation or palliative surgery is provided with the primary goal of symptom management rather than prolonging survival—for example, palliative radiation for painful bone metastases. As the promises of highly targeted and low-toxicity systemic cancer treatments are now being realized, should we be rethinking how we approach goals of care and how best to measure the value of these new therapies?
Importance of Symptom Management in Assessing Treatments
Many clinical studies have demonstrated the benefit of chemotherapy in patients with advanced cancer when compared to best supportive care, as it may provide a survival advantage over supportive care alone for these individuals.12-14 However, given that the survival benefit of systemic treatments in patients with advanced disease may be modest, and costs and toxicities may be high, there is an increasing recognition of the importance of providing supportive care as published by national and international standards, as well as measuring QoL endpoints to assess the impact of treatment on relevant symptoms.15-17 Furthermore, Temel et al. demonstrated QoL benefits from an early, integrated palliative care intervention among patients with advanced lung cancer that also improved survival compared to standard treatment alone.18 This highlights the close relationship between symptom control and other clinical endpoints.
The recent conceptual framework for assessing value of cancer treatments proposed by ASCO highlights the importance of symptom management in assessing cancer treatments.19 The proposed framework focuses on three of the six Institute of Medicine quality indicators: clinical benefit, toxicity, and cost. Within this framework, treatments that have shown improvement in cancer-related symptoms would be given additional “points,” indicating value beyond traditional endpoints, such as overall and disease-free survival.
It is notable that drug approval by the U.S. Food and Drug Administration (FDA) has a standard of safety and effectiveness but does not specify how “effective” is defined. Thus, the door is open for approvals based upon meaningful QoL impact. The use of patient-reported outcome (PRO) QoL measures in clinical trials to drive drug regulatory approval is rarely employed. Johnson et al. reported only four of 57 approved new cancer drugs from January 1990 to November 2002 were related to improvement in symptoms.20
One proof of concept is the approval of gemcitabine for advanced pancreatic cancer.21 One hundred and twenty-six patients with advanced, symptomatic pancreatic cancer were randomly assigned to gemcitabine versus 5-fluorouracil chemotherapy with the primary aim to improve clinical benefit defined as pain, performance status, and weight for 4 weeks or longer. Patients receiving gemcitabine had a clinical benefit rate of 23.8% versus only 4.8% in the 5-fluorouracil arm along with a small median survival benefit of 1.21 months. Based on this study, the FDA approved gemcitabine as first-line therapy for patients with advanced pancreatic cancer.
The concept of true palliative chemotherapy is commonly overlooked in drug development. Just as in the use of palliative versus curative-radiation treatment, could chemotherapy be utilized with a different dose and schedule to optimize its use for palliation rather than disease control? This concept is increasingly relevant with the recent approval of so-called “targeted” agents, such as specific pathway inhibitors that are often associated with fewer toxicities than traditional chemotherapy. Perhaps the sequencing of therapy could thus appropriately be based on patient symptom burden, with more toxic traditional cytotoxics reserved for subsequent use after symptoms have been improved with less-toxic treatments.
In order to properly address the impact of new systemic treatments as palliative interventions, three key challenges must be addressed:
- Use of standardized supportive care interventions that meet established guidelines are necessary to ensure proper control arms for clinical trials. In other words, all patients in routine practice and in clinical trials should receive aggressive supportive care.22
- Large phase II and phase III clinical trials require routine assessments of symptoms and QoL using reliable and clinically meaningful measures. The ASCO Value in Cancer Care Task Force notes that QoL is not easily incorporated into the assessment of value, in part, because of the lack of consistent collection of high-quality evidence PROs and QoL data.19 Indeed, current methodologies likely underestimate the QoL impact of chemotherapy, and the use of electronic PRO tools may help improve the quality and efficiency of these assessments.23,24
- Broad acceptance of the clinical relevance of PRO measures is a prerequisite in order to fully address the potential role of anticancer treatments as true palliative interventions.
In summary, new advances in systemic treatments for patients with advanced cancers will allow us to evaluate the value of palliative chemotherapy that focuses on improving QoL in addition to improved survival. The incorporation of new technologies will also be key to routine integration of PROs and QoL assessments within clinical trials and daily practice in order to provide more patients with greater treatment options to manage their cancer diagnosis.