Moving Beyond 'Best Supportive Care'

In their article, Dr. Jamie Von Roenn and Dr. Jennifer Temel demonstrate the value of enhanced symptomatic and palliative care for symptom reduction, improvement in quality of life, and, in some instances, better survival. Related studies often attract much public attention and, periodically, spur renewed effort to integrate symptom management and palliative care into routine oncology practice. This makes common sense. If cancer therapies are to work, the integrity of the patient host is critical; if a patient is distressed by pain, inability to eat, poor sleep, disabling fatigue, and a depressed mood, then host integrity is greatly compromised.

The authors and reviews by others[1-3] have commented on the lack of a uniform definition of supportive care in most trials in which best supportive care is given to patients in one arm of the study. It is reasonable to assume that supportive care is liable to be quite variable across practice settings, and this has been documented for pain management here in the United States and abroad.[4] Even greater variations in supportive care can be expected in multi-national studies: patients in less-developed countries likely receive not only less-adequate symptom control,[5] but also less of a number of other components of supportive care (management of neutropenia, nutritional supplements, management of pulmonary complications).[6] Although clinical-trial sponsors might argue that randomization manages national differences in supportive care between treatment arms, the treatment protocol likely specifies some supportive care in the active treatment arm while leaving supportive care to physician discretion in the comparison arm, potentially enhancing the overall survival of those receiving the treatment.[1] Including components of supportive care in the protocol would ensure that a minimum standard of supportive care is provided to patients in all study arms.[2]

It is non-controversial that optimizing the health and comfort of patients undergoing cancer therapy improves function and quality of life. Not only is it the right and ethical thing to do, but it also greatly improves standard quality metrics such as the utilization of medical care, patient/caregiver comfort and productivity, and family cohesion. Even so, the impact of supportive care is often isolated from the “hard” endpoints of oncology trials, such as overall survival.

The true survival benefit of improving symptom management and optimizing supportive care, as suggested by Temel et al,[3] is not fully explored and is difficult to establish in a prospective study. It is unthinkable to randomize patients to less-adequate supportive care or symptom management, or to deny them the benefits of psychosocial support. A partial solution could include better documentation of the symptom status and supportive management of patients in large clinical trials. Even though the intensity of supportive care and symptom management may vary widely across sites, especially in multi-national studies, the effects of these variables, if collected routinely in clinical trials, could be examined in post-hoc analyses of overall and progression-free survival.

There is another important issue: even now, “best supportive care” is not good enough. If the overall health of the patient affects host integrity and possibly survival, components of the large scientific enterprise now working on curative pathways need to be shifted toward working on the symptomatic effects of cancer and cancer therapy. We know precious little about the mechanisms that underlie cachexia, organ failure, neural damage, fatigue and mood impairment, decreased motivation, and other consequences of disease and treatment that significantly limit functioning and even shorten survival. Without this mechanistic understanding, we are unable to use existing agents or develop new ones that might control or even prevent some of these negative effects.

Realization of the need for increasingly sophisticated toxicology in drug development[7] has not translated into an urgency for a deeper understanding of toxicity and symptom management that ultimately could improve symptom control and palliative care, and which might well enhance survival. As a starting point, we need better epidemiological information about cancer patients’ disproportionate risk for non–cancer-related morbidities and mortality.

Developing a scientific strategy for symptom and toxicity reduction thus seems a worthy enterprise. In 2005, The National Cancer Institute created a Translational Research Working Group (TRWG) to speed the application of molecular oncology findings to patient care.[8] To address this goal, the TRWG developed a model for a translational research pathway, to conceptualize how to move from better understanding of mechanisms underlying medical complications of cancer and its therapy to new therapeutic approaches that could be applied in the clinic.

Just as with the curative translational pathway, the research pathway towards enriching our resources for improving patients’ symptom status would, by its nature, have to be multidisciplinary. Steps in the pathway include developing discovery models based on prospective studies (observational studies or studies embedded in clinical trials) in which data on symptoms and toxicities are collected over time, along with biomarkers (genetic and proteomic information) based on a developing set of mechanistic hypotheses.[9] Much of biomedical research is dependent on having animal models of the targets of interest. The same applies to understanding toxicities and symptoms; exploratory and confirmatory studies in humans can be conducted in parallel with animal models of translational symptom research in a bedside-to-bench and bench-to bedside collaboration, which could provide further, in-depth evidence of involved mechanisms. Animal models of neurobehavioral effects of cancer and cancer therapy could then provide a platform for pre-clinical testing of agents that might greatly increase our options for preventing or ameliorating symptoms. Agents that give some signal of effectiveness in preventing or reducing symptoms would then move forward into patient research to determine their appropriate doses, effectiveness, and risk of toxicity in humans.

Finally, if best supportive and palliative care is to be implemented and a research program to improve supportive care is to gain traction, there needs to be greater insistence on these action steps by patient advocacy, oncology society, and cancer policy groups.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Currow DC, Foley K, Zafar SY, et al. The need for a re-evaluation of best supportive care studies reported to date. Br J Cancer. 2011;104:390-1.

2. Cherny NI, Abernethy AP, Strasser F, et al. Improving the methodologic and ethical validity of best supportive care studies in oncology: lessons from a systematic review. J Clin Oncol. 2009;27:5476-86.

3. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-42.

4. Deandrea S, Montanari M, Moja L, et al. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol. 2008;19:1985-91.

5. Foley KM, Wagner JL, Joranson DE, et al. Pain control for people with cancer and AIDS. In: Jamison DT, Breman JG, Measham AR, et al, eds. Disease Control Priorities in Developing Countries, 2nd ed. Washington DC: World Bank, 2006:981-93.

6. Lee SJ, Astigarraga CC, Eapen M, et al. Variation in supportive care practices in hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14:1231-8.

7. Abernethy DR, Woodcock J, Lesko LJ. Pharmacological mechanism-based drug safety assessment and prediction. Clin Pharmacol Ther. 2011;89:793-7.

8. Schilsky RL, Gordon G, Gilmer TM, et al. The Translational Research Working Group developmental pathway for anticancer agents (drugs or biologics). Clin Cancer Res. 2008;14:5685-91.

9. Cleeland CS, Fisch MJ, Dunn AJ. Symptom research: looking ahead. In: Cleeland CS, Fisch MJ, Dunn AJ, eds. Cancer Symptom Science: Measurement, Mechanisms, and Management. Cambridge UK: Cambridge University Press, 2011:341-8.