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Complicated and complex: Helping the older patient with cancer to exit the labyrinth

2013; Elsevier BV; Volume: 5; Issue: 1 Linguagem: Inglês

10.1016/j.jgo.2013.11.003

1879-4076

Lodovico Balducci, Matti Aapro,

Effects of Radiation Exposure

The myth of the Minotaur[1]Minotaur Encyclopædia Britannica. Encyclopædia Britannica Online Academic Edition. Encyclopædia Britannica Inc., 2013Google Scholar is more than 4000 years old. Yet it offers a cogent metaphor of the complexity of modern cancer treatment. Like cancer, the Minotaur with the head of the bull and the body of a man was a biological aberration. Like many cancers, the Minotaur originated from the interaction of the human body with a foreign substance that perverts the normal body function (think of cigarette smoking or other environmental carcinogens). The monster was the product of the adulterine intercourse of Pasiphae, King Minos's spouse with a bull. Like cancer, the Minotaur was a cannibal. Perhaps the most relevant part to the story concerns the dwelling of the Minotaur. His stepfather enclosed him in a labyrinth. Even if he succeeded in killing the Minotaur, the brave warrior would have remained imprisoned in the labyrinth and starved to death. To find the exit from the labyrinth is the dilemma of most forms of cancer treatment: how to eliminate the cancer without hurting the patient. This is particularly true of older patients with cancer. The value of antineoplastic treatment is minimized in persons with a limited life-expectancy and increased risk of therapeutic complications. The treatment of cancer in older individuals is a complex, not just a complicated task. These two words, complicate and complex are used interchangeably, which is regrettable, as their meanings are quite different. Complicate derives from the Latin “cum plicare” that means “to fold.” Something that is folded, such as a fabric, may be straightened up. One refers to chemotherapy-induced neutropenia as a “complication” that may be straightened up by appropriate use of myelopoietic growth factors or a dose reduction when dose is not an essential component of the treatment's potential success. Complex derives from “cum plexere” that means “to weave together.” A beautiful carpet epitomizes a complex situation. Any attempt to correct a design flaw risks dissolving the whole composition. A clinical example of complexity is the case of a patient with brain metastases from breast cancer and myelodysplasia from high dose chemotherapy.[2]Balducci L. Perspectives in geriatric oncology: how to structure a decision in face of uncertainty.J Ger Oncol. 2010; 1: 114-117Abstract Full Text Full Text PDF Scopus (1) Google Scholar The practitioners managing older patients have become aware that aging is a complex situation. The substitution of the term comorbidity with “polymorbidity” reflects this awareness.[3]Boyd C.M. Ritchie C.S. Tipton E.F. Studenski S.A. Wieland D. From bedside to bench: summary from the American Geriatric Society National Institute on Aging research conference on Comorbidity and Multiple Morbidity in Older Adults.Aging Clin Exp Res. 2008; 20: 81-88Crossref PubMed Scopus (66) Google Scholar Comorbidity implies a major disease threatening to the life and function of the patient, whose management is “complicated” by other diseases. Polymorbidity implies that multiple diseases conspire to compromise a patient's survival and independence. The management of a single disease may not improve and may even worsen the overall outcome. It is not enough to kill the Minotaur. It is necessary to exit the labyrinth! The assessment tools used in geriatrics mirror the complexity of the clinical situation. They are utilized for three purposes: to assess clinical needs, to estimate the risks of mortality, and to evaluate loss of independence. Biological markers, such as the concentration of inflammatory markers in the circulation,[4]Cohen H.J. Harris T. Pieper C.F. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly.Am J Med. 2003; 114: 180-187Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar the length of lymphocytic telomeres,[5]Mather K.A. Jorm A.F. Parslow R.A. Christensen H. Is telomere length a biomarker of aging? A review.J Gerontol A Biol Sci Med Sci. 2011; 66: 202-213Crossref PubMed Scopus (297) Google Scholar and the expression of p16INK4a in normal cells,[6]Waaijer M.E. Parish W.E. Strongitham B.A. Van Hemst D. Slagboom P.E. DeCraen A.J. The number of P16INK4a positive cells in human skin reflects biologic age.Aging Cell. 2012; 11: 722-725Crossref PubMed Scopus (169) Google Scholar have been proposed to assess the physiologic age of a person, but they lack specificity. The same may be said of single tests of functional assessment, including the “timed get up and go” test[7]Ekstrom H. Dahlin-Ivanoff S. Elmstahl S. Effects of walking speed and results of “timed get up and go tests” on quality of life and social participation in elderly individuals with a history of osteoporosis-related fractures.J Aging Health. 2011; 23: 1379-1399Crossref PubMed Scopus (36) Google Scholar or the clinical definition of frailty.[8]Balducci L. Frailty: a common pathway in aging and cancer.Interdiscip Top Gerontol. 2013; 38: 61-72Crossref PubMed Scopus (32) Google Scholar The most useful tools in estimating needs and prognosis of the individual patient take into account the complexity of the situation by examining multiple domains, as is done in the comprehensive geriatric assessment (CGA).[9]Puts M.T. Hardt J. Monette J. Girre V. Springai E. Ahlbai S.M. Use of geriatric assessment for older adults in the oncology setting: a systematic review.J Natl Cancer Inst. 2012; 104: 1133-1163Crossref PubMed Scopus (258) Google Scholar The CGA may be used to estimate risk of mortality and functional decline[10]Yourman L.C. Lee S.J. Schonberg M.A. Widera E.V. Smith A.K. Prognostic indices for older adults: a systematic review.JAMA. 2012; 307: 182-192Crossref PubMed Scopus (551) Google Scholar and, along with other instruments, predict the risks of surgical[11]Audisio R.E. Pope D. Ramesh H.S. Gennari R. van Leuween B.L. West C. Shall we operate? Preoperative assessment of elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study.Crit Rev Oncol Hematol. 2008; 65: 156-163Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar and medical12Hurria A. Togawa K. Mohile S.G. Osuwu C. Kepin H.D. Gross C. et al.Predicting chemotherapy toxicity in older patients with cancer. A prospective multicenter study.J Clin Oncol. 2011; 29: 3457-3465Crossref PubMed Scopus (1173) Google Scholar, 13Extermann M. Boler I. Reich R.R. Brown R.H. Defelice J. Levine R.M. et al.Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) score.Cancer. 2012; 118: 3377-3386Crossref PubMed Scopus (741) Google Scholar complications of cancer treatment. The estimate of the risk of mortality and therapeutic complications is just a step, albeit an important one, in the approach to the complex interactions of aging and cancer. This step represents a post sign around which to construct a decisional road map. The first step of this pathway assesses the prognosis of the disease itself. In addition to the clinical and standard pathologic assessment, molecular and genomic biomarkers should allow one to identify diseases that are rapidly lethal from those that may be safely observed. The second step is the geriatric evaluation, which provides an estimate of therapeutic risks and benefits. This includes the benefits of antidotes to treatment toxicity. For example, age is a risk factor for neutropenia and neutropenic infections with regimens that may be well tolerated by younger people.[14]Aapro M.S. Bohlius J. Cameron D.A. Dal Lago L. Donnelly J.P. Kearney N. et al.2010 update of EORTC guidelines for the use of granulocytecolony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.Eur J Cancer. 2011; 47: 8-32Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar Prophylactic growth factors ameliorate this risk and allow the administration of chemotherapy in full doses. The third step is perhaps the most critical one, and involves the art of medicine, one of the situations where a physician is still asked to act as a “doctor” rather than as a provider. From the Latin “docere” or “to teach”, to be a doctor means to provide counseling based on one's knowledge, experience and most of all care. This step includes the communication of prognosis, and the exploration of the patient's goals. In addition to the hope of a cure and symptom relief, these goals may include prolongation of survival up to a specific landmark (a wedding, a graduation), a pain-free death, and the prolongation of “active life expectancy”.[15]Balducci L. Fossa S.D. Rehabilitation of the older cancer patient.Acta Oncol. 2013; 52: 233-238Crossref PubMed Scopus (30) Google Scholar The loss of independence is the major threat to the quality of life of older individuals.[16]Ozturk A. Simsec T.T. Yumin E.T. Sertel M. Yumin M. The relationship between physical functional capacity and quality of life among elderly people with chronic disease.Arch Gerontol Geriatr. 2011; 53: 278-283Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The fourth step involves monitoring of the treatment, which includes readjustment of goals according to the antineoplastic effectiveness, the patient direct experience of complications, and the emergence of unexpected toxicity. The fifth step is outcome assessment and identification of previously unrecognized predictive factors. The diversity of the older population may be harnessed by the prospective study of the outcome of older individuals receiving different forms of cancer treatment. Instruments to predict the risk of complications of cancer treatment were initially developed in this way11Audisio R.E. Pope D. Ramesh H.S. Gennari R. van Leuween B.L. West C. Shall we operate? Preoperative assessment of elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study.Crit Rev Oncol Hematol. 2008; 65: 156-163Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 12Hurria A. Togawa K. Mohile S.G. Osuwu C. Kepin H.D. Gross C. et al.Predicting chemotherapy toxicity in older patients with cancer. A prospective multicenter study.J Clin Oncol. 2011; 29: 3457-3465Crossref PubMed Scopus (1173) Google Scholar, 13Extermann M. Boler I. Reich R.R. Brown R.H. Defelice J. Levine R.M. et al.Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) score.Cancer. 2012; 118: 3377-3386Crossref PubMed Scopus (741) Google Scholar and may be progressively refined. Electronic health records[17]Terry M.P. Meaningful adoption: what we know or think we know about the financing, effectiveness, quality, and safety of electronic medical records.J Leg Med. 2013; 34: 7-42Crossref PubMed Scopus (10) Google Scholar may facilitate such endeavors in two ways: 1) uniform assessment of function, morbidity, and social needs of older patients; and 2) an enlarging data base necessary to make predictions of benefits and risks more accurately. Classical clinical trials play an important role for older individuals. Randomized phase III trials provide proofs of principles, such as the benefits of adjuvant chemotherapy when indicated in patients age 65 and older with breast cancer.[18]Muss H.B. Berry D.A. Cirrincione C.T. Theodoulou M. Mauer A.M. Kornblith A.B. et al.Adjuvant chemotherapy in older women with early stage breast cancer.N Engl J Med. 2009; 360: 2055-2065Crossref PubMed Scopus (430) Google Scholar Phase II studies allow investigators to explore the pharmacokinetics and pharmacodynamics of new drugs in the elderly. These trials have very selective enrollment criteria and offer little help in assessing individual prognosis in a population whose hallmark is diversity. Complexity is with us. The approach to complexity represents an important clinical challenge with the aging of the population. In this paper we have described the nature of complexity and proposed a five-step roadmap through it. The pathway is far from perfect and many more older patients will not be able to exit the labyrinth. In the meantime, we have offered a blueprint for building more and more reliable assessment instruments able to maximize the benefits and minimize the risks of cancer treatment in older individuals. The author have no conflicts of interest to disclose related to this manuscript. Concept and design: L. Balducci and M. Aapro Manuscript writing and approval: L. Balducci and M. Aapro