Cancer Screening Across the Aging Continuum

,
The American Journal of Managed Care, May 2008 - Theme Issue, Volume 14, Issue 5

The article reviews the current state of knowledge regarding screening guidelines for older adults and gives recommendations for healthcare providers working with older adults.

Objectives:

To review current screening guidelines and practice related to cancer screening among older adults and to establish a best practice approach to screening for older individuals applicable to all levels of care.

Study Design: A comprehensive literature search was performed with consideration given to research and practice.

Methods: Review article.

Results: There is some evidence to support the effectiveness of screening for cancer among older adults, particularly when comorbidity, functional status, and life expectancy are considered. Moreover, most older individuals (at least the subpopulations of well-educated individuals of white race/ethnicity) have positive attitudes about cancer screening and are willing to engage in available screening tests. However, strict adherence to any of the selected guidelines for all older individuals can result in unnecessary stress and burden to some individuals related to screening and subsequent testing. Furthermore, screening for all older adults regardless of age and status has ethical implications for the community at large.

Conclusion: Providers should take an individualized approach to screening that addresses the immediacy of the screening benefit, associated risks of screening, preferences of the patient or his or her proxy, ethical concerns (eg, the futility of screening or treatment), and the patient’s life expectancy, health status, and quality of life.

(Am J Manag Care. 2008;14(5):267-276)

With regard to older adults, it is generally recommended that screening be based on the life expectancy of the individual, the risk vs benefit associated with screening, and the preferences of the patient or his or her caregiver.

  • Screening for breast, prostate, and colorectal cancer should be addressed with older adults as per our guidelines.
  • Routine screening for other types of malignant neoplasms is not recommended for older adults.

The older population has increased by 3.2 million, or 9.4%, since 1995, and approximately 1 in 8 individuals (12.5% of the population) is older than 65 years.1 With increased age, it is well known that there is an increased risk for the development of cancer.1,2 Most new cancers and cancer deaths occur in persons older than 65 years.3 Readers are referred to specific comprehensive review articles related to the science of cancer and aging.4,5 Specifically, these reviews address the mechanisms of aging that affect the development and suppression of cancer.

In older adults, cancer affects life expectancy and has a major effect on quality of life. Moreover, older adults who experience cancer are likely to be living with additional comorbidities such as heart disease, diabetes mellitus, dementia, or arthritis. The associated comorbidities, life expectancy, and perceived health status of these individuals influence decisions regarding screening, treatment, and ongoing cancer surveillance and care.

The objectives of this article are to consider what is known about screening for cancer among older adults and to address how this knowledge can be applied to current clinical practice and to the direction of future research. Screening refers to testing in individuals who have not previously been diagnosed as having a malignancy. However, some consideration is also given to ongoing cancer surveillance, which includes patients who continue to undergo screening procedures (eg, mammography) but have already been diagnosed as having cancer.

CANCER SCREENINGThere are numerous published recommendations for cancer screening among older adults, and Medicare has specific guidelines for coverage of the recommended screening tests6-11 (Table 1). However, the recommendations established by the United States Preventive Services Task Force (USPSTF)11 are the only ones that are solely evidenced-based. With regard to older adults, it is generally recommended that screening be based on the life expectancy of the individual, the risk vs benefit associated with screening, and the preferences of the patient or his or her caregiver.12-14 Recognizing the heterogeneity of older adults, it is critical to consider the overall health status of the individual.15,16

When comorbidity, functional status, and life expectancy are taken into consideration,17 evidence supports the effectiveness of screening for cancer among older adults.18,19 Moreover, most older individuals (particularly well-educated individuals of white race/ethnicity) realize the benefits of cancer screening and are willing to engage in screening tests.20 Similar findings have been noted by B. Resnick, PhD (unpublished data, 2007). However, it is apparent that adherence to screening guidelines for all older individuals may not always be in the best interest of the individual because the tests may result in unnecessary stress, morbidity, and even mortality without affecting the life span.16,21,22 Conversely, there may be a decrease in quality of life (eg, pain from a tumor or other consequences of a missed malignancy) associated with not screening a particular individual based purely on health status and life expectancy. For example, performing breast cancer screening in an 85-year-old woman in the upper quartile of health status and life expectancy (ie, those in better health with a >20-year life expectancy) is more likely to be beneficial for that particular individual compared with breast cancer screening in a 75-year-old woman in the lower quartile of health status and life expectancy (ie, those in worse health with a <3-year life expectancy).16

Breast Cancer ScreeningThe USPSTF11 recommends a screening mammography (with or without clinical breast examination) every 1 to 2 years for women 40 years and older. There is insufficient evidence to recommend for or against routine clinical breast examination without mammography to screen for breast cancer.11 Mammograms optimally identify tumors when the breast tissue is fatty, as occurs in the postmenopausal woman. Fatty breast tissue has fewer areas of density (white areas on the mammogram) that can obscure a suspicious area (Figure). For this reason, the sensitivity of mammography increases as a woman ages.7

Screening recommendations related to breast cancer do not address the potential risks of performing mammography in older adults. These risks include undergoing additional tests and biopsies associated with false-positive test results, emotional distress and anxiety, and exposure to futile evaluations and treatments.23,24 For example, if a breast malignancy is found in a frail older adult with limited life expectancy, treatment options may be limited and may engender significant morbidity or even mortality.

Mammography has a high false-positive rate and is unable to detect about 5% of breast cancers.7 Because of this, other screening modalities are being explored such as the use of dualenergy x-ray absorptiometry to accurately detect breast density25 and the use of breast density to help determine the risk of breast cancer.26-28 The measurement of breast density, along with other known risk factors associated with breast cancer diagnosis such as age, race / ethnicity, family history of breast cancer, a prior breast procedure, body mass index, natural menopause, the use of hormone therapy, and a false-positive mammogram in the past, can be used to help identify those at particular risk.28 Alternatively, magnetic resonance imaging has been used to detect breast cancer (particularly in situations in which mammography alone has poor sensitivity),29 to help identify age-related changes in the breast,30 or to detect local chest wall tumor recurrence after mastectomy.31 Magnetic resonance imaging is recommended by the American Cancer Society as an adjunct to mammography in women at high risk for breast cancer.27 However, there is no evidence to suggest the usefulness of this type of testing in older adults.32 Likewise, digital or computer-aided diagnostic mammography, while more accurate in identification of breast tumors in younger women, has not been shown to be advantageous for older women.33

Mammography Surveillance Recommendations in Breast Cancer SurvivorsThere are approximately 2 million women with a known diagnosis of breast cancer, more than half of whom are older than 65 years.34 Most of these women had no metastatic disease at diagnosis but are at risk for local or systemic recurrence. In addition, after an initial diagnosis of breast cancer, a woman is at an approximately 2-fold increased risk for a second breast cancer, which may be in the same breast if breast-conserving surgery was used or in the ipsilateral breast.35 Guidelines for follow-up include an annual history, a physical examination, and a surveillance mammogram.7 In a study23 that included a sample of 1846 older women with stage I and stage II breast cancer, there was a 0.69-fold decrease in the odds of breast cancer mortality with each additional surveillance mammogram and an almost one third reduction in the mortality rate. The protective association of a surveillance mammogram was strongest among those with stage I disease, those who had a mastectomy, and those in the oldest age group (>85 years). As with initial breast cancer screening, surveillance screening should consider the individual&#8217;s comorbidities, life expectancy, health status, and quality of life.

Colorectal Cancer Screening

The USPSTF11 and the American Cancer Society6 recommend against screening women older than 65 years for cervical cancer if they have had negative test results in the past and have no risk factors for cervical cancer such as a history of cervical cancer, immunosuppression, diethylstilbestrol exposure before birth, or documented human papillomavirus infection. Older women who have never had a Papanicolaou (Pap) test should be screened annually until there are 2 negative test results (Table 1). These recommendations are based in part on new data implicating human papillomavirus as a cause of almost all cases of cervical cancer. The natural history of human papillomavirus infection and the long latency between infection and development of cervical cancer45 imply that older women with at least 2 negative Pap smear results and no evidence of human papillomavirus infection are at extremely low risk.

There are no consistent recommendations regarding screening for prostate cancer (Table 1). The American Cancer Society6 recommends a digital rectal examination and prostate-specific antigen (PSA) test annually for all men older than 50 years. Men who have a first-degree relative with prostate cancer or individuals who have urinary symptoms should be considered at high risk, and testing should be encouraged. Combining digital rectal examination with a PSA test has been noted to be more effective than either test alone.46 Based on findings indicating that PSA testing measures an increase in prostate size rather than the presence of prostate cancer tumors47 and the lack of evidence that PSA testing improves outcome,47-49 the USPSTF 43 in 2002 concluded that there was insufficient evidence to recommend for or against routine PSA screening. Further preliminary findings from the Prostate, Lung, Colorectal and Ovarian cancer screening trial48 indicate that (compared with annual PSA screening) PSA screening every 5 years in men with a baseline PSA level of less than 1 ng/mL (to convert PSA level to micrograms per liter, multiply by 1.0) and every 2 years for men with a PSA level of 1 to 2 ng/mL could result in a 50% reduction in PSA tests (compared with annual screening).

This reduction in PSA tests would miss identifying fewer than 1.5% of men whose PSA level rose to greater than 4 ng/mL during the screening interval. However, the effect of this level of screening on prostate cancer mortality is not known.48 The indolent nature of many low-grade prostate cancers has contributed to a 10-year survival rate of approximately 89.2% in men diagnosed as having prostate cancer at 65 years or older.49 Therefore, many more men are diagnosed as having prostate cancer than die of it.50 Consequently, the value of intensive screening regimens for older men with limited life expectancy is doubtful.

Other Cancers

Although generally lower than the cancer screening rates reported among younger adults, screening rates as recommended by the USPSTF varied among older adults based on factors such as socioeconomic status and frailty.16,22,52 The percentage of older individuals who were up-to-date with screenings likewise varied depending on the state in which the individual lived.53 Furthermore, there is some concern that older adults, particularly the old old (>85 years), may be overscreened given their health status and life expectancy.24 In studies8,12,16,20,22,54,55 focused on screening for prostate, breast, and cervical cancer, there was some decline in the incidence of screenings among those with advanced age, but there was not a significant difference among these older individuals undergoing screening based on health status.16,22 For example, among men 85 years or older, 34% in the best health had a PSA test compared with 36% in the worst health. Among women tested for breast or cervical cancer, there was no difference in screening behavior among those 80 years or older based on health status.

FACTORS ASSOCIATED WITH ADHERENCE TO SCREENING GUIDELINES

Some of the persistence in screening of older adults, regardless of comorbidities and health status, may be due to the fact that there are no good models for predicting life expectancy beyond the effect of age. Furthermore, providers may interact with individuals who have multiple comorbid conditions more frequently than healthy older individuals, thereby providing more opportunity for screening to be addressed and encouraged. It is similarly possible that older adults continue to request screening or that providers fear potential litigation or some negative effect for not adhering to screening guidelines.16,20,22,52,56

There are some specific healthcare provider characteristics that may influence whether screening occurs. Heflin et al,54 following administration of a survey that included 2003 physicians, reported that overscreening with mammography testing was more common than underscreening among female physicians and among those who were not board-certified geriatricians. In addition, healthcare providers seem to serve as mediators for screening decisions made by older adults.57,58 The patient&#8211;provider relationship (eg, such things as the level of trust between the patient and the provider) may have a greater influence on screening outcomes than the independent characteristics of the provider or the patient.59

Patient Factors

Preference for screening among patients and rationale for recommending screening vary among individual patients and providers.71 Consequently, there is some interest in the use of a shared decision-making process to optimally help older individuals make screening-related decisions.20,71-75 Older adults, particularly those with poorer perceived health, expressed an interest in discussing cancer screening risks and benefits with their primary healthcare provider.74

Knowledge about screening tests and about the associated risks and benefits with screening is not the only factor to influence screening behavior. Older adults make decisions regarding screening based on what they believe about screening outcomes.24,76 Unfortunately, these beliefs may be unrealistic such as the belief that screening will prevent them from getting cancer.20,77 Such beliefs should be discussed and misconceptions corrected before making a definitive screening decision.

Not all patients are interested in taking or are willing to take an active or collaborative role in their healthcare decisions. Whether or not the individual is willing to participate in a shared decision-making process, an individualized approach to decision making should be considered.8,12,16,22,52,71,76,78,79 This approach moves beyond age and life expectancy and includes the consideration of such things as health status, comorbidities, and quality of life.

ETHICAL CONCERNS ASSOCIATED WITH SCREENING

Based on recommendations for screening from multiple organizations (Table 1) and on current knowledge associated with screening, we developed some general guidelines to follow when making screening decisions with older adults (Table 2). Most important, providers should take an individualized approach to screening that addresses the immediacy of the screening benefit, associated risks of screening, preferences of the patient or his or her proxy, ethical concerns (eg, the futility of screening or treatment), and the patient&#8217;s life expectancy, health status, and quality of life.

From a research perspective, we have not adequately considered screening and the effect of screening among older adults, particularly among the old old (>85 years). At the most basic level, we need to be vigilant to include older adults, particularly the old old, in ongoing testing of the effectiveness and cost&#8211;benefit of newer types of screening.

We must continue to develop our understanding of how to evaluate comorbidities in older individuals and how screening may be related to comorbidities, underlying health status, and quality of life. We can no longer consider age as a 1-dimensional construct. Rather, an individual&#8217;s function, frailty, and resilience are critical factors that likely influence the usefulness of cancer screening. Research is needed to develop clinical tools that integrate age, risk of cancer, life expectancy, and comorbidity to help healthcare providers work with patients to make informed decisions about screening.

Cancer screening in the context of genomics has likewise been largely ignored with regard to older adults. The most common hereditary cancer syndromes are hereditary breast and ovarian cancers and nonpolyposis colon cancer. These syndromes usually result in cancer development at younger ages. Therefore, careful evaluation of the cost&#8211;benefit ratio of genetic screening for those 65 years and older is needed.

Another area that has been ignored among older adults is cancer surveillance, which is relevant for individuals who have survived 1 or multiple types of cancers. Particularly critical is the relationship between cancer surveillance and health status or life expectancy. For example, what is the risk&#8211;benefit to continued screening of an 85-year-old woman who is a 20-year survivor of breast cancer given her current health status and life expectancy?

With the increase in life expectancy among older adults, it is equally important that we explore the effect of screening vs not screening on the quality of life and cost of care of these individuals. Regardless of age, health status, life expectancy, or current quality of life, undetected colorectal cancer may cause pain and inability to eat that might have been avoided if a polyp or smaller tumor was identified and removed. Research is needed to establish if it is better to provide chemoprevention or to identify and treat early-stage cancers in older adults with, for example, tailored radiation therapy, brachytherapy, or hormone therapy. Chemoprevention has been shown to be effective among those 60 years and older, although the risk of adverse events (eg, deep vein thrombosis) was also increased among these older individuals.82,83 Treatment at late stages of cancer or for associated complications may be more costly than screening and intervention at an earlier time point.

CONCLUSIONSBased on the current screening guidelines as established by the USPSTF along with others (Table 1), we recommend the following: (1) For women older than 70 years, risk factors associated with breast cancer should be explored every 1 to 2 years, and a discussion about breast cancer screening may be initiated that addresses the risks and benefits associated with screening and the individual&#8217;s comorbidities, life expectancy, health status, and quality of life. (2) Women 65 years and older should cease getting Pap tests if they have had normal test results up to this age. (3) For adults older than 50 years, risk factors associated with colorectal cancer should be explored every 1 to 2 years and considered in light of the risks and benefits associated with screening and the individual&#8217;s comorbidities, life expectancy, health status, and quality of life. (4) For men 50 years and older, the risk factors associated with prostate cancer should be reviewed every 1 to 2 years, and PSA test and digital rectal examination may be discussed in light of the risk and benefits associated with screening, comorbidities, life expectancy, health status, and quality of life. Routine screening for other types of malignant neoplasms is not recommended for older adults. Given the current state of the science, the general guideline for cancer screening among older adults should be to use an individualized approach that incorporates the ethical issues of futility of care. Ongoing research is needed to provide additional information to guide providers and older adults in these decisions.

Author Affiliations: School of Nursing, University of Maryland, Baltimore (BR, SWM).

Funding Source: None.

Author Disclosures: The authors (BR, SWM) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (BR, SWM); acquisition of data (BR); analysis and interpretation of data (BR); drafting of the manuscript (BR, SWM); critical revision of the manuscript for important intellectual content (BR, SWM); statistical analysis (BR); provision of study materials or patients (BR); administrative, technical, or logistic support (BR); and supervision (BR).

Address correspondence to: Barbara Resnick, PhD, CRNP, School of Nursing, University of Maryland, 655 W Lombard St, Baltimore MD 21201. E-mail: resnick@son.umaryland.edu.

1. U.S. Department of Health and Human Services. A Profile of Older Americans: 2006. http://www.nicoa.org/PDFs/AoA%20Profile%20of%20Older%20Americans%202006.pdf. Accessed February 16, 2008.

3.Yancik R, Ries LAG. Cancer in older persons: an international issue in an aging world. Semin Oncol. 2004;31(2):128-136.

5. Hornsby PJ. Senescence as an anticancer mechanisms. J Clin Oncol. 2007;25(14):1852-1857.

7. Khatcheressian JL,Wolff AC, Smith TJ, et al; American Society of Clinical Oncology. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol. 2006;24:5091-5097.

9. American Geriatrics Society Web site. AGS position statement: screening for cervical carcinoma in older women. http://www.americangeriatrics.org/products/positionpapers/cer_carc_2000.shtml. Accessed February 15, 2008.

11. U.S. Preventive Services Task Force. Guide to clinical preventive services. 2005. http://www.ahrq.gov/clinic/pocketgd05/gcps2.htm. Accessed February 15, 2008.

13. Mandelblatt J.Treating breast cancer: the age old dilemma of old age. J Clin Oncol. 2006;24(27):4369-4370.

15.Yancik R, Ganz PA,Varricchio CG, Conley B. Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. J Clin Oncol. 2001;19(4):1147-1151.

17. Schonberg MA, McCarthy EP, Davis RB, et al. Breast cancer screening in women aged 80 and older: results from a national survey. J Am Geriatr Soc. 2004;52:1688-1695.

19. Mandelblatt J, Schechter CB,Yabroff KR, et al.Toward optimal screening strategies for older women. J Gen Intern Med. 2005;20:487-496.

21.Walter LC, Eng C, Covinsky KE. Screening mammography for frail older women. J Gen Intern Med. 2001;16:779-784.

23. Lash TL, Fox MP, Buist DSM, et al. Mammography surveillance and mortality in older breast cancer survivors. Clin Oncol. 2007;25(21):3001-3006.

25. Shepherd JA, Herve L, Landau J, Fan B, Kerlikowske K, Cummings SR. Clinical comparison of a novel breast DXA technique to mammographic density. Med Phys. 2006;33(5):1490-1498.

27. Kerlikowske K, Ichikawa L, Miglioretti DL, et al. Longitudinal measurement of clinical mammographic breast density to improve estimation of breast cancer risk. J Natl Cancer Inst. 2007;99(5):386-395.

29. Lord SJ, Lei W, Craft P, et al. A systematic review of the effectiveness of magnetic resonance imaging (MRI) as an addition to mammography and ultrasound in screening young women at high risk of breast cancer. Eur J Cancer. 2007;43(13):1905-1917.

31.Yilmaz MH, Esen G, Ayarcan Y, et al.The role of US and MR imaging in detecting local chest wall tumor recurrence after mastectomy. Diagn Interv Radiol. 2007;13(1):13-18.

33. Del Turco MR, Mantellini P, Ciatto S, et al. Full-field digital versus screen-film mammography: comparative accuracy in concurrent screening cohorts. AJR Am J Roentgenol. 2007;189(4):860-866.

35. Hayes DF. Follow-up of patients with early breast cancer. N Engl J Med. 2007;356(24):2506-2513.

37. Li S,Wang H, Hu J, et al. New immunochemical fecal occult blood test with two-consecutive stool sample testing is a cost-effective approach for colon cancer screening: results of a prospective multicenter study in Chinese patients. Int J Cancer. 2006;118(12):3078-3083.

39. Matsushita H, Matsumura Y, Moriya Y, et al. A new method for isolating colonocytes from naturally evacuated feces and its clinical application to colorectal cancer diagnosis. Gastroenterology. 2005;129(6):1918-1927.

41. Itzkowitz SH, Jandorf L, Brand R, et al. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol. 2007;5(1):111-117.

43. Pignone M, Saha S, Hoerger T, Mandelblatt J. Cost-effectiveness analyses of colorectal cancer screening: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137(2):96-104.

45.Woodman CB, Collins SI,Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7(1):11-22.

47. Stamey TA.The era of serum prostate specific antigen as a marker for biopsy of the prostate and detecting prostate cancer is now over in the USA. BJU Int. 2004;94(7):963-964.

49. Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence–SEER 17 Regs Limited-Use, Nov 2006 Sub (1973-2004 Varying). Bethesda, Md: Cancer Statistics Branch, Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute; 2007.

51. Buys SS, Partridge E, Greene MH, et al; PLCO Project Team. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial [published correction appears in Am J Obstet Gynecol. 2005;193(6):2183-2184]. Am J Obstet Gynecol. 2005;193(5):1630-1639.

53. Shenson D, Bolen J, Adams M, Seeff L, Blackman D. Are older adults up-to-date with cancer screening and vaccinations? Prev Chronic Dis. 2005;2(3):A04.

55. Heflin MT, Oddone EZ, Pieper CF, Burchett BM, Coehn HJ.The effect of comorbid illness on receipt of cancer screening by older people. J Am Geriatr Soc. 2002;50:1651-1658.

57. Ross LE, Richardson LC, Berkowitz Z.The effect of physician-patient discussions on the likelihood of prostate-specific antigen testing. J Natl Med Assoc. 2006;98(11):1823-1829.

59. Matthews BA, Nattinger AB,Venkatesan T, Shaker R, Anderson RC. Objective risk, subjective risk, and colorectal cancer screening among a clinic sample. Psychol Health Med. 2007;12(2):135-147.

61. Bao Y, Fox SA, Escarce JJ. Socioeconomic and racial/ethnic differences in the discussion of cancer screening: “between-” versus “within-” physician differences. Health Serv Res. 2007;42(3):950-970.

63. Ananthakrishnan AN, Schellhase KG, Sparapani RA, Laud PW, Neuner JM. Disparities in colon cancer screening in the Medicare population. Arch Intern Med. 2007;167(3):258-264.

65. Ross LE, Richardson LC, Berkowitz Z. The effect of physician-patient discussions on the likelihood of prostate-specific antigen testing. J Natl Med Assoc. 2006;98(11):1823-1829.

67. Fiscella K, Holt K, Meldrum S, Franks P. Disparities in preventive procedures: comparisons of self-report and Medicare claims data. BMC Health Serv Res. 2006;6:122.

69. Ko CW, Kreuter W, Baldwin LM. Effect of Medicare coverage on use of invasive colorectal cancer screening tests. Arch Intern Med. 2002;162(22):2581-2586.

71. Dolan JG. Patient priorities in colorectal cancer screening decisions. Health Expect. 2005;8(4):334-344.

73. Resnick B. Health promotion practices. In: Ham RJ, Sloane PD, Warshaw GA, Bernard MA, Flaherty E, eds. Primary Care Geriatrics: A Case-Based Approach. 5th ed. Philadelphia, Pa: Mosby Elsevier; 2007.

75. Mandelblatt J, Kreling B, Figeuriedo M, Feng S. What is the impact of shared decision making on treatment and outcomes for older women with breast cancer? J Clin Oncol. 2006;24(30):4908-4913.

77. Schonberg MA, Ramanan RA, McCarthy EP, Marcantonio ER. Decision making and counseling around mammography screening for women aged 80 or older. J Gen Intern Med. 2006;21(9):979-985.

79. Ozanne EM, Klemp JR, Esserman LJ. Breast cancer risk assessment and prevention: a framework for shared decision-making consultations. Breast J. 2006;12(2):103-113.

81. Bernat JL. Medical futility: definition, determination, and disputes in critical care. Neurocrit Care. 2005;2(2):198-205.

83. Geiger AM,Thwin SS, Lash TL, et al. Recurrences and second primary breast cancers in older women with initial early-stage disease. Cancer. 2007;109(5):966-974.