Epidemiology of ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) is a relatively common diagnosis among women undergoing screening mammography. The greatest increases in DCIS incidence have been in non-comedo subtypes of DCIS that are not associated with subsequent invasive cancer. After a 500% increase in DCIS from 1983 to 2003, the incidence of DCIS declined in women aged 50 years and older, whereas the incidence in women younger than age 50 continues to increase. Having undergone mammography is one of the strongest and most prevalent risk factors associated with a diagnosis of DCIS. Other risk factors for DCIS are similar to that for invasive cancer including increasing age, family history of breast cancer, high mammographic breast density, and postmenopausal hormone therapy use. Treatment for DCIS is relatively aggressive with the use of both surgery and radiation therapy and most recently adjuvant hormonal therapy. Breast cancer mortality is low and similar with all types of treatment. New information regarding incidence of DCIS and subtypes of DCIS according to frequency of mammography and risk factors could lead to insights into the biology of DCIS.     

Breast recurrence after conservative treatment of cancers of the breast: predictive factors and prognostic significance

The prognostic significance of local relapse after conservative treatment of early stage breast cancer has been controversial. To determine the prognostic value of breast relapse occurrence and the factors predisposing to local failure, we analysed the results obtained in a series of 324 patients conservatively treated for breast invasive carcinomas of 2 cm or less. All patients were treated by tumorectomy and axillary dissection, radiation therapy, and adjuvant medical treatment in 85 of 109 patients with involved nodes. The overall 5-yr survival rate was 91.5%. The actuarial 5-yr local control rate was 91.9%. Local relapses occurred in 25 patients. In these patients, the overall 5-yr survival rate was significantly decreased as compared to that of patients without local relapse (76.9% versus 93.4%, P less than 0.001). Recurrence in the breast within 2 yr of initial treatment of severely affected the risk of metastasis occurrence as compared to later relapses (metastasis-free survival rate of 14.3% versus 63.9% at 3-yr from local relapse, P less than 0.01). Local relapse occurred more frequently in premenopausal patients, in patients with low bodymass index, and in patients with small breast size. Local control was not significantly affected by age, tumor size or node involvement. We conclude that the occurrence of a breast relapse after a local conservative treatment has a negative significance and is predictive of a high risk of distant metastasis development, especially when local relapse occurred within 2 yr of initial treatment. There is a need to determine individual factors that could allow discrimination of patients with a high probability of local relapse and subsequent metastasis.     

Overexpression of p53 is correlated with poor outcome in premenopausal women with breast cancer treated with tamoxifen after chemotherapy

The aim of this study was to evaluate the difference in outcomes based on p53 overexpression of patients with breast cancer who received adjuvant therapy following local treatment for invasive ductal carcinoma, not otherwise specified. We analyzed data from 4,683 patients with cancer enrolled in two institutions between 1997 and 2006. We analyzed the correlation between p53 overexpression and relapse, response to adjuvant therapy, breast cancer-specific survival (BCSS), and relapse-free survival (RFS) in patients with primary breast cancer. Overexpression of p53 was noted in 1,091 patients (23.3%). A significant correlation existed between p53 overexpression and poor prognostic factors, an increased frequency of regional recurrence, visceral metastasis, and worse BCSS and RFS. Based upon subgroup analyses, combined age (<35, 35–50, and >50 years) and adjuvant therapy (hormone therapy only, chemotherapy only, and hormone therapy following chemotherapy), the greatest reduction of survival based on p53 overexpression was noted in patients 35–50 years of age who received hormone therapy following chemotherapy (P < 0.05). Multivariate analysis showed that p53 overexpression is an independent prognostic factor in patients treated with hormone therapy and chemotherapy (relative risk for BCSS, 2.003; 95% CI, 1.105–3.631; P = 0.022). The p53-overexpressing patients with breast cancer between 35 and 50 years of age who received tamoxifen following chemotherapy had the greatest adverse effect on outcome. Overexpression of p53 is significantly associated with tamoxifen resistance in premenopausal women with breast cancer.     

Aging and cancer

The world's population is aging. Older age is associated with an increase in the incidence of cancer, especially cancer of the breast, lung, prostate, and colon. The management of older patients with cancer is biased by the simple fact of their chronologic age. Underscreening, understaging, less aggressive therapy, lack of participation in clinical trials, or no treatment at all reflect this bias. Although an age-related reduction in the physiologic function of many organs occurs with age, these are not contraindications to treatment with surgery, radiation therapy, or chemotherapy. Chronologic age alone should not be used as a guide for cancer management. Rather, physiologic function or existence of comorbid conditions should be major factors in determining treatment. As a result of the impending need for improved cancer management in older persons, a new subspecialty is evolving: geriatric oncology. This field stresses an important interaction between geriatricians and oncologists, development of research directed at the problems of cancer in older persons, and education at all levels with respect to cancer prevention, cancer detection, and cancer therapy. Physicians and oncologists need to be prepared for the projected increase of cancer in older persons.     

The impact of age on outcome in early-stage breast cancer

Multiple studies have shown that breast-conserving therapy (BCT) and mastectomy have equivalent outcomes for large populations of women with early-stage breast cancer. For individual treatment decisions, however, it is important to appreciate the heterogeneity of disease. Recent molecular studies have suggested that "breast cancer" includes biologically distinct classes of disease; although these molecular distinctions are important, other patient-related factors also affect outcome and influence prognosis. One of the most important of these patient factors is the age of the patient at diagnosis. Numerous studies have shown very different breast cancer outcomes based on patient age; younger women typically have more aggressive tumors that are more likely to recur both locoregionally and distantly, and older women more commonly have less aggressive disease. The overall disease-specific outcomes, techniques, and doses for adjuvant radiation therapy and toxicity of treatments should be discussed within the context of age because breast cancer is a very different disease based on this factor. Arguments can be made that more aggressive locoregional therapy is warranted in populations of young women with breast cancer and perhaps less aggressive therapy in the elderly.     

Prognostic significance of breast relapse after conservative treatment in node-negative early breast cancer

The prognostic significance of local relapse after conservative treatment of early stage breast carcinoma has been controversial. To determine the incidence and the prognostic value of a breast relapse, we analyzed the results obtained in a series of patients with pT1pN0 presentation of breast carcinoma treated conservatively without adjuvant medical treatment. From 1976 to 1986, 202 patients with invasive breast carcinoma of less than 2 cm without lymph node involvement were treated with surgery and radiation therapy. The overall survival rate was 97.2% at 5 years. Locoregional relapses occurred in 16 patients (7.9%). In these patients, the overall survival rate was significantly decreased as compared to that of patients without local relapse (87.5% versus 98.3% at 5 years, p less than 0.001). The probability of remaining metastasis-free was also significantly decreased (80.2% vs 91.3%, p less than 0.001). Most relapses (94%) appeared at or close to the primary site. Salvage local treatment was possible in 14/16 patients (87.5%). Age, menopausal status, size and site of primary tumor, histological grade, and boost technique did not influence significantly the risk of local relapse occurrence. We concluded that the occurrence of a breast relapse after a successful local conservative treatment is a pejorative prognostic factor predictive of a high risk of distant metastasis development. There is a need to individualize factors that could allow discrimination of patients with a high probability of local relapse and subsequent metastasis.     

A retrospective study of breast cancer subtypes: the risk of relapse and the relations with treatments

Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate relapse for patients with the major subtypes of breast cancer as classified using immunohistochemical assay and to investigate the patterns of benefit from the therapies over the past years. The study population included primary, operable 2,118 breast cancer patients, all non-specific infiltrative ductal carcinoma, with the median age of 53.2 years. All patients underwent local and/or systemic treatments. The clinicopathological characteristics and clinical outcomes were retrospectively reviewed. The expression of estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 were analyzed by immunohistochemistry. All patients were classified into the following categories: luminal A, luminal B, HER2 overexpressing, basal-like, and unclassified subtypes. Ki-67 was detected in luminal A subtype. The median follow-up time was 67.9 months. Luminal A tumors had the lowest rate of relapse (12.7%, P < 0.001), while luminal B, HER2 overexpression, and basal-like subtypes were associated with an increased risk of relapse (15.7, 19.1, 20.9%). Molecular subtypes retained independent prognostic significance (P < 0.001). In luminal A subtype, adjunctive radiotherapy could decrease the risk of relapse (P = 0.005), Ki67 positive was a high-risk factor for relapse (P < 0.001), and adjuvant chemotherapies could reduce the relapse for the patients with risk factors (P < 0.001). Adjuvant hormone therapy was an effective treatment for ER-positive tumors (P < 0.001). Molecular subtypes of breast cancer could robustly identify the risk of recurrence and were significant in therapeutic decision making. The model combined subtype and clinical pathology was a significant improvement. Luminal A tumors might represent two distinct subsets which demonstrated distinct prognosis and therapy response.     

Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer.

BACKGROUND: Although the conservation management of breast cancer has become a routine method of treatment in most centers, there is still considerable controversy surrounding the ultimate minimum treatment required for node-negative breast cancer to achieve adequate local control. PURPOSE: Our purpose was to assess the value of breast irradiation in reducing breast relapse following conservation surgery for node-negative breast cancer. We attempted to define low-risk groups of women for breast and distant site relapse (i.e., recurrence outside the breast) who might be spared breast irradiation or adjuvant systemic therapy. METHODS: Eight hundred thirty-seven patients were randomly assigned to receive radiation therapy or no radiation therapy following lumpectomy and axillary dissection for node-negative breast cancer. RESULTS: Breast irradiation reduced relapse in the breast from 25.7% in the controls to 5.5% in the irradiated patients. There was no difference in survival between the two groups (median follow-up, 43 months). A low-risk group (less than 5% chance of relapse in the breast without irradiation) could not be defined. Tumor size (greater than 2 cm), age (less than 40 years), and poor nuclear grade were important predictors for breast relapse. Age (less than 50 years) and poor nuclear grade were important predictors for mortality. The presence of ductal carcinoma in situ did not predict breast relapse. CONCLUSIONS: Breast irradiation significantly reduces breast relapse, but it does not influence survival. Important predictors of breast relapse are age, tumor size, and nuclear grade, but not the presence of ductal carcinoma in situ. Age and, in particular, nuclear grade predict survival. IMPLICATIONS: Further follow-up may define an acceptable low-risk group for breast relapse. Until then, we recommend that all patients receive breast irradiation. Systemic adjuvant therapy should be considered for patients with poor nuclear grade tumors.     

Expression of prostate-specific antigen (PSA) correlates with poor response to tamoxifen therapy in recurrent breast cancer

Prostate-specific antigen (PSA) is a serine protease which may play a role in a variety of cancer types, including breast cancer. In the present study, we evaluated whether the level of PSA in breast tumour cytosol could be associated with prognosis in primary breast cancer, or with response to tamoxifen therapy in recurrent disease. PSA levels were determined by enzyme-linked immunosorbent assay (ELISA) in breast tumour cytosols, and were correlated with prognosis in 1516 patients with primary breast cancer and with response to first-line tamoxifen therapy in 434 patients with recurrent disease. Relating the levels of PSA with classical prognostic factors, low levels were more often found in larger tumours, tumours of older and post-menopausal patients, and in steroid hormone receptor-negative tumours. There was no significant association between the levels of PSA with grade of differentiation or the number of involved lymph nodes. In patients with primary breast cancer, PSA was not significantly related to the rate of relapse, and a positive association of PSA with an improved survival could be attributed to its relationship to age. In patients with recurrent breast cancer, a high level of PSA was significantly related to a poor response to tamoxifen therapy, and a short progression-free and overall survival after start of treatment for recurrent disease. In Cox multivariate analyses for response to therapy and for (progression-free) survival, corrected for age/menopausal status, disease-free interval, site of relapse and steroid hormone receptor status, PSA was an independent variable of poor prognosis. It is concluded that the level of PSA in cytosols of primary breast tumours might be a marker to select breast cancer patients who may benefit from systemic tamoxifen therapy.     

Management issues for elderly patients with breast cancer

Opinion statement Fifty percent of breast cancers occur after the age of 65 years and 25% occur after the age of 75 years. Encountering a breast cancer in an older woman is frequent. After years of dearth of data specific to the elderly, some evidence is beginning to accumulate concerning breast cancer in the older woman. Recent data from mammography studies confirm its effectives in women with 10 years or more of life expectancy (perhaps even 5 years). Epidemiologic and randomized studies demonstrate that a proper surgery and adjuvant treatment can decrease relapse and improve survival in patients older than 80 years. Radiation therapy studies show a decrease in local relapse even in patients older than 70 years. Adjuvant hormonal therapy has essentially the same effectiveness as in younger women. Chemotherapy has a role in patients older than 70 years. Consensus statements, such as the St. Gallen consensus, have dropped the age limit of 70 years from their recommendations. Comorbidity and life expectancy should be taken into account for proper selection of adjuvant treatment. The treatment of metastatic breast cancer has evolved significantly with the introduction of aromatase inhibitors, new chemotherapeutic agents, and targeted biologic agents. New chemotherapeutic agents are as effective as single agents compared to older and more toxic drug combinations. The cumulative result of the introduction of these new agents, at a population level, is a 7.5-month increase in the median survival time of patients with metastatic breast cancer over the past decade.     

Prognostic and predictive factors in breast cancer.

Around 570 000 women develop breast cancer worldwide. In the U.K. it affects 33 000 women and causes 16 000 deaths each year. Treatment of early breast cancer is surgical, comprising breast conserving surgery (followed by radiotherapy) for small unifocal tumours, or mastectomy for larger or multifocal tumours.Survival of patients with breast cancer depends on two different types of prognostic factors: tumour size reflecting how long the tumour has been present, and biological factors (i.e. grade) which represent tumour aggressiveness. In women with a tumour that has adverse features predicting early recurrence (i.e. lymph node positivity, large size, high grade) adjuvant systemic chemo- or hormonal therapy is given to reduce the risk of relapse. Chemotherapy is given to pre-menopausal women for oestrogen receptor negative post-menopausal breast cancer, whereas hormone therapy is reserved for oestrogen receptor positive cancer.Since 50% of patients will never relapse, identification of which women are at high risk of recurrence is necessary so as to offer treatment with adjuvant therapy. The use of hormone therapy and chemotherapy has been aided by factors predicting the likelihood of response, e.g. oestrogen receptor status. The value of newer prognostic and predictive markers is addressed.     

Prognostic gene network modules in breast cancer hold promise

A substantial proportion of lymph node-negative patients who receive adjuvant chemotherapy do not derive any benefit from this aggressive and potentially toxic treatment. However, standard histopathological indices cannot reliably detect patients at low risk of relapse or distant metastasis. In the past few years several prognostic gene expression signatures have been developed and shown to potentially outperform histopathological factors in identifying low-risk patients in specific breast cancer subgroups with predictive values of around 90%, and therefore hold promise for clinical application. We envisage that further improvements and insights may come from integrative expression pathway analyses that dissect prognostic signatures into modules related to cancer hallmarks.     

Treatment options for early breast cancer in elderly women

In clinical practice, approximately 50% of new cases of breast cancer occur in women over the age of 65 years, although very few elderly women have been enrolled in the numerous randomized trials conducted so far. Notwithstanding less aggressive biologic features compared with younger patients, breast cancer impacts on mortality of elderly women, especially if not adequately treated. As confirmed by meta-analyses, hormonal therapy is the most effective adjuvant measure for patients with localized disease, whereas the decrease in the benefit of cytotoxic treatment with increased risk of toxicity make the decision on when and how to administer it a major challenge for the medical oncologist. Careful evaluation of biological prognostic factors, performance status and geriatric parameters, such as functional independence, comorbidities and cognitive function of the patient, along with determination of her life expectancy and preferences, represent the relevant information on which the oncologist should ground their decision for integrated treatment with conservative surgery, radiotherapy and hormonochemotherapy in otherwise healthy women, or attenuated or palliative measures for the frail patients, in order to maximize the balance of benefits and toxicities. The aims of this review are to summarize the most relevant concepts for decision making in the clinical practice and discuss the results of recent research concerning the additional needs of elderly women with early breast cancer.     

Survival of Triple Negative versus Triple Positive Breast Cancers Comparison and Contrast

Background Triple negative (TN) and triple positive (TP) breast cancers both are aggressive types but TN generally has a shorter survival. Objectives To compare the clinical characteristics and treatment outcomes for patients with TN versus TP breast cancer and to assess various prognostic factors affecting overall survival. Materials and Methods A retrospective audit of 85 breast cancer patients was conducted in the Department of Radiation Oncology and Medical Oncology on patients from 2006 to 2013 for whom IHC for ER, PgR and Her-2 neu were available. The patients were strati ed into ER-, PR- and Her-2 neu- (Arm A, n47) and ER+, PgR+ and Her-2 neu+ (Arm B, n38). Results TN subtype had higher numbers of premenopausal and advanced stage patients as compared to TP subtype. The locoregional recurrence (LRR) and distant metastatic rate was also higher in TN subtype but there was no de nite pattern in both the arms. Among the prognostic factors, patients with premenopausal status and advanced stage in TN breast cancer had inferior survival (P0.07) whereas for those with postmenopausal status and early stage there was no survival difference between the two arms. Conclusions TN subtype tends to be more aggressive in terms of younger age and advanced stage at presentation, higher tumour grade, LRR and metastasis, suggesting need for future research efforts on providing aggressive treatment to these patients. We could attribute better outcome for TP subtype to receptor positivity enabling role of hormonal treatment and targeted therapy, although less number of patients received targeted therapy.     

Prognostic-significance of multifocality in primary breast-cancer

The impact of multicentricity in primary breast cancer on relapse or death after radical or modified radical mastectomy was evaluated in 1336 consecutive patients. Multiple tumor foci were found in 11.7% of breast cancers: in 8.4% multicentricity was infiltrating, while in 3.3% of cases an in situ growth pattern was observed. There was a statistically significant association between multicentric primaries and lobular infiltrating carcinoma, age less than or equal to 50 years, large tumors and metastatic axillary nodes, while no relationship was observed with histological grade. Both 5-year disease-free survival and overall survival were shorter in patients with infiltrating multicentric primary tumors. Multivariate analysis confirmed the prognostic role of infiltrating multicentric tumors after adjusting for nodal status, tumor size, age and adjuvant therapy.     

New criteria for selecting elderly patients for breast cancer adjuvant treatment studies

About 50% of breast cancers occur in women aged 65 years and older, and both the incidence and prevalence of breast cancer among older women are expected to increase in the future. Aging implies a reduction in life expectancy and tolerance to treatments that should be considered in elderly patients with early breast cancer. In fact, treatment options often carry short-term risks and toxicities that might be tempered by long-term survival gains. The choice of adjuvant treatment for elderly patients should be based on the same criteria that are currently used for younger patients: endocrine responsiveness and assessment of risk of relapse. Adjuvant endocrine therapy should be considered for women with endocrine-responsive disease, regardless of age. The value of adjuvant chemotherapy is controversial. Older women are frequently undertreated with adjuvant chemotherapy and are underrepresented in clinical trials. In particular, no convincing data are available on the role of adjuvant chemotherapy in endocrine nonresponsive tumors, partly because most of the time these tumors represent a relatively small subset in adjuvant studies focusing on the elderly population. Several phase III trials are currently ongoing in elderly patients with early breast cancer to evaluate different options of adjuvant treatments. Only one trial, coordinated by the International Breast Cancer Study Group, is investigating the role of adjuvant chemotherapy for postmenopausal women of advanced age with endocrine nonresponsive early breast cancer. Disclosure of potential conflicts of interest is found at the end of this article.     

Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy: long-term results of European Organisation for Research and Treatment of Cancer studies

The aim of this study was to evaluate prognostic factors for isolated loco-regional recurrence in patients treated for invasive stage I or II breast cancer. The study population comprised 3602 women who had undergone primary surgery for early stage breast cancer, who were enrolled in European Organisation for Research and Treatment of Cancer (EORTC) trials 10801, 10854, or 10902, by breast conservation (55%) and mastectomy (45%). The median follow-up time varied from 5.3 (range: 0.6-9.5) to 11.9 years (range: 0.6-17.4). Main outcome was the occurrence of isolated loco-regional recurrence. The results of multivariate analysis showed that younger age and breast conservation were risk factors for isolated loco-regional recurrence (breast cancer under 35 years of age versus over 50 years of age: hazard ratio 2.80 (95% CI 1.41-5.60)); breast cancer age 35-50 years versus over 50 years: hazard ratio 1.72 (95% CI 1.17-2.54); breast conservation (hazard ratio: 1.82 (95% CI 1.17-2.86)). After perioperative chemotherapy, less isolated loco-regional recurrences were observed (hazard ratio 0.63 (95% CI 0.44-0.91)). No significant interaction effects were observed. It is concluded that young age and breast conserving therapy are both independent predictors for isolated loco-regional recurrence. As an isolated loco-regional recurrence is a potentially curable condition, women treated with breast conservation or diagnosed with breast cancer at a young age should be monitored closely to detect local recurrence at an early stage.     

Factors that influence the incidence of breast cancer in Arica, Chile (Review)

Breast cancer is a common disease estimated to occur in 1 in 9 women over their lifetime. Epidemiological research has identified a number of risk factors for breast cancer. Racial and ethnic differences in breast cancer mortality rates have been difficult to ascertain. The present review reports that there was an increase in the incidence of breast cancer in Arica, Chile, from 1997 to 2007, particularly in 2005, reaching 55.1% per 100,000 women, while the percentage decreased in 2006 and 2007. A greater percentage of breast cancer was found in individuals between 46 and 65 years of age when the population was distributed by age. The Indian population, Aymara, had only a 13.9% incidence of the disease. The incidence for breast cancer for patients with no family background reached approximately 88%, with or without Indian ethnicity, and 98.4% of these women did not have prior hormonal therapy. When the stage of the disease and the number of pregnancies were considered, results showed that there was an increase in the progression of the disease from stage I to stage III in women that had 1-3 pregnancies. Results also showed that 20.9 and 33.2% who received prior tamoxifen treatment were in stages I and IIA, respectively. The breast cancer incidence reached 42.4% when patients had a sister with the disease. It can be concluded that important differences in the risk factors of breast cancer should be identified in the future for a comparison with other biological factors, such as genetic and molecular factors. This may provide greater insight into breast cancer aetiology in different populations.     

Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer.

PURPOSE: To explore the independent prognostic impact of medial hemisphere tumor location in early breast cancer. PATIENTS AND METHODS: A comprehensive database was used to review patients referred to the British Columbia Cancer Agency from 1989 to 1995 with early breast cancer. Patients were grouped according to relapse risk (high or nonhigh) and adjuvant systemic therapy received. Multiple regression analysis was used to determine whether the significance of primary tumor location (medial v lateral hemisphere) was independent of known prognostic factors and treatment. RESULTS: In the adjuvant systemic therapy groups, medial location was associated with a 50% excess risk of systemic relapse and breast cancer death compared with lateral location. Five-year systemic disease-free survival rates were 66.3% and 74.2% for high-risk medial and lateral lesions, respectively (P <.005). Corresponding 5-year disease-specific survival rates were 75.7% and 80.8%, respectively (P <.03). No significant differences were observed between medial and lateral location for low-risk disease regardless of adjuvant therapy or for high-risk disease with no adjuvant therapy. Local recurrence rates were similar for all risk and therapy groups. CONCLUSION: The two-fold risk of relapse and breast cancer death associated with high-risk medial breast tumors may be due to occult spread to internal mammary nodes (IMNs). Enhanced local control, such as with irradiation of the IMN chain, may be one way to reduce the excess risk. Ongoing randomized controlled trials may provide prospective answers to the question of the optimal volume of radiotherapy.     

Breast cancer and aging. Clinical interactions

The incidence and mortality rates of breast cancer increase with age. As the geriatric population grows, the number of breast cancer cases will reach epidemic proportions. The number of coexisting medical conditions also increases with advancing age. The presence and severity of comorbid conditions influences an individual's ability to tolerate procedures and treatments and must be considered in making disease-management decisions. Screening mammography can potentially save lives in older women. Women whose life expectancy exceeds 5 years should continue annual screening mammography. Choices for local definitive therapy, systemic adjuvant therapy, and treatment of metastatic disease should be based on patient preference and ability to tolerate the planned procedure. In general, otherwise healthy older women should be offered the same treatment options given to younger, postmenopausal women. Alternative, less aggressive, or nonstandard approaches are warranted in women whose life expectancy is limited or who are unable or unwilling to undergo standard management procedures.