Appendix c.2.doc

Western Canada Waiting List Project
Literature Review – General Surgery: Breast Cancer
Cheryl M. Martin, Helen M. Roman-Smith, and David C. Hadorn
May 31, 2000
Table of Contents
1. Introduction2. Search Strategy3. Condition and Treatment Description 3.1 Prevalence and Incidence3.2 Risk Factors3.3 Diagnosis and Staging3.4 Treatment Options3.5 Recurrence and Survival 4.1 Practice Guidelines4.2 Definition and Causes of Delay4.3 Influence of Delay on Survival 4.3.1 Delay worsens survival4.3.2 Delay does not worsen survival 4.4 Other Factors Related to Delay4.5 Delay of Radiation 5.1 Function5.2 Pain5.3 Psychological5.4 Other Quality of Life Measures 7. Prognostic Indicators of Treatment Benefit 7.1 Age/Menopausal Status7.2 Axillary Lymph Node Involvement7.3 Estrogen/Progesterone Receptors7.4 Tumor Size7.5 Histopathologic Grade7.6 Stage of Disease7.7 Margins of Resection7.8 Adjuvant Chemotherapy7.9 Adjuvant Radiation Therapy7.10 Tamoxifen7.11 Miscellaneous Appendix A: Search TermsAppendix B: Summary of Survival RatesAppendix C: Articles Related to Delay Affecting SurvivalAppendix D: Quality of Life Measurement ToolsAppendix E: Scores Used for Calculation in Table 11 1. Introduction
Prognostic indicators such as tumor size and stage are generally accepted to affect survival in
breast cancer patients. The impact of other factors on survival is less clear. This review
addresses several prognostic factors, with an emphasis on how delay of surgical treatment affects
outcome. The review was conducted under the auspices of the Western Canada Waiting List
Project for use by the general surgery panelists while developing priority criteria and associated
criteria weights. Panelists will be asked to assess the extent to which the review provided
meaningful assistance in this regard.
This report focuses on four major questions: (1) what impact does delay of surgery have onoutcomes; (2) what is the severity of suffering and disability pre-operatively (baseline); (3) whatis the degree of benefit from treatment with regard to suffering, disability, and/or extended life;and (4) which pre-operative variables predict the degree of benefit experienced by patientsfollowing surgery for breast cancer.
2. Search Strategy
A comprehensive search was completed to obtain relevant literature. The search consisted of the
• References were searched for with the use of the electronic databases Medline, Best Evidence, Cochrane Library, LegalTrac, HealthSTAR, and CancerLit.
• Recent review articles, practice guidelines, and consensus reports were searched for on the web by professional organizations such as the National Cancer Institute and Society ofSurgical Oncology.
• In an ancestry analysis, references were obtained from bibliographies of articles retrieved • Informal consultation with Western Canada Waiting List Project surgical panelists was used to request more information and ask whether they knew of additional data of which weshould be aware.
See Appendix A for the search terms and limitations used to retrieve citations, and a list of theweb sites accessed. Most terms searched electronically were limited to articles publishedbetween 1989 and 2000, and were written in English. Articles on delay were retrieved for years1970 to 2000 to ensure an extensive coverage of the literature.
Approximately 3,300 citations were found from these searches. The abstracts of these citationswere first screened to eliminate items not relevant to the review. Articles were retrieved andwere screened once more for relevance to the four research questions mentioned above. A totalof 130 references were cited in this report.
3. Condition and Treatment Description
3.1 Prevalence and incidence
Breast cancer is the most common cause of cancer death for women in Canada. The lifetime
probability of a woman developing and dying from breast cancer is 10.7 percent and 4.0 percent
respectively.[1] An estimated 19,200 new cases are expected to be diagnosed in Canada in 2000,
with 5,500 women dying of the disease in the same year.[2] Male breast cancer accounts forabout one percent of all new cases and stage for stage, has a natural history similar to that infemales.[3] 3.2 Risk factors
The causes of breast cancer remain unknown, but numerous factors have been associated with an
increase in breast cancer risk (Table 1). Age, personal history of breast cancer and a family
history of breast cancer have the greatest relative risks. Despite the recognition of these risk
factors, approximately 50 percent of women who develop breast cancer have no identifiable risk
factors beyond being female and aging.[4]
Table 1: Risk factors for breast cancer [3]
Postmenopausal hormone replacement (estrogen ± progestin) Proliferative breast disease without atypia Moderate alcohol intake (2-3 drinks per day) Age of first birth > yr. or nulliparous Personal history of endometrial or ovarian cancer Personal history of breast cancer (in situ or invasive) Atypical hyperplasia and 1st-degree relative The incidence of breast cancer increases dramatically with increasing age; more than 65 percentof breast cancer cases are among women age 60 and older (Table 2).
Table 2: Lifetime probability of developing breast cancer by age (%)[1]
3.3 Diagnosis and staging
Breast cancer is usually first detected as a palpable mass or as a mammographic abnormality, but
it can also be manifested initially by nipple discharge, breast skin change, or breast pain.
Suspicious palpable and mammographic breast lesions are investigated by biopsy. Most breast
masses, especially those that are found in young premenopausal women are benign. Most (75 to
85 percent) of the masses found to be cancerous are invasive with the remaining 15 to 25 percent
in situ. Carcinoma in situ is characterized by the proliferation of malignant cells within the ducts
or lobules of the breast without invasion of stromal tissue. The two major subtypes are ductalcarcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS).[3] LCIS, unlike DCIS, is microscopic and lacks both clinical and mammographic signs. LCIS isalso more likely to have bilateral involvement. The cells are grouped in a small, solid mass andhave small, uniform, round to oval nuclei.[4] All breast cancers are classified using a scheme that encompasses all attributes of the tumor thatdefine its life history. The American Joint Committee on Cancer (AJCC) TNM classification isbased on the premise that cancers of the same anatomic site and histology share similar patternsof growth and extension. The system is based on the size of the primary tumor (T), regionallymph node involvement (N), and distant metastasis (M) (Table 3). The combination of the T, N,and M classification indicates the extent of the disease at the time of clinical evaluation.
Table 3: The TNM system of staging of breast cancer [5]
Carcinoma in situ: intraductal carcinoma, lobular carcinoma in situ, or Paget’s disease of thenipple with no tumor Tumor >2 cm but not > 5 cm in greatest dimension Tumor of any size with direct extension to chest wall* or skin (includes inflammatory carcinoma) Regional lymph nodes cannot be assessed (e.g., previously removed, not removed) Metastasis to movable ipsilateral axillary nodes Metastasis to ipsilateral axillary nodes fixed to one another or to other structures Metastasis to ipsilateral internal mammary lymph nodes Distant metastases (including metastases to ipsilateral supraclavicular lymph nodes) *The chest wall includes the ribs, intercostal muscles, and serratus anterior but not the pectoral muscle.
The stage grouping system is often used for the purposes of tabulation and analysis (Table 4).
This grouping system was adopted to ensure, as far as possible, that each group is more or lesshomogeneous in respect of survival, and that the rates of these groups for each are distinctive.[5] Table 4: Stage grouping system of staging of breast cancer: Conversion from TNM [5]
Notes:1. T1 includes T1mic;2. The prognosis of patients with pN1a is similar to that of patients with pN0.
3.4 Treatment options
Effective means of treating breast cancer are widely available and may be used alone or in
combination, depending on individual circumstances. Surgery is the most commonly used
treatment for localized breast cancer. The surgical procedures most often used are lumpectomy
with axillary node dissection and modified radical mastectomy. Lumpectomy with axillary node
dissection entails excision of the tumor mass, including a clear margin of normal breast around
the tumor, along with lymph nodes under the arm. Modified radical mastectomy entails
complete removal of the breast, the underlying pectoral fascia, and some of the axillary nodes.[4]
The use of radiation therapy in the management of breast cancer has been increasing in recentyears. For many early-stage cancers, radiation of the breast is used in combination withlumpectomy and surgical examination of the axillary lymph glands. In larger but still localizedcancers, the breast, axilla, and chest wall may be irradiated following surgical treatment. Anumber of complications due to the spread of cancer to a distant site (e.g., pain) may besuccessfully treated with radiation. In these situations, hormone or drug treatment may be givenas well.
Surgery and radiotherapy are very effective in removing or destroying cancerous tissue if it isknown exactly where the cancer is and if adjacent normal organs and tissues can be preservedwithout injury. Chemotherapy, on the other hand, is distributed through the body and is capableof destroying cancer cells wherever they exist. Chemotherapy is often used, as adjuvant therapywhere the primary tumor has been controlled by surgery or radiotherapy but a secondary tumor isknown to exist. It is also used in some situations where the cancer is localized to one site.
In a great many cases the growth of breast cancers has been shown to be dependent on thehormonal environment provided by the individual’s body. Hormonal therapy provides anotherapproach to suppress the growth of hormone-sensitive tumors. Sometimes suppression of tumorgrowth is achieved by reducing the level of appropriate hormones in the body through surgicalremoval or x-ray destruction of the organ that normally produces those hormones (such as theovary or adrenal gland). Drugs are now also available that counteract the action of certainhormones. Tumor suppression is sometimes achieved by elevating the level of certain otherhormones by providing them in the form of drugs.
3.5 Recurrence and survival
Observed and relative survival rates, based on the AJCC staging classification of 50,383 patients
with breast cancer are listed in Tables 5 and 6, respectively. Relative survival rate refers to the
ratio of the observed survival rate to the expected rate for a group of people in the general
population similar to the patient group with respect to race, sex, and age. The data summarized
in these tables were taken from the National Cancer Data Base (Commission on Cancer of the
American College of Surgeons and the American Cancer Society) for the year 1989[6]. Both the
observed and relative survival rates progressively decline by years after diagnosis and by stage
with stage IV disease declining the most dramatically.
Table 5: Observed survival rates. [6]
Table 6: Relative survival rates. [6]
Recurrence of breast cancer is dependent upon the stage of cancer at diagnosis and the treatmentchoice used, whether it is single or in combination.[7-10] A study that followed 407 patientsbetween 1976-1987 with axillary node negative breast cancer treated by surgery alone showed a10-year recurrence rate (RR) of 19 percent (95% confidence interval ± 5%). Predictors ofrecurrence in order of strength were found to be: (1) tumor size (p = 0.0006); (2) histologicdifferentiation (p = 0.017); (3) age (p = 0.046) (Table 7). Groups with the highest risk forrecurrence were patients with tumors less than two centimeters (RR 32 ± 12), and patients withtumors 1.1-2 cm, poorly differentiated/ anaplastic tumors (RR 24% ± 8).[9] Table 7: Ten-year recurrence rate in node-negative breast cancer patients according to
clinical parameters [9]

Histologic differentiationWell or moderate Nodal disease was found to be the most important single variable as a predictor of relapse.[8, 11]In a study of 416 patients, the annual rate of relapse of breast cancer was found to increaseprogressively over the first four years. The annual hazard rate for relapse for node positivepatients in the first year was five percent; this increased to 10 percent and 14 percent in yearsthree and four respectively. In contrast, in those patients who were node negative at diagnosis (n= 302; 73 percent), the hazard rate for relapse was 1 percent in year one, increasing to fivepercent in years three and four.[11] Reintgen and colleagues found in a multivariate regressionanalysis of clinical variables of 435 women, that the most important predictor of disease-freesurvival was lymph node status (p = 0.0046) and not tumor size.[8] The use of combined treatment modalities has been found to decrease recurrence rates. Slotmanand colleagues investigated the timing of radiotherapy in breast conserving treatment for earlystage breast cancer. The recurrence rate determined for 508 patients with stage I-II invasivebreast cancer, treated between 1980-89 with a lumpectomy and axillary lymph node dissectionand postoperative irradiation, and adjuvant hormonal treatment (postmenopausal node-negativepatients) or adjuvant chemotherapy (premenopausal node-negative patients). Breast cancerrecurrence was detected in 17 patients (3.3 percent). The 5-year and 10-year recurrence rateswere 5.7 percent and 10.3 percent for stage I, 16.2 percent and 33.2 percent for stage IIA and32.7 percent and 73.9 percent for stage IIB (p < 0.001).[10] In a retrospective review of patientsreceiving the same type of surgery, the overall incidence of recurrence was not affected by theorder in which chemotherapy and radiation were administered.[7] The survival rates noted during this review are summarized in Appendix B.
4. Effects of Waiting for Treatment
4.1 Practice guidelines
At least ten clinical practice guidelines have been developed concerning the management of
patients with breast cancer. Most of these guidelines addressed how to treat the patient, but not
when treatment should be initiated or the consequence of delay. The National Comprehensive
Cancer Network (NCCN) Guidelines for the Treatment of Breast Cancer (updated 1997), for
example, made no mention of when treatments should be undertaken in relation to diagnosis.[12]
The Canadian consensus document “Clinical practice guidelines for the care and treatment of
breast cancer” also did not recommend a time period in which treatment should begin (other than
suggesting that a patient may take one to two weeks to decide on the type of treatment
Nor did any of the following guidelines address the appropriate timing of surgery orconsequences of delay: • the “Standard for Diagnosis and Management for Invasive Breast Carcinoma” adopted by the • “Surgical Management of Early Stage Invasive Breast Cancer (Stage I and II)” from the Cancer Care Ontario Practice Guideline Initiative[15]; • the NIH Consensus Statement “Treatment of Early-Stage Breast Cancer”[16];• Clinical Practice Guidelines For The Management Of Early Breast Cancer: Second Edition (1999) from Australia’s National Health and Medical Research Council[17]; • “Breast Cancer Surgical Practice Guidelines” from the Society of Surgical Oncology[18];• “Practice Guidelines for Breast Cancer” produced by the University of California Cancer Consortium Breast Cancer Clinical Pathways Committee[19].
Two guidelines discussed the question of timing of surgery, if only briefly. In Breast Cancer inwomen – a national clinical guideline, published by the Scottish Intercollegiate GuidelinesNetwork in 1998, the only reference to timing for surgery was a comment that treatment delaysof less than three months were unlikely to be associated with a measurable difference insurvival.[20] A more specific recommendation provided in “The British Association of Surgical OncologyGuidelines for surgeons in the management of symptomatic breast disease in the UK (1998revision)” indicated that an operation for diagnostic purposes should take place within two weeksof the decision to operate. The guideline further recommended that an initial therapeuticoperation be performed within three weeks of the decision to operate. The maximum acceptablewait for therapeutic surgery was considered to be four weeks, unless there was a therapeuticreason for delay.[21] 4.2 Definition and causes of delay
It is generally accepted that cancer should be detected as early as possible. However, the delay
of diagnosis or the initiation of treatment can occur for a number of reasons. The first signs of
breast cancer may be discovered by patients, or found incidentally by the doctor or through a
screening program and delay can be associated with each activity. Similarly, delays may also
occur between the first consultation with the primary-care physician to a hospital referral orbetween the first hospital visit and the start of definitive treatment. Hospital delay is of interestto the legal profession, and claims for delay in diagnosis of breast cancer are common, rising innumber and expense.[8] Patient delay is defined as the interval between the first symptom or sign of breast cancerrecorded by the patient and first visit to the doctor. Patient delay is extremely variable rangingfrom several days to years. It was found that younger women sought medical advice earlier thandid the older patients (p < 0.0001). The median patient’s delay was 10 days in patients youngerthan 40 years compared to 20 days in patients older than 80 years.[22] It has been cited thatdelay is due to a complex interaction of unconscious psychological processes inherent within theindividual, while others have attributed it to the nature and sequence of physical symptomsand/or signs.[23] Afzelius et al. believed that the reason for the shorter period for youngerwomen was due to a more rapid progression of disease in younger women and a higherawareness of breast disorders. The longer delay was found with older patients was ascribed to acohort effect, which at any age would lead to a delay in this age group. It was indicated thatolder patients may be less inclined to seek medical advice for breast disorders, especially in thepresence of other concurrent diseases related to aging. [22] Doctor delay is generally defined as the interval between the first visit and the time of definitivesurgery or biopsy if this was the only intervention. Doctor’s delay decreased with patient age (p< 0.0001). A median of 31 days in patients younger than 40 years was recorded compared to 19days in patients aged 80 years or more.[22] The reason for this may be that the diagnostic work-up is more difficult in younger patients due to a higher frequency of dense and lumpy breasttissues in this age group.
A limitation of studies of delay is that the information about first symptom or sign of breastcancer, and thus patient’s delay, is generally not as accurate as the information of doctor’s delay.
The time of first symptom may be difficult to establish since patients usually make no record ofthe exact date and, therefore, many patients might misjudge the delay. Another limitation isrelated to lead-time bias, the systematic error arising when follow-up of groups does not begin atcomparable stages in the natural history of a condition.[24] For this reason measurement ofsurvival is generally from the time that a patient first notices symptoms, rather than from thetime of diagnosis.
Appendix C summarizes the key points of the articles reviewed on delay that are discussedbelow in greater detail.
4.3 Influence of delay on survival
A comprehensive review of observational studies (worldwide) was completed by Richards and
colleagues in 1999 to study the influence of delay on survival among patients with breast cancer
[29]. Eighty-seven studies (101,954 patients) published between 1907 and 1996 with direct data
linking delay (including delay by patients) and survival were identified and reviewed. Each study
was assigned to one of three classifications for the purpose of analysis: category I, in which
actual survival rates at five years after diagnosis were available for groups with delays of less or
more than three months, less or more than six months, or both; category II, in which actual
survival rates at five years were not reported in the paper, but in which the investigators reportedother analyses (e.g., univariate actuarial analyses, multivariate Cox’s regression analyses, orboth), all published after 1970; or category III, which consisted of studies that did not fall intothe first two categories, including a few studies with no data but in which the investigatorscommented on the relation between delay and survival (e.g., increasing delays seemed to have noadverse effect on survival).
Statistical analysis of the 38 category I studies (n = 53,912) revealed that patients with delays ofthree months or more had 12 percent lower five-year survival than those with shorter delays(odds ratio for death 1.47 [95% CI 1.42-1.53]) and those with delays of three to six months hadseven percent lower survival than those with shorter delays (1.24 [1.7-1.30]). In category II, 13of 14 studies with unrestricted samples (i.e., encompassing all age groups, all stages, and allpathological subtypes; n = 21,753) showed a significant adverse relation between longer delaysand survival, whereas four of five studies of only patients with operable disease showed nosignificant relation. In category III, all three studies with unrestricted samples (n = 12,312)supported the primary hypothesis that longer delays between onset of symptoms and diagnosis ortreatment are associated with worse survival rates among patients with breast cancer.
Richards and colleagues tested a secondary hypothesis that patients with longer duration ofsymptoms would generally present with more advanced disease. All the thirteen relevant studiessupported this hypothesis. The group also wanted to look at whether relation between delay andstage would account for the poorer survival anticipated among patients with longer delays. Eightstudies showed a significant relation between delay and tumor size but one study showed nosignificant association between these variables. Three studies with unrestricted samplessignificantly reported on the relation between delay and survival within individual stages. Ineach study, longer delays were associated with lower survival rates when all patients wereincluded in analyses, but longer delay was not associated with poorer survival among patientswith stage I disease. In a fourth study, which was restricted to patients with a stage III disease,longer delays were associated with better survival rates. In four studies, multivariate analysesshowed that delay was a significant adverse prognostic factor when stage was excluded from themodel, but not when stage was included.
The authors of this review concluded that delays of three to six months are associated with lowersurvival. They claimed that these effects could not be accounted for by lead-time bias, and thatefforts should be made to keep delays by patients and providers to a minimum.
For the purposes of this paper, thirty-three original studies were reviewed that addressed thequestion of the impact of delay of surgery on outcomes. Fourteen studies found that delayworsened survival prospects and 16 (three from the same study project on different patient types)did not. An additional, ten studies indicated that delay affects tumor characteristics orprogression of disease. Highlights from these studies are presented below.
4.3.1 Delay worsens survival
Several studies have found that a longer delay before treatment may reduce the patient’s survival.
In a study of 1,784 cases of histologically confirmed breast cancer diagnosed from 1969 to 1974
and followed through 1976, those patients in whom surgery was performed within two months
had significantly better survival (estimated 50th percentile survival from graph = 63 months; p <
0.001) than those who delayed three to six months or more than six months (estimated 50thpercentile survival from graph = 41 months for both groups).[25] A study conducted by Richards et al.[26] evaluated the influence of delay presentation andtreatment on survival among 2,964 patients of all stages of cancer who were referred to hospitalbetween 1975 and 1990 in England. These patients were followed for a median of 12.5 years.
The investigators found that longer delay in presentation were significantly associated withworse survival (p < 0.0001). At ten years following diagnosis, the all-cause survival rates fordifferent delay groups were as follows: 51 percent (delay < 12 weeks); 44 percent (delay 12-26weeks), and 40 percent (delay > 26 weeks). At 20 years, the survival rates were 33 percent, 26percent, and 24 percent, respectively. When only breast cancer mortality was considered, thecomparable survival rates at ten years were 58 percent, 51 percent, and 47 percent, respectively,and those at 20 years were 48 percent, 40 percent, and 32 percent, respectively. The impact ofdelay in presentation on survival remained highly significant (p = 0.003), but the survival curvesonly started to diverge markedly after about four years.
At ten years from the onset of symptoms, a five percent difference in survival was observedbetween patients with delays of less versus more than 12 weeks (52 percent vs. 47 percent). At20 years, the difference in absolute survival rate was 10 percent (34 percent vs. 24 percent).
When deaths from causes other than breast cancer were excluded, similar survival differencesaccording to delay were observed. At ten years, the survival rates were 57 percent and 53percent, respectively, and at 20 years they were 48 percent and 33 percent. When survival wasmeasured from the date of diagnosis, those with longer delays within each stage tended to havebetter survival, though none of the differences reached statistical significance. When survivalwas measured from the onset of symptoms, these trends were more marked and reachedsignificance among patients in stages II (p = 0.01), III (p = 0.001), and IV (p < 0.001). Forpatients with ductal carcinomas, delays of 12 or more weeks in presentation had an adverseimpact on survival in each tumor grade (grade I, p = 0.05; grade II, p = 0.001; grade III, p =0.007).
After analyzing the records of 1,591 women with histologically confirmed primary breast cancerdiagnosed in the years 1945, 1950, 1955, 1960, 1965, 1970, or 1975, Elwood and Mooreheaddetermined that patients with long delays between the appearance of first symptom and diagnosishad a poorer survival from the date of diagnosis, with a relative survival rate at five years of 57percent compared with 70 percent in the short delay group. Within stage categories, however,there were no consistent or statistically significant differences in survival between the long andshort delay groups.[27] In some cases delay was only associated with survival under certain conditions. Feldman et al.
divided cancers into five classes to determine the relationship of survival in breast cancer todelay in treatment. Class 0 included in situ carcinomas (Tis). Class I cancers included tumors upto five centimeters with no nodal involvement (T1-2; N0). Class II included tumors the samesize as Class I but with nodal involvement (T1-2; N1-3) Class III included were larger tumors,node positive with no metastases (T3-4; N1-3). Lastly, Class IV included invasive carcinomawith metastases (M1). The study (n = 664) found that patient-induced delay in treatment of morethan three months was associated with poor overall (p < 0.05) and disease-free survival (p < 0.01) in patients diagnosed from 1975 to 1979 with Class III disease. Class III patients withdelay less than three months had a four-year overall survival rate of 76 percent, compared to 51percent for patients in the three to 11 months group and 45 percent in the >12 months group.
Disease-free survival was 68 percent for the short delay group, in comparison to 34 percent and37 percent, respectively. The presence of symptoms other than a lump was associated withlonger delay and poorer survival in patients with Class II and III disease.[28] In an early study of 1,840 patients diagnosed between 1954 and 1965, Sheridan et al. reportedsurvival rates for different delay periods for stage I and II disease.[29] As shown in Table 8,delay was not associated with poorer survival among patients with stage I disease. However,increasing delay among patients with stage II resulted in a greater deterioration.
Table 8: Five-year survival rates for 1,840 patients diagnosed from 1954-1965[29]
In a study of 621 cancer patients (including 101 patients with breast cancer (16.3 percent))referred to an oncology clinic in Israel in 1974, delay of at least six weeks between first symptomand diagnosis for all stages was associated with poorer survival at 96 months: 45 percent forpatients without delay and 32 percent having experienced delay (values estimated from graph).[30] Both Neale et al. and Dohrmann et al. reported that delays over six monthsnegatively affected survival.[31, 32] Neale examined 10-year survival following breast cancerdiagnosis among 1,261 women treated in Texas between 1949 and 1968. Ten-year survival wasfound to be inversely related to delay in seeking treatment (p < 0.001) with the cumulativeproportion surviving 47 percent, 38 percent, and 25 percent for less than three months, three tosix months, and more than six months delay, respectively. In the Dohrmann study, 435 patientsunderwent surgery for breast cancer between 1950 and 1980. Of these patients, symptomduration data and tumor staging was available for 353 patients. Cancer-specific survival timewas better for the total patient series and for those treated by potentially curative operation whensymptoms had been present for one week or less as compared with those who had symptomduration of six months or more, p = 0.007. Survival prospects were also better in those patientswho had symptoms from one week to one month as compared with those who had six months ormore symptom duration, p = 0.005. An M.D. Anderson study on the differences in 10-yearsurvival rates of white, black, and Hispanic breast cancer patients (n = 1983) operated onbetween 1949 and 1968 found that ethnicity, socioeconomic status, stage of disease, and delay inseeking treatment all affected survival when considered separately.[33] In a study of 7,608 patients conducted by Afzelius et al., regression analysis demonstrated that,in addition to age, both patient- and doctor-induced delay had prognostic value. If the patientdelay was more than two months, the mortality was 24 percent higher than for a short orintermediate delay (p < 0.0001). If a doctor-induced delay was less than 15 days, the mortalitywas 13 percent higher than for longer delays (p = 0.0002). The prognostic value of delay in terms of excess mortality increased to 34 percent for a long patient delay compared to a shorter delayand to 19 percent for a short doctor delay compared to a longer delay when omitting age from themodel.[22] The results of the Afzelius study give an example of a trend that has been found in a few otherstudies, in that there appears to be a subgroup of patients with short delay that have a worsesurvival rate. Two reasons have been suggested for this phenomenon. One is the ability of thedoctor to recognize and recommend immediate surgery for the patients with the worst diagnoses,and the other is the theory that certain types of tumors progress very rapidly.[23, 29, 34, 35] The following table (Table 9) is a summary of the studies that found longer delay associated withdecreasing survival. The “worst survival period” indicates the time period that had the worstsurvival statistics (i.e. patients who had surgery delayed for over 1.5 months had worse survivalstatistics [either disease-free, overall or both] than patients with less than 1.5 months of delay.) Table 9: Period of worst survival
4.3.2 Delay does not worsen survival
A number of studies have determined that delay does not affect outcome. In the review
conducted by Richards et al., seven studies identified did not support their hypothesis that longer
delays between onset of symptoms and diagnosis or treatment are associated with worse survival
rates among patients with breast cancer. Six of the seven studies had restricted samples (four of
operable patients only; one of locally advanced disease only; one of patients older than 65 years).
These studies ranged in size from 184 to 1539 patients (median 258 patients) and only one
involved more than 1000 patients. The lack of a relation between delay and survival in these
studies might, therefore be related to the size of the studies or to restrictions by stage.[37]
It is not uncommon for patients operated on immediately to have the poorest survival, but thesepatients frequently have some of the diagnoses with the worst prognoses. A review by Facionehas also called into question the practice of using multivariate analysis to determine the effect ofdelay.
In a retrospective analysis of 36,222 women, Sainsbury, Johnston, and Haward found thatpatients with delays of less than 30 days between family-physician referral and treatment had worse survival than patients in any other time period (p < 0.001). The authors concluded thatdelays of longer than 60 days did not significantly impair survival, and delays of more than 90days were unlikely to impact survival. Patients receiving treatment within 30 days had worsesurvival statistics.[35] In a study on node-negative patients, patients whose tumor was detectedwithin six months before surgery (n = 701) had a recurrence rate of 21 percent. Those who hadsurgery between six and twelve months after detecting the mass (n = 121) had a 23 percentrecurrence rate, and those waiting over 12 months (n = 83) had a 25 percent recurrence rate (p =0.433; log-rank = 0.64). The differences were not significant.[38] Fisher, Redmond, andFisher[39] found that there was a trend toward a reduction in treatment failure rate in patientswhose symptom period was greater than 9 months.
Neave, Mason, and Kay, in a study on 1,675 breast cancer patients, found no difference insurvival among patients experiencing different lengths of delay, although the variables tumorsize, skin attachment, and nipple retraction were more common in the group with longer delay,and histologically grade III tumors were more common in patients with shorter delay.[23] Charlson found that out of 685 breast cancer patients, those with delays of three months or morefrom the time of first symptom to treatment had a more advanced clinical stage than those withshorter delays; however, within each stage, prognosis was not affected by delay. Progression ofdisease did not invariably occur among patients with longer delays. The author estimated thatthe number of patients in the cohort who would have benefited by a reduction in delay was amaximum of five percent.[40] Machiavelli et al. had results similar to Charlson. In a study on596 patients with breast cancer, patients with a delay of less than three months had a higher 10-year survival rate than those in the longer delay groups (p = 0.034), but within each stage nostatistically significant difference in survival according to delay was observed.[41] In fouradditional studies (three of which were a series of studies on node-negative, node-positive, andmetastatic patients), delay was not found to be associated with survival.[42-45] In a literature review on delay, Facione refers to the Charlson and Machiavelli studies findingthat delay is insignificant to survival, and states that “the ill-conceived use of statistical methodsof data analysis might be the culprit responsible for this dangerous and illogical inference.” Sheclaimed that multiple regression analyses that include the variables of tumor stage, tumor sizeand delay, particularly hierarchical regressions where tumor stage is introduced as the firstcovariate, will tend to show that delay “contributes no additional explained variance.”[46]However, this explanation is unlikely to account for all of the findings described above, showingthat delay in treatment is not necessarily related to outcome.
4.4 Other factors related to delay
Besides survival, several other factors have been associated with delay of treatment, including
stage of disease, tumor size, and lymph node involvement at diagnosis. The risk of nodal
involvement was almost doubled for patients with a greater than 6-month delay (compared with
patients with less than three month’s delay; adjusted by age) who also had between three and
four times the risk of being diagnosed with advanced disease.[47]
In reviewing the records of 1,014 patients, delay in diagnosis was found to average 11 months(range three months to more than six years) in one doctor’s practice. Tumors of patients with delay were significantly larger than tumors of patients without delay (2.3 vs. 1.8 cm), but nodalinvolvement was no more frequent. The cancers of patients with delay were similar to those ofpatients without delay. Pathology, tumor differentiation, and estrogen receptor status were allcomparable.[48] A study on the symptom to diagnosis interval (SDI) in seven different types ofcancer, found that only in breast cancer was the status of the tumor significantly affected by theduration of symptoms.[49] Robinson, Mohilever, and Borovik found that delay in diagnosis of over six weeks affected thelikelihood of being diagnosed with an advanced stage of disease in 523 patients. Women with nodelay were more likely to be diagnosed at stage I (52 percent) than those with delay (35 percent).
Of the patients without delay, 42 percent were diagnosed with stage II cancer and five percentwith stage III cancer, as compared to 52 percent and 12 percent of delayed patients,respectively.[50] Of 1,784 cases of histologically confirmed breast cancer, a larger proportion of patients whodelayed two months or less before seeking treatment were diagnosed as having localized diseasecompared to those delaying three to six months or more than six months. However, 50 percentof those waiting three to six months were diagnosed with regional involvement as opposed to 41percent of those waiting two months or less, and 49.5 percent of those waiting more than sixmonths. Twenty-five percent of patients waiting more than six months compared to 6 percent ofpatients waiting two months or less demonstrated distant metastases at the time of diagnosis.[25]In a study by Gould-Martin et al. on 274 patients diagnosed with breast cancer, increased relativerisks for regional disease were observed with increasing intervals between self-discovery oftumor or onset of symptoms and first contact with physician. This relationship persisted for upto five months.[34] Nettleton et al. analyzed the data from a study published by Silverstein at al. on the correlation ofthe size of primary breast cancer with the incidence of positive axillary nodes in order todetermine the risk of axillary nodal metastases due to delayed treatment of breast cancer duringpregnancy. The data included 939 patients with stage T1 and T2 breast cancer who underwentconservative surgical treatment of the primary tumor and axillary node dissection. At the time ofdiagnosis, a patient with a 2.5 mm tumor was calculated to have a 1.4 percent risk of axillarymetastases. A 1-month delay in treatment for an early-stage primary breast cancer with a 130-day doubling time increased the risk of axillary lymph node involvement by 0.9 percent, makingthe total risk (risk at diagnosis + 1-month risk) 2.3 percent. A 3-month delay increased the riskby 2.6 percent, and a six-month delay by 5.1 percent. For breast cancer with a 65-day doublingtime, a 1-month delay increased the risk by 1.8 percent, a three-month delay by 52 percent, and asix-month delay by 10.2 percent. Patients with tumors averaging 35.5mm had a 45.7 percent riskof axillary metastases with a 65-day doubling time, compared to 59.3 percent risk after ninemonths with the 65-day doubling time. With a 130-day doubling time, the risk was 44.8 percentat one month and 51.6 percent at nine months.[51] In a review of court cases designed to determine the patient and physician factors that lead tobreast cancer malpractice litigation, 24 cases provided the TNM stage at diagnosis. According tolinear regression analysis, no correlation was noted between the increasing delay in diagnosisand the advancing TNM stage (p = 0.91). In eight cases, size of the tumor was plotted against the months of diagnostic delay. Linear regression analysis showed no statistically significantcorrelation between tumor size and final diagnosis and diagnostic delay (p = 0.91).[52] In a literature review, Caplan and Helzlsouer[53] reported on an article by Pilipshen et al.[54],which followed patients treated by radical or modified radical mastectomy. Those delaying morethan six months were about twice as likely to have tumors of at least four centimeters and 40percent more likely to have axillary metastases than patients delaying six months or less.
4.5 Delay of radiation
Several studies have tested the impact of delay of radiation therapy on survival. In a study on the
impact of delaying irradiation after chemotherapy on patients with node-positive cancer, Hartsell
et al. determined that delays over 120 days increased the risk of relapse. The five-year actuarial
survival rates were 87 percent and 82 percent for the early and delayed groups, respectively (p =
0.39). The disease free survival and distant disease free survival rates were 85 percent and 85
percent for the early group, compared with 69 percent and 81 percent for the delayed group (p =
0.04 and 0.34, respectively). For the 42 patients receiving delayed irradiation, there were six
local recurrences, for a 5-year actuarial rate of 14 percent (p = 0.05).[55]
In a study on the effect of delaying radiation after chemotherapy, Buchholz et al. found that localcontrol rates (the percentage of patients who did not have local recurrence) were 98 percent forthe early radiation group compared to 76 percent for the delayed group at eight years. Thedifference was significant at a value of p = 0.004. Overall survival was 80 percent for the earlygroup compared to 52 percent for the delayed radiation patients (p = 0.016). Eight-year actuarialdisease-free survival rates for the early patients and the delayed patients were 71 percent and 48percent, respectively (p = 0.008).[56] Among patients who received breast-conserving surgerywith and without chemotherapy, local and systemic failure rates were determined based ontiming of irradiation. Those who did not receive chemotherapy had higher local and systemicfailure rates if radiation was undertaken more than seven weeks after surgery. In the group thatdid receive chemotherapy, local, regional, and systemic failures only occurred in women with adelay of radiation exceeding 24 weeks. There were no differences in survival rates.[57] Slotmanet al. also found delay of radiotherapy to be an independent factor predictive of recurrence in 508patients with stage I and II invasive cancer.[10] Two studies did not find an association between delay of radiation therapy and lower survivalrates. Leonard et al., in a study on 262 patients, could not identify any surgery-radiotherapyinterval that resulted in increased local recurrence if radiotherapy was delayed for administrationof adjuvant chemotherapy.[58] Vujovic et al. found that patients treated with radiation within 12weeks of surgery had a local recurrence rate of 7.8 percent (34/436), compared to a rate of 3.8percent for the patients treated after 12 weeks (5/132).[59] 5. Baseline Health Status Measures
5.1 Function
The effect of breast cancer on function has not been frequently studied. At best, function-related
factors may be included in an overall quality of life assessment. The McCorkle and Young
Symptom Distress Scale (SDS) includes the domains of fatigue and mobility in its assessment.
Cimprich used the SDS to assess 74 newly-diagnosed breast cancer patients prior to surgery (seeTable 10). The affect of a cancer diagnosis on mobility was low in all patients (mean of 1.3 outof a worst possible five). Fatigue was noted to be more of a problem by the patients, followinginsomnia and mood disturbance.[60] See Appendix D for a description of measurement tools.
Table 10: Preoperative McCorkle and Young Symptom Distress Scale (SDS) [60]
* SEM refers to the standard error of the mean or the standard error 5.2 Pain
Breast pain is reported as a symptom in about 10 percent of patients with breast cancer.[3] In the
Cimprich study, the overall pain score was 1.31 out of five, with premenopausal women scoring
a mean 1.44 and postmenopausal women scoring 1.24. Other discomforting problems assessed
by the SDS were bowel disturbance and nausea (See Table 10).[60]
5.3 Psychological
The psychological affects of breast cancer are more frequently studied, but the period between
diagnosis and surgery has seen little research. Again, the Cimprich study provides some
information. On the SDS, patients found that psychological problems were the most difficult to
handle while awaiting surgery, with insomnia (2.88) and mood disturbance (2.72) rating the
worst scores. After fatigue (2.41), loss of concentration (2.24) was the next most often reported
difficulty. In all domains, premenopausal women had more difficulty dealing with a cancer
diagnosis than did their older counterparts. (See Table 10) [60]
Three studies used the Profile of Mood States (POMS) to evaluate the psychological status ofpatients between diagnosis and surgery. Rather than developing high and low scores for theindividual scales on the POMS, the creators of this tool, McNair, Lorr, and Droppleman,produced mean comparison groups using college women and psychiatric outpatients. With theexception of the “vigor” scale, a higher score indicates worse status. For the purposes ofcomparing breast cancer patients to a normal population, the college women scores are includedin Table 11.[61] A second comparison group of healthy women has been extracted from a studyby Anderson, Anderson and deProsse.[62] Cimprich[60] evaluated 51 patients, 39 of whom were postmenopausal and 12 werepremenopausal. Table 11 shows the POMS scores for each group. Cimprich noted thatpremenopausal patients had notably higher scores than postmenopausal patients. Two otherstudies, Romsaas et al. and Stanton and Snider[63, 64], also assessed patients after diagnosis andbefore surgery, and the scores of these three groups have been averaged in Table 11 in the “All”column. All patients who were awaiting surgery at the time of evaluation with the POMSassessment had much worse (higher) scores in the areas of depression-dejection and tension-anxiety than those in the healthy women group, but were not much different than the collegewomen evaluated by the creators of the POMS. All women waiting for surgery had a muchworse (lower) score for vigor than did either of the comparison groups or the postmenopausalwomen.
Table 11: Comparison of average preoperative Profile of Mood States (POMS) mean
scores for diagnosed breast cancer patients and other groups.

For all scales except “vigor,” Worst = high score; Best = low score.
For “vigor,” Worst = low score; Best = high score.
(Maximum and minimum scores are not used for this questionnaire.) *See Appendix E for the scores used to calculate the “All” category in Table 11.
**Total mood disturbance = anger + confusion + depression + fatigue + tension – vigor.
Separately, a study by Seckel and Birney examined the relationship among stress, age, and socialsupport in 30 women scheduled for biopsy. The authors determined that patients who perceivedhaving less social support reported greater anxiety while awaiting surgery. In addition, thepatients tended to have increased stress with aging until age 40, then stress decreased withincreasing age, which agrees with the data found by Cimprich in the pre- and postmenopausalpatients.[65] 5.4 Other quality of life measures
Of the studies reviewed which measured quality of life between the time of diagnosis and
surgery, there were no other elements studied which would indicate a worse status for the patient
during this specific time period and which were specifically the result of the knowledge thatsurgery was pending.
6. Surgical Outcomes
6.1 Function
The only pre- and postoperative comparison of function encountered during the review was that
performed by Stanton and Snider using the Profile of Mood States (POMS). In Table 12, fatigue
and vigor were compared among patients over 40. (Note that for fatigue a high score is worse,
but for vigor a high score is better.) The changes in these domains between pre- and
postoperative scores were not major.[64]
6.2 Pain
Of the studies reviewed, no data was available on the difference between pain for breast cancer
patients before and after surgery.
Table 12. Profile of Mood States (POMS)[64]
6.3 Psychological
One study evaluated the mental status of breast cancer patients prior to and after surgery (see
Table 12). Patients indicated similar improvements in the scales of depression-dejection and
tension-anxiety, with an increase in score of approximately 4.4 points. Other changes showed
improvements in the patients’ status, but were not large differences.
7. Prognostic Indicators of Treatment Benefit
7.1 Age/menopausal status
Age is frequently tested as a prognostic indicator for survival. Not all studies find the
association significant. In some studies, age was only associated with recurrence. Vujovic et al.
found that patients under 40 years had increased risk of recurrence. Under univariate analysis,
age was a significant prognostic factor associated with local recurrence and disease-free survival.
Age was also a significant factor for disease-free survival under multivariable analysis.[59] In
another study, younger patients were more likely to have local failure.[66] In a group of 407
axillary node negative breast cancer patients having received surgery alone, age (p = 0.046) was
a significant predictor of outcome. Patients under 35 had a higher recurrence rate.[9] Of 3,585
patients entered into a study on adjuvant therapies, postmenopausal patients had a greater hazard
of recurrence (p = 0.0009) for the entire 12-year follow-up interval.[67] In a study by Merchant
et al., no differences were observed regarding disease-free or overall survival between the two
groups of < 65 and > 65 patients, but at both five and ten years, there was a statisticallysignificant improvement in local control for older patients (numerical values not reported).[68] Other studies have found age to be a predictor in the overall survival rates or risk of death. In astudy by Byrne et al., the five-year survival rate for patients under 40 was 74.8 percent. Forpatients between 40 and 79, survival rates ranged from 82.7 to 85.2 percent. After 80 years ofage, survival decreased to 40.9 percent.[69] Among 611 patients with breast cancer, undermultivariate analysis, age older than 74 years was significantly and independently associatedwith a shorter disease-specific survival as compared with patients younger than 75 years.[70] La Rosa et al. found that relative survival at one year from diagnosis was stable up to 69 years(between 0.97-0.91). After 69 years, the prognosis progressively worsened with increasing age.
At five years from diagnosis, the highest relative survival values referred to women under 35years of age (0.83). Thereafter chances of survival generally diminished with increasing age upto 0.59 in women of 75 and over. There was a difference among women of 45-49 years (0.81)and 60-64 years (0.76), for whom the prognosis was six percent and 13 percent betterrespectively, than the preceding age groups.[71] Patients not receiving adjuvant cytotoxic treatment had a significantly increased risk of dyingwith decreasing age (adjusted relative risk: 45-49 years: 1(baseline); 40-44 years: 1.12 (95%confidence interval 0.89 to 1.40); 35-39 years: 1.40 (1.10 to 1.78); < 35 years: 2.18 (1.64 to2.89)). Young patients receiving adjuvant cytotoxic therapy did not show the same increase ofrisk.[72] Numerous studies have reported on both rates of disease recurrence and death with regard to age.
In a study on age as a prognostic factor for breast cancer, patients under 33 years (n = 67) had theworst actuarial overall survival rate of 67.8 percent at five years compared to patients in groupsof 34 to 40 years and over 40 years. The youngest patients also had the lowest disease-specificsurvival rate of 68 percent, compared to 76.5 percent for the 34-40 group and 84.6 percent for theover 40 group. The disease-free survival was, again, worst for the youngest patients at 52.7percent compared to 60.4 percent and 70 percent for the older groups.[73] In 980 patients with stage I and II breast cancer who underwent excisional biopsy, axillarydissection, and radiation, younger women (< 35) were found to have a statistically significantdecreased 8-year actuarial relapse-free survival, 53 percent compared to 67 percent for womenbetween 36 and 50, and 74 percent for women 50 and over (p = 0.009). The younger group alsohad lower cause-specific survival (73 percent vs. 84 percent vs. 90 percent, p = 0.02), freedomfrom distant metastasis (76 percent vs. 75 percent vs. 83 percent, p = 0.02), and a significantlyincreased risk of breast recurrence (24 percent vs. 14 percent vs. 12 percent, p = 0.001), andregional node recurrence (seven percent vs. one percent vs. one percent, p = 0.0002).[74] In reviewing data on 125,000 breast cancer patients, Yancik, Ries, and Yates determined thatpatients with localized disease could expect a relative survival rate of about 99 percent regardlessof age at one year. After five years, 90 percent of the women in the age groups between 45 and85 years continued to survive. Rates for those in the age groups younger than 45 and 85 years orolder had lower survival rates by three to seven percentage points. Survival rates for localized disease decline in the eighth year post-diagnosis to 84 percent. Women younger than 35 yearshad the lowest 8-year survival rate.[75] Bonnier et al. reported on 1,266 patients treated for breast cancer. The three groups were: <35(Group A), premenopausal >35 (Group B), postmenopausal <70 (Group C). Metastasis-freesurvival and overall survival were significantly poorer for the <35 group. Group A also hadhigher risk of local recurrence.[76] For the premenopausal patients, long-duration chemotherapy significantly increased bothdisease-free survival and overall survival compared with the short-duration treatment. For thepostmenopausal patients, while differences in terms of disease-free survival were highlysignificant, those in terms of overall survival appeared late during follow-up and were notstatistically significant.[77] Younger patients displayed better survival than older patients. However, patients under 45demonstrated good survival for about 25 to 26 months, after which survival began to decline,eventually becoming similar to patients over 55.[25] Age has also been associated with cancer characteristics that can ultimately increase survivalrates. In developing a series of Markov-chain models to estimate tumor progression rates andsensitivity, Duffy et al. determined that tumor progression to the clinical phase, and with respectto node status and tumor size, is faster in the age group 40-49 than in older age groups.[78]Callies et al. found that younger patients with a tumor size of T1 and T2 had a significantlybetter prognosis than older patients with the same tumor stage. Influence of age becamesignificantly weaker in patients with a T3 or T4 tumor. In patients with a primarily M1 stage,very little dependence on age was shown.[79] In seven additional studies, age was found to be a prognostic indicator for survival [59, 73, 80-84]. Eight additional studies did not find age to be a significant indicator (three of which are partof the same study series on different types of patients) [43-45, 85-89].
7.2 Axillary lymph node involvement
The number of axillary lymph nodes involved has frequently been found to be a significant
prognostic indicator. In an analysis by Wheeler et al., there was a significant difference in
disease-free survival rate in patients presenting with node-negative disease compared with those
presenting with node-positive disease (p < 0.0001). Multivariate analysis showed that nodal
stage was the most important single prognostic indicator. Patients with node-negative disease at
diagnosis had a five-year disease-free survival rate of approximately 82 percent (95% CI 78-86)
compared with a 64 percent (95% CI 55-73) for node-positive patients.[11]
In patients having unilateral invasive ductal breast cancer in stages I-III, positive node status wasfound to significantly increase the risk of developing local-regional recurrence, distantrecurrence, or death.[84] In 903 stage I and II cancer patients, nodal status had a strong affect onsurvival and distant relapse, and a lesser, but significant, affect on local relapse.[90] Buzdar etal. found nodal status to be a significant predictor for disease-free survival, but not for overallsurvival.[85] Markiewicz et al. found that for node-positive patients, outcome at five and 10 years,respectively, were 86 percent and 70 percent for overall survival, 78 percent and 67 percent fordisease-free survival, and 82 percent and 69 percent for freedom from distant metastases. Fornode-negative patients, outcomes at five years were 94 percent for overall survival, 94 percentfor disease-free survival, 94 percent for freedom from distant metastases.[91] An additional 15 studies associated nodal status with disease-free or overall survival [8, 35, 45,56, 67, 69, 73, 76, 86, 87, 92-96]. Three studies [44, 81, 97] did not associate lymph nodeinvolvement with survival. Two additional studies [94, 97] connected the number of lymphnodes examined to survival.
7.3 Estrogen/progesterone receptors
There have been mixed results in efforts to determine if estrogen and progesterone receptor (ER
and PR, respectively) status have an effect on survival. Quiet et al. determined that patients with
a negative or borderline ER status had a statistically improved DFS period (p = 0.008) compared
to those with positive ER status. DFS was worse in premenopausal patients with ER-positive
tumors as compared to ER-negative tumors. In postmenopausal patients, ER status was not a
predictor of long-term survival.[38] In a study of 1,266 patients treated for breast cancer,
multivariate analysis revealed that ER status was a significant predictor of survival. PR status
was not correlated with survival.[76] In 3,585 patients entered into a study on adjuvant
therapies, up through year five, ER-negative patients had a higher hazard of recurrence. Beyond
year five, the hazard rate was higher for ER-positive patients (p = 0.0002).[67]
In five other studies [73, 87, 93, 94, 97], ER status was a predictor of survival, but in eightstudies [9, 43, 45, 81, 85, 86, 88, 92] the factor was not associated with survival. Forprogesterone receptor status, four studies [45, 56, 73, 87] found the factor to be significant andfour [9, 43, 88, 92] did not.
7.4 Tumor size
Tumor size is one of the prognostic indicators most consistently associated with survival. Of the
25 studies reviewed, which tested the impact of tumor size, only one did not report it to be a
predictor of recurrence or death. Quiet et al. found that tumor size was the strongest predictor of
outcome in node-negative breast cancer. For tumors less than 20 mm, the 20-year DFS rate was
79 percent, as compared to 64 percent for patients with tumors over 20 mm (p < 0.001). The
median time to recurrence was 48 months for tumors less than one centimeter, 44 months for
tumors between 2.1 and 3.0 cm, and 37 months for tumors between 4.1 and 5.0 cm. Patients
with smaller tumors developed metastatic disease later than patients with larger tumors.[38] In a
group of 407 axillary node negative breast cancer patients having received surgery alone, large
tumor size (p = 0.0006) was the most significant predictor of outcome.[9]
In a report on treatment results of 508 patients with stage I and II invasive breast cancer, patientswith T2 tumors had a shorter survival than those with T1 tumors (p < 0.001).[10] In 24,740breast cancer patients, actuarial five-year relative survival rates varied from 45.5 percent fortumor diameters equal to or greater than five centimeters with positive axillary nodes to 96.3percent for tumors less than two centimeters and with no involved nodes.[98] Perrone et al.
found that tumor size was closely associated with the number of metastatic nodes andsignificantly and independently affected DFS and OS in a univariate analysis. P values for thestratified analyses were all less than 0.0001.[99] Nineteen other studies indicated that tumor size was a predictor of survival [8, 43-45, 59, 67, 69,73, 76, 87, 90, 92, 94-97, 100-102].
The one study reviewed that did not associate tumor size with survival[86], was a retrospectiveanalysis on 966 patients who had tumors under the size of five centimeters. The study wasdesigned to determine the clinical significance of local recurrence after simple mastectomy andnode biopsy for primary operable breast cancer without postoperative irradiation or systemicadjuvant therapy.
7.5 Histopathologic grade
The histopathologic grade or differentiation of the tumor indicates the extent to which a tumor
resembles the normal tissue at the cancer site. Joensuu, Pylkkanen, and Toikkanen conducted a
study on 265 node negative patients with tumor size less than or equal to two centimeters and
treated with mastectomy and axillary lymph node dissection without adjuvant therapy. At 20-
years, no patients with a well-differentiated pT1a-b tumor died during follow-up, but the survival
rate after correction for intercurrent death was 81 percent in patients with Grade 2-3, pT1a-b
tumors or pT1c tumors.[101]
Under both univariate and multivariate analysis, grade was a significant prognostic factorassociated with disease-free survival in the study by Vujovic et al.[59] In a study on patientshaving unilateral invasive ductal breast cancer in stages I-III, high grade was found tosignificantly increase the risk of developing local-regional recurrence, distant recurrence, ordeath.[84] In six additional studies, histopathologic grade was associated with survival [9, 43, 45, 69, 73,76, 86]. Three studies did not support the association.[56, 87, 92].
7.6 Stage of disease
Stage has frequently been found to significantly affect survival. In a study by Neale, Tilley, and
Vernon, survival curves indicated that stage at diagnosis may be the most important variable in
predicting survival. Within the first year, women with metastatic disease evidenced greater
mortality than those diagnosed in-situ. After 10 years, about 60 percent of women with localized
disease were still living, about 30 percent with regional disease remained alive, and virtually all
of the metastatic cases had died.[31] In patients having unilateral invasive ductal breast cancer
in stages I-III, Broet et al. found that high clinical stage significantly increased the risk of
developing local-regional recurrence, distant recurrence, or death.[84]
Except for Stage IV disease, the survival rates for each individual stage in a study by Henson,Ries, and Carriaga were similar regardless of the number of years lived after diagnosis. At thetime of diagnosis, however, patients with Stage I-III cancers had a 93 to 100 percent probabilityof surviving the first year, while Stage IV patients only had a 64 percent probability of survivalin the first year.[72] In a study by Byrne et al., breast cancer survival among women with in situ breast cancer was 98.6 percent at five years. Patients with invasive disease had a rate of 81.4percent. Women with Stage III cancer had the poorest survival rate at 51.4 percent.[69] In six other studies [11, 25, 82, 93, 103-105], stage was significantly associated with survival.
Two studies [81, 85] did not find a relationship between stage and outcome.
7.7 Margins of resection
Of five studies reviewed, four found the margin of resection to be a prognostic indicator for
survival. Hartsell et al. determined that local recurrence was more common in patients with
widely negative margins of excision. In a multiple regression analysis, margin of excision
(negative vs. close/unknown/positive) was the only factor that predicted local recurrence (p =
0.04).[55] In a report on treatment results of 508 patients with stage I and II invasive breast
cancer, patients with close and positive pathological margins had a significantly higher risk of
breast recurrence, 8.3 percent and 9.7 percent, respectively, compared to 2.6 percent for patients
with negative margins.[10] Vujovic et al.[59] and Fortin et al.[66] also found the resection
margin to be associated with survival, but Buchholz et al. did not[56].
7.8 Adjuvant chemotherapy
Studies on chemotherapy, radiation therapy, and, more recently, tamoxifen have been carried out
to determine the affect of these treatments on recurrence and death.
Haffty et al. conducted a study on 548 patients to determine the impact of adjuvant systemicchemotherapy and adjuvant hormonal therapy on local relapse in the conservatively treatedbreast cancer. Patients who underwent conservative surgery, axillary dissection, and radiationtherapy to the intact breast were likely, at least in the short term, to have a lower breast relapserate if they received adjuvant systemic chemotherapy.[81] In a study by Gelber, Cole, and Goldhirsch, on premenopausal patients, the long-durationchemotherapy significantly increased both disease-free survival and overall survival comparedwith the short-duration treatment. For postmenopausal patients, while differences in terms ofdisease-free survival were highly significant, differences in overall survival appeared late duringfollow-up and were not statistically significant.[77] In a study of 1,124 positive-node breastcancer patients aged > 50 years, Fisher et al. determined that patients had a better disease-freesurvival rate at three years with prolonged tamoxifen use and short-course chemotherapy(Adriamycin and cyclophosphamide) than from prolonged tamoxifen therapy alone (84 percentvs. 67 percent; p = 0.0004).[106] Five other studies [72, 107-110] showed a relationship between adjuvant chemotherapy andimproved recurrence and survival rates.
Bonnier et al. did not find a significant association between adjuvant chemotherapy andsurvival[76], and Broet et al. reported that for patients having unilateral invasive ductal breastcancer in stages I-III who received chemotherapy, the rate of metastases or death was increased(RR = 1.22).[84] 7.9 Adjuvant radiation therapy
Diab et al. found that among 618 breast cancer patients with 10 or more positive axillary lymph
nodes, radiation therapy to the loco-regional area lowered failure rates and improved overall
survival. The adjusted 5-year loco-regional failure rate was 13 percent with radiation and 38
percent without radiation (p = 0.0001). The adjusted five-year distant failure rate was 48 percent
with radiation and 58 percent without radiation (p = 0.02). The adjusted five-year overall
survival rate was 56 percent with radiation and 42 percent without radiation (p = 0.001).[111]
In a study on 1,708 premenopausal patients who had undergone mastectomy for stage II or IIcancer, the group who received chemotherapy plus irradiation had reduced local/regionalrecurrence and longer survival in comparison to the group that received chemotherapyalone.[112] Boyages et al. conducted a meta-analysis of published studies to identify the factors that may bepredictive of local recurrence after management of ductal carcinoma in situ by mastectomy,conservative surgery (CS), or conservative surgery plus radiation therapy (RT). The analysisyielded a summary recurrence rate of 22.5 percent (95% CI = 16.9-28.2) for studies using CSalone, 8.9 percent (6.8-11.0) for CS plus RT, and 1.4 percent (0.7-2.1) for studies involvingmastectomy alone. Local recurrence among patients treated by CS alone was approximately 20percent, and one-half of the recurrences were invasive cancers. For most patients, RT reducedthe risk of recurrence after CS alone by at least 50 percent.[113] Three additional studies [80, 114, 115] also showed that adjuvant radiation therapy reducedrecurrence and death rates.
7.10 Tamoxifen
Muss[116] conducted a meta-analysis of randomized trials to determine if tamoxifen improves
relapse-free and overall survival for postmenopausal women, including those older than age 70
years. Tamoxifen therapy was shown to significantly decrease the annual odds of recurrence (28
percent) and death (21 percent) in women over 70. The reduction was seen in both estrogen-
receptor positive (36 percent decrease) and estrogen-receptor negative (16 percent decrease)
patients. Over two years of tamoxifen therapy was also associated with greater benefit. Horobin
et al. found that 113 patients aged 70 and older treated with tamoxifen alone had an actuarial
five-year survival rate of 49.4 percent. Of the 38 women who had a complete response, the rate
was 92 percent.[117]
In a study on patients diagnosed in 1974 and 1984, tamoxifen was recommended in the 1984group for postmenopausal women with involved lymph nodes or lymphatic, vascular, or neuralinvasion unless their tumors were negative for estrogen receptors. The seven-year disease-specific survival for women from 50 to 89 years in 1984 (n = 977) was 70.4 percent compared to63.2 percent in the 1974 group (n = 711). The actuarial overall survival seven years afterdiagnosis for the 50 to 89 group diagnosed in 1984 (n = 986) was 58.3 percent compared to 56percent for the 1974 group (n = 717).[110] In comparing chemotherapy alone and chemotherapy plus tamoxifen, Taylor et al. found thatdisease-free survival favored chemotherapy plus tamoxifen, but overall survival rates did not differ.[97] Fisher and Redmond, in a study on 2,844 estrogen receptor positive patients,compared postoperative tamoxifen for five years to placebo. The tamoxifen group had asignificant improvement in disease-free survival (82 percent vs. 72 percent at five years; p <0.000005) regardless of age, surgery type, tumor size, ER status, or PR status. There was nosignificant difference in overall survival.[118] The Scottish Cancer Trials Breast Group foundthat adjuvant tamoxifen given for a minimum of five disease-free years had a beneficial effectoverall and in both premenopausal and postmenopausal node-negative patients.[119] Comparisons of two vs. five years of tamoxifen therapy have shown that the longer treatmentinterval increases time to relapse, but treatment over five years does not appear to make adifference. In a comparison of two years versus five years of tamoxifen treatment in women 50years and older, patients who received the longer treatment demonstrated a statisticallysignificant delay in the time to relapse.[120] After five years of tamoxifen treatment, a group of194 patients was randomized to continue tamoxifen or be in an observation group. At five yearsafter randomization no statistically significant differences were noted in either time to relapse orsurvival between the two groups.[121] 7.11 Miscellaneous
Numerous prognostic indicators for breast cancer have been studied. Table 13 lists other
predictors that were encountered during this review, as well as citations of the articles which
found the indicators significant or non-significant in relation to disease-free or overall survival.
Table 13. Miscellaneous prognostic factors studied for effect on breast cancer survival
Absence of axillary lymph node dissection Low levels of serum albumin and hemoglobin Table 13. Miscellaneous prognostic factors studied for effect on breast cancer survival

8. Conclusion
There has been little effort to develop standards to recommend the appropriate timing of surgical
treatment for patients with breast cancer. This is despite the fact that longer delays between the
onset of symptoms and diagnosis or treatment are associated with worse survival rates, except
for those with stage I disease. Patients with a longer duration of symptoms tend to present with
larger tumors and with a more advanced stage of disease. In addition, the presence of symptoms
other than a lump has been shown to be associated with poorer survival in breast cancer patients.
Although studies differ in their conclusions regarding the impact of delay in treatment for breastcancer, there is no doubt that the time between diagnosis and treatment of breast cancer can bevery stressful for women. Insomnia, mood disturbances, depression, and tension have beenidentified as primary problems facing preoperative breast cancer patients. Tension anddepression appear to be reduced once surgery has taken place; therefore, every effort should betaken to ensure a short waiting period for surgical treatment.
Stage of disease and tumor size are primary predictors of disease-free and overall survival inbreast cancer patients, further indicating the need for prompt diagnosis and surgical treatment.
Other significant prognostic indicators include age, axillary lymph node involvement,histopathologic grade, margins of resection, the type of adjuvant therapy used, among manyothers. Some of the more promising indicators of survival that are beginning to be examinedinvolve genetic factors.
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