Attending the breast screening programme after breast cancer treatment: a population-based study.

INTRODUCTION: In the Netherlands, breast cancer patients are treated and followed at least 5 years after diagnosis. Furthermore, all women aged 50-74 are invited biennially for mammography by the nationwide screening programme. The relation between the outpatient follow-up (follow-up visits in the outpatient clinic for 5 years after treatment) and the screening programme is not well established and attending the screening programme as well as outpatient follow-up is considered undesirable. This study evaluates potential factors influencing women to attend the screening programme during their outpatient follow-up (overlap) and the (re-)attendance to the screening programme after 5 years of outpatient follow-up. METHODS: Data of breast cancer patients aged 50-74 years, treated for primary breast cancer between 1996 and 2007 were selected from the Netherlands Cancer Registry and linked to the National Breast Cancer Screening Programme in the Northern region. Cox regression analyses were used to study women (re-)attending the screening programme over time, possible overlap with the outpatient follow-up and factors influencing this. RESULTS: In total 11227 breast cancer patients were included, of whom 19% attended the screening programme after breast cancer treatment, 4.4% within 5 years and 15.4% after more than 5 years. Factors that independently influenced attendance within 5 years as well as more than 5 years after treatment were: interval tumours (HR 0.77; 95%CI 0.61-0.97 and HR 0.69; 95%CI 0.53-0.88, ref: screen-detected tumours), receiving adjuvant radiotherapy (HR 0.65; 95%CI 0.47-0.90 and HR 0.66; 95%CI 0.47-0.93; ref: none) and diagnosis of in situ tumours (HR 1.67; 95%CI 1.25-2.23 and HR 1.39; 95%CI 1.05-1.85; ref: stage I tumours). Non-screen related tumours (HR 0.41; 95%CI 0.29-0.58) and recent diagnosis (HR 0.89 per year; 95%CI 0.86-0.92) were only associated with attendance within 5 years after treatment. CONCLUSION: The interrelation between outpatient follow-up and screening should be improved to avoid overlap and low attendance to the screening programme after outpatient follow-up. Breast cancer patients should be informed that attending the screening programme during the outpatient follow-up is not necessary.

Do screen-detected breast cancers have positive margins less often than clinically detected breast cancers?

Positive tumour margins after breast-conserving surgery (BCS) have been selected as one of the major quality criteria for the surgical treatment of localized primary breast cancer. The national guideline states that the rate of positive margins should not exceed 30% in ductal carcinoma in situ and 20% in invasive cancers. We aimed to determine whether BCS in women with screen-detected breast cancer (SDBC) will have positive margins less often compared with women with clinically detected breast cancer (CDBC). Furthermore, the choice of subsequent therapy is studied when margins were positive after initial BCS. Women 50-75 years of age who underwent BCS for invasive breast cancer between July 2008 and December 2009 were selected from the Netherlands Cancer Registry. Data were merged with the National Cancer Screening Program, regions North and East, to identify women with SDBC. The relation to screening history, clinical and pathological factors was evaluated for correlation with margin status using multilevel analysis. Of 1537 women with an invasive breast cancer, 873 (57%) were diagnosed through the screening programme. SDBCs were significantly smaller (87 vs. 69% T1 tumours, i.e. ≤2 cm), more often well differentiated (33 vs. 26%), preoperatively confirmed (98 vs. 96%), diagnosed in a nonteaching hospital (60 vs. 66%) and more often had negative lymph nodes (LNs) (80 vs. 68%). In 170 out of 1537 women, the resection margins were positive. Multivariable analysis showed that hospital, tumour size, multifocality, positive LNs and absent preoperative confirmation were predictors of positive margins. No difference was found between women with SDBC and CDBC. Of women with positive margins, 90% underwent additional surgery. Women diagnosed with SDBC do not have a lower risk of having positive margins after BCS than women with CDBC. Although positive margins may occur in 11% of women with invasive tumours, well below the percentage recommended by the national guideline, the presence of encouraging factors by SDBC such as a smaller tumour size, unifocality, negative LNs and the presence of preoperative confirmation should not lead to performing a more sparing excision than is considered usual for comparable CDBC.

Early-stage young breast cancer patients: impact of local treatment on survival.

PURPOSE: In young women, breast-conserving therapy (BCT), i.e., lumpectomy followed by radiotherapy, has been associated with an increased risk of local recurrence. Still, there is insufficient evidence that BCT impairs survival. The aim of our study was to compare the effect of BCT with mastectomy on overall survival (OS) in young women with early-stage breast cancer. METHODS AND MATERIALS: From two Dutch regional population-based cancer registries (covering 6.2 million inhabitants) 1,453 women <40 years with pathologically T1N0-1M0 breast cancer were selected. Cox regression survival analysis was used to study the effect of local treatment (BCT vs. mastectomy) stratified for nodal stage on survival and corrected for tumor size, age, period of diagnosis, and use of adjuvant systemic therapy. RESULTS: With a median follow-up of 9.6 years, 10-year OS was 83% after BCT and 78% after mastectomy, respectively (unadjusted hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.09-1.72). In N0-patients, 10-year OS was 84% after BCT and 81% after mastectomy and local treatment was not associated with differences in OS (HR 1.19; 95% CI, 0.89-1.58; p = 0.25). Within the N1-patient group, OS was better after BCT compared with mastectomy, 79% vs. 71% at 10 years (HR 1.91; 95% CI, 1.28-2.84; p = 0.001) and in patients treated with adjuvant hormonal therapy (HR 0.34; 95% CI, 0.18-0.66; p = 0.001). CONCLUSIONS: In this large population-based cohort of early-stage young breast cancer patients, 10-year OS was not impaired after BCT compared with mastectomy. Patients with 1 to 3 positive lymph nodes had better prognosis after BCT than after mastectomy.

Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial.

The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53-SLP) vaccine, twenty patients with recurrent elevation of CA-125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53-SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no > or = grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN-gamma producing p53-specific T-cell responses were induced in all patients who received all 4 immunizations as measured by IFN-gamma ELISPOT. An IFN-gamma secretion assay showed that vaccine-induced p53-specific T-cells were CD4(+), produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53-specific response. P53-specific T-cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53-specific T-cells. As best clinical response, stable disease evaluated by CA-125 levels and CT-scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine-induced immunity. This study shows that the p53-SLP vaccine is safe, well tolerated and induces p53-specific T-cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper-1 polarization and clinical efficacy.

Effect of tamoxifen on the endometrium and the menstrual cycle of premenopausal breast cancer patients.

OBJECTIVE: Tamoxifen, a nonsteroidal antiestrogen, is the agent of choice in the treatment of premenopausal receptor-positive breast cancer. This study aimed to investigate the influence of tamoxifen on the menstrual cycle and serum hormone levels and the subsequent endometrial response in premenopausal breast cancer patients. METHODS: In tamoxifen-using breast cancer patients aged 55 years or younger, the last menstrual period was registered, serum hormone levels measured, and the endometrial response visualized by transvaginal ultrasonography every 6 months. Premenopausal status was defined as serum levels of estradiol (E2) 0.10 nmol/L or more and follicle-stimulating hormone 30 IU/L or less. Premenopausal patients with an endometrial response of greater than 12 mm were offered a hysteroscopy and curettage. RESULTS: In 121 patients, a total of 241 measurements were performed. Amenorrhea predicted menopausal status incorrectly in 85 (35%) of the 241 measurements in 47 patients. In 8 of 47 endocrinologic premenopausal patients, transvaginal ultrasonography showed an endometrial response of greater than 12 mm (range,15-29 mm). Histopathology in women with an endometrial thickness of greater than 12 mm showed no malignancy. No relation between E2 levels and endometrial thickness was found. CONCLUSIONS: Tamoxifen leads to a disconnection between clinical and endocrinologic menopause in breast cancer patients aged 55 years or less. In premenopausal patients, tamoxifen has a predominantly antiestrogenic effect on the endometrium without a correlation between E2 levels and endometrial response.

Sexual function in patients with metastatic midgut carcinoid tumours.

BACKGROUND: Sexual dysfunction is a poorly studied aspect of quality of life in patients with midgut carcinoid tumours. We investigated whether carcinoid patients experience sexual problems. METHODS: Patients with metastatic midgut carcinoid tumours filled in a validated questionnaire for sexual dysfunction. The prevalence of dysfunction on the subscales arousal, erection, lubrication, orgasm and dyspareunia was compared to a Dutch reference population. Plasma concentration of gonadal hormones, tryptophan and urinary 5-hydroxyindolacetic acid concentrations were measured. RESULTS: 43 patients were studied, 27 men and 16 women. Sexual dysfunction was present in 29.6% of men and 6.3% of women. The prevalence of sexual dysfunction on the different subscales did not differ from the reference population. Patients with a sexual dysfunction had, compared to those without a sexual dysfunction, a longer duration of disease, 95.3 months (range 5.4-314.5) versus 18.6 months (range 0.6-167.9) (p = 0.024), lower plasma tryptophan concentration (+/-SD) of 31.5 +/- 16.1 and 48.9 +/- 14.5 micromol/l (p = 0.031), and more often used interferon-alpha, 50% of patients versus 10.5% of patients (p = 0.044). CONCLUSION: Patients with metastatic midgut carcinoid tumours do not experience sexual problems more often than a reference population. Male patients with sexual dysfunction are characterised by more long-standing disease and lower tryptophan concentration.

Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind, randomized cross-over study.

PURPOSE: Breast cancer patients with treatment-induced menopause experience frequent and severe hot flashes (HF). We compared venlafaxine and clonidine for the treatment of HF with regard to side effects, efficacy, quality of life and sexual functioning. METHODS: In a double-blind, cross-over study, 60 breast cancer patients experiencing HF were randomized to 8 weeks venlafaxine followed by 2 weeks wash-out, and 8 weeks clonidine or vice versa. HF frequency and severity, side effects, quality of life and sexuality were assessed. RESULTS: Thirty patients started with venlafaxine and 30 with clonidine. Premature discontinuation for toxicity occurred in 14/59 during venlafaxine and 5/53 during clonidine (P = .038). Venlafaxine induced more side effects. Median reduction in HF score was 49% for venlafaxine and 55% for clonidine (ns). CONCLUSION: Venlafaxine and clonidine are equally, but moderately effective in HF reduction. Side effects are the main reason for drug discontinuation, occurring more often with venlafaxine.

The influence of endocrine treatments for breast cancer on health-related quality of life.

UNLABELLED: Many hormonal modalities are available for breast cancer treatment, such as selective oestrogen receptor modulators (SERMs), aromatase inhibitors, progestins and luteinising hormone-releasing hormone (LHRH) agonists. The long-term impact of these endocrine manipulations is an issue, because the duration of adjuvant treatment is still increasing, as is the number of breast cancer survivors. Premature menopause is induced at a young age, and may often be permanent after chemotherapy. The purpose of this review is to provide a literature-based overview of the side effects of endocrine treatment in pre- and postmenopausal breast cancer patients and the influence on HRQoL, especially on sexual functioning. The collection of health-related quality of life (HRQoL) data can result in better treatment recommendations during endocrine therapy. METHODS: This review was limited to prospective randomised studies in English literature from between 1977 and 2007 and provides an overview of the effects on HRQoL and sexuality of various hormonal treatment in pre- and postmenopausal breast cancer patients, both in the adjuvant and palliative setting. Relevant clinical studies were identified by using the Medline database. RESULTS: HRQoL mostly is severely influenced by chemotherapy and part of these symptoms may be lasting, especially when associated with the induction of premature menopause. Similar symptoms may be encountered during ovarian suppression therapy by LHRH analogs, but they will usually prove to be reversible. The varying side effect profiles of tamoxifen and aromatase inhibitors did not lead to significant difference in overall HRQoL. HRQoL during progestins and the SERM fulvestrant has been compared to this during aromatase inhibitors, and a large number of studies on HRQoL during endocrine therapy will be discussed.

Risk of new primary nonbreast cancers after breast cancer treatment: a Dutch population-based study.

PURPOSE: To assess the risk of secondary nonbreast cancers (SNBCs) in a recently treated population-based cohort of breast cancer patients focused on the association with treatment and prognostic implications. PATIENTS AND METHODS: In 58,068 Dutch patients diagnosed with invasive breast cancer between 1989 and 2003, SNBC risk was quantified using standardized incidence ratios (SIRs), cumulative incidence, and Cox regression analysis, adjusted for competing risks. RESULTS: After a median follow-up of 5.4 years, 2,578 SNBCs had occurred. Compared with the Dutch female population at large, in this cohort, the SIR of SNBCs was increased (SIR, 1.22; 95% CI, 1.17 to 1.27). The absolute excess risk was 13.6 (95% CI, 9.7 to 17.6) per 10,000 person-years. SIRs were elevated for cancers of the esophagus, stomach, colon, rectum, lung, uterus, ovary, kidney, and bladder cancers, and for soft tissue sarcomas (STS), melanoma, non-Hodgkin's lymphoma, and acute myeloid leukemia (AML). The 10-year cumulative incidence of SNBCs was 5.4% (95% CI, 5.1% to 5.7%). Among patients younger than 50 years, radiotherapy was associated with an increased lung cancer risk (hazard ratio [HR] = 2.31; 95% CI, 1.15 to 4.60) and chemotherapy with decreased risk for all SNBCs (HR = 0.78; 95% CI, 0.63 to 0.98) and for colon and lung cancer. Among patients age 50 years and older, radiotherapy was associated with raised STS risk (HR = 3.43; 95% CI, 1.46 to 8.04); chemotherapy with increased risks of melanoma, uterine cancer, and AML; and hormonal therapy with all SNBCs combined (HR = 1.10; 95% CI, 1.01 to 1.21) and uterine cancer (HR = 1.78; 95% CI, 1.40 to 2.27). An SNBC worsened survival (HR = 3.98; 95%CI 3.77 to 4.20). CONCLUSION: Breast cancer patients diagnosed in the 1990 s experienced a small but significant excess risk of developing an SNBC.

The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: a population based study in the Netherlands.

BACKGROUND: The impact of age and adjuvant therapy on contralateral breast cancer (CBC) risk and prognostic significance of CBC were evaluated. PATIENTS AND METHODS: In 45,229 surgically treated stage I-IIIA patients diagnosed in the Netherlands between 1989 and 2002 CBC risk was quantified using standardised incidence ratios (SIRs), cumulative incidence and Cox regression analysis, adjusted for competing risks. RESULTS: Median follow-up was 5.8 years, in which 624 CBC occurred <6 months after the index cancer (synchronous) and 1,477 thereafter (metachronous). Older age and lobular histology were associated with increased synchronous CBC risk. Standardised incidence ratio (SIR) of CBC was 2.5 (95% confidence interval (95% CI) 2.4-2.7). The SIR of metachronous CBC decreased with index cancer age, from 11.4 (95% CI 8.6-14.8) when <35 to 1.5 (95% CI 1.4-1.7) for > or =60 years. The absolute excess risk of metachronous CBC was 26.8/10,000 person-years. The cumulative incidence increased with 0.4% per year, reaching 5.9% after 15 years. Adjuvant hormonal (Hazard rate ratio (HR) 0.58; 95% CI 0.48-0.69) and chemotherapy (HR 0.73; 95% CI 0.60-0.90) were associated with a markedly decreased CBC risk. A metachronous CBC worsened survival (HR 1.44; 95% CI 1.33-1.56). CONCLUSION: Young breast cancer patients experience high synchronous and metachronous CBC risk. Adjuvant hormonal or chemotherapy considerably reduced the risk of CBC. CBC occurrence adversely affects prognosis, emphasizing the necessity of long-term surveillance directed at early CBC-detection.

Distinguishing benign and malignant pelvic masses: the value of different diagnostic methods in everyday clinical practice.

OBJECTIVE: To optimize referral to specialized gynaecologists for surgical treatment of ovarian cancer by improving preoperative discrimination between benign and malignant pelvic tumours. STUDY DESIGN: In a prospective multicentre study 143 patients with a pelvic mass were included. At several occasions during the diagnostic work-up the gynaecologist estimated the chance of malignancy (educated guess/expert opinion). MRI in the local setting was suggested for uncertain cases. All MRI images were reviewed by an expert radiologist. The datasheet designed for the study further allowed for determining the risk of malignancy index (RMI). RESULTS: The diagnostic accuracy of the gynaecologist's final estimation of the chance of malignancy and the calculated RMI were comparable (area under the ROC curve of 0.87 and 0.86). MRI did not improve the accuracy of the diagnostic work-up for the study population as a whole. Subgroup analysis did however show improved diagnostic accuracy in cases with an estimated chance of malignancy between 20 and 80% when the MRI was read by an expert radiologist. CONCLUSION: Patient selection for surgery of a pelvic mass should be based on the chance of malignancy as assigned by the referring gynaecologists. In case of uncertainty MRI improves diagnostic accuracy, when judged by an expert.

Prospective study of long-term impact of adjuvant high-dose and conventional-dose chemotherapy on health-related quality of life.

PURPOSE: To evaluate and compare health-related quality of life (HRQOL) after conventional- and high-dose adjuvant chemotherapy in patients with high-risk breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to either a conventional or high-dose chemotherapy regimen; both regimens were followed by radiotherapy and tamoxifen. HRQOL was evaluated until disease progression using the Short Form-36 (SF-36), Visual Analog Scale, and Rotterdam Symptom Checklist and assessed every 6 months for 5 years after random assignment. For the SF-36, data from healthy Dutch women with the same age distribution served as reference values. RESULTS: Eight hundred four patients (conventional-dose chemotherapy, n = 405; high-dose chemotherapy, n = 399) were included. Median follow-up time was 57 months. Directly after high-dose chemotherapy, HRQOL decreased more compared with conventional chemotherapy for all SF-36 subscales. After 1 year, the reference value of healthy women was reached in both groups. Small differences were observed between the two groups in the role-physical and role-emotional subscales, but 1 year after treatment, these differences were minor and not clinically relevant. During follow-up, patients with a lower educational level and many complaints before chemotherapy experienced a worse HRQOL. CONCLUSION: Shortly after high-dose chemotherapy, HRQOL was more affected than after conventional-dose chemotherapy. One year after random assignment, differences were negligible. Identifying patients who have a higher chance of persistent impaired quality of life after treatment (which, in the present study, included patients with a lower educational level and many complaints before chemotherapy) is important and may open the way for better patient-tailored prevention strategies.

Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours.

Survival of patients with disseminated midgut carcinoid tumours varies. We investigated which factors predict survival at referral and during follow-up, with emphasis on urinary 5-hydroxyindolacetic acid (5-HIAA) levels. Between 1992 and 2003, 76 patients were studied; urine was prospectively collected over a 24 h period every 3 months in order to measure 5-HIAA levels. Uni- and multivariate analyses were performed. Median follow-up was 55 months with a median survival of 54 months. Prognostic factors for poor survival were high age, high gamma-glutamyltransferase levels and greatly increased 5-HIAA levels (>20 mmol/mol creatinine) The Hazard Ratio (HR) of a greatly increased 5-HIAA level was 3.33 (95% confidence interval (CI) 1.66-6.66, p=0.001). In a multivariate survival analysis with the 5-HIAA level as time dependent covariable, the HR for the 5-HIAA level was 1.007 (95% CI 1.004-1.010, p=0.000). In conclusion, patients with persistent moderately increased urinary 5-HIAA levels (< or =20 mmol/mol creatinine) have favourable outcome.

Gynecologic examination and cervical biopsies after (chemo) radiation for cervical cancer to identify patients eligible for salvage surgery.

PURPOSE: The aim of this study was to evaluate efficacy of gynecologic examination under general anesthesia with cervical biopsies after (chemo) radiation for cervical cancer to identify patients with residual disease who may benefit from salvage surgery. METHODS AND MATERIALS: In a retrospective cohort study data of all cervical cancer patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IB1 to IVA treated with (chemo) radiation between 1994 and 2001 were analyzed. Patients underwent gynecologic examination under anesthesia 8 to 10 weeks after completion of treatment. Cervical biopsy samples were taken from patients judged to be operable. In case of residual cancer, salvage surgery was performed. RESULTS: Between 1994 and 2001, 169 consecutive cervical cancer patients received primary (chemo) radiation, of whom 4 were lost to follow-up. Median age was 56 years (interquartile range [IQR], 44-71) and median follow-up was 3.5 years (IQR, 1.5-5.9). In each of 111 patients a biopsy sample was taken, of which 90 (81%) showed no residual tumor. Vital tumor cells were found in 21 of 111 patients (19%). Salvage surgery was performed in 13 of 21 (62%) patients; of these patients, 5 (38%) achieved long-term, complete remission after salvage surgery (median follow-up, 5.2 years; range, 3.9-8.8 years). All patients with residual disease who did not undergo operation (8/21) died of progressive disease. Locoregional control was more often obtained in patients who underwent operation (7 of 13) than in patients who were not selected for salvage surgery (0 of 8 patients) (p < 0.05). CONCLUSIONS: Gynecologic examination under anesthesia 8 to 10 weeks after (chemo) radiation with cervical biopsies allows identification of those cervical cancer patients who have residual local disease, of whom a small but significant proportion may be salvaged by surgery.

Quality of life versus prolongation of life in patients treated with chemotherapy in advanced colorectal cancer: A review of randomized controlled clinical trials.

Oncologists disagree if chemotherapy in advanced cancer can improve quality of life (QoL), to prolong duration of life, or both. The objective of this study was to clarify the main treatment intention of palliative chemotherapy (PCT): the prolongation of life (PoL); or QoL. Randomized controlled clinical trials of PCT in advanced colorectal cancer that included HRQoL assessment were selected from PubMed and reviewed. Authors' conclusions were based on both PoL- and QoL-related outcomes. However, if PoL and QoL outcomes of the experimental arm were opposite, which was the case in 13 out of 28 trials, the authors generally based their conclusion on PoL outcomes. Authors' conclusions focused mainly on PoL-related outcomes, while QoL-related outcomes were of overriding importance in only 1/28 case. QoL can therefore not be considered as the main outcome of PCT. The review shows that in the context of chemotherapy in advanced colorectal cancer, 'palliative' refers to a life-prolonging intention, whereas within palliative care it refers to an improvement in QoL.

The prognostic effect of the number of histologically examined axillary lymph nodes in breast cancer: stage migration or age association?

BACKGROUND: The number of pathologically examined axillary nodes has been associated with breast cancer survival, and examination of >or=10 nodes has been advocated for reliable axillary staging. The considerable variation observed in axillary staging prompted this population-based study, which evaluated the prognostic effect of a variable number of pathologically examined nodes. METHODS: In total, 5314 consecutive breast cancer patients who underwent mastectomy or breast-conserving surgery and axillary dissection between 1994 and 1999 were included. The prognostic effect of the examined number of nodes was assessed with crude and relative survival analysis. RESULTS: A median number of 12 (range, 1-43) nodes were histologically examined, and 59% of the patients had no nodal tumor involvement. The number of examined nodes decreased with age (P<.001) and increased with tumor size (P<.001). Stratified for the number of tumor-positive nodes, overall survival seemed to be worse for patients with <10 compared with patients with >or=10 examined nodes (P<.001), whereas the relative survival did not differ. After adjusting for age, tumor size, number of positive nodes, and detection by screening in a multivariate analysis, the number of examined nodes was not associated with relative survival. CONCLUSIONS: This study shows that the association between the number of pathologically examined axillary nodes and overall survival in node-negative and node-positive patients results from stage migration. The absence of an association between the number of examined nodes and relative survival further indicates that the association between the number of examined nodes and crude survival is confounded by age.