Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases.

BACKGROUND: The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown. PATIENTS AND METHODS: A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out. RESULTS: In the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was €363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort. CONCLUSIONS: In this population of breast cancer patients with isolated tumor cells or micrometastases, €36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis.

Relevant impact of central pathology review on nodal classification in individual breast cancer patients.

BACKGROUND: In the MIRROR study, pN0(i + ) and pN1mi were associated with reduced 5-year disease-free survival (DFS) compared with pN0. Nodal status (N-status) was assessed after central pathology review and restaging according to the sixth AJCC classification. We addressed the impact of pathology review. PATIENTS AND METHODS: Early favorable primary breast cancer patients, classified pN0, pN0(i + ), or pN1(mi) by local pathologists after sentinel node procedure, were included. We assessed the impact of pathology review on N-status (n = 2842) and 5-year DFS for those without adjuvant therapy (n = 1712). RESULTS: In all, 22% of the 1082 original pN0 patients was upstaged. Of the 623 original pN0(i + ) patients, 1% was downstaged, 26% was upstaged. Of 1137 patients staged pN1mi, 15% was downstaged, 11% upstaged. Originally, 5-year DFS was 85% for pN0, 74% for pN0(i + ), and 73% for pN1mi; HR 1.70 [95% confidence interval (CI) 1.27-2.27] and HR 1.57 (95% CI 1.16-2.13), respectively, compared with pN0. By review staging, 5-year DFS was 86% for pN0, 77% for pN0(i + ), 77% for pN1mi, and 74% for pN1 + . CONCLUSION: Pathology review changed the N-classification in 24%, mainly upstaging, with potentially clinical relevance for individual patients. The association of isolated tumor cells and micrometastases with outcome remained unchanged. Quality control should include nodal breast cancer staging.

Less mammographic density after nasal versus oral administration of postmenopausal hormone therapy.

OBJECTIVE: Nasal administration gives a more acute but shorter rise in serum hormone levels than oral administration and may therefore have less effect on the fibroglandular tissue in the breasts. We studied the change in mammographic breast density after nasal vs. oral administration of postmenopausal hormone therapy (PHT). METHODS: We studied participants in a randomized, controlled trial on the impact of nasal vs. oral administration of PHT (combined 17ß-estradiol plus norethisterone) for 1 year. Two radiologists classified mammographic density at baseline and after 1 year into four categories. Also, the percentage density was calculated by a computer-based method. The main outcome measure was the difference in the proportion of women with an increase in mammographic density category after 1 year between the nasal and oral groups. Also, the change in the percentage density was calculated. RESULTS: The study group comprised 112 healthy postmenopausal women (mean age 56 years), of whom 53 received oral and 59 intranasal PHT. An increase in mammographic density category after 1 year was seen in 20% of the women in the nasal group and in 34% of the oral group. This resulted in a non-significant difference in the proportion of women in whom mammographic breast density had increased by 214% (95% confidence interval (CI) 230% to 2.7%). The mean change in percentage density was 21.2% in the nasal group and + 1.2% in the oral group, yielding a 22.4% differential effect (95% CI 27.3% to 2.5%). CONCLUSIONS: One year of nasal PHT gave a smaller, although not statistically significant, increase in mammographic density than oral PHT. Remaining issues are the relation between the route of administration of PHT and breast complaints and breast cancer risk.

Variations in treatment of ductal carcinoma in situ of the breast: a population-based study in the East Netherlands.

AIMS: Differences in treatment of ductal carcinoma in situ (DCIS) of the breast were analysed for a geographically defined population in the East Netherlands. METHODS: Data from the Cancer Registry of the Comprehensive Cancer Centre East Netherlands were analysed for treatment of DCIS in the period between January 1989 and December 2003. The study population consisted of 800 female patients with a first diagnosis of DCIS of whom 798 underwent surgical treatment. The distribution of tumour characteristics and treatment were compared for several time periods. RESULTS: Surgical treatment was specified for 648 patients: 51% underwent breast-conserving surgery. The proportion of patients treated with breast-conserving surgery increased: 43% in the period 1994-1998 and 55 after 1999 (p<0.01). An axillary staging procedure was performed in 149 patients (19%), of whom 2 (1%) had tumour-involved lymph nodes. Of patients treated with breast-conserving surgery, 133 (40%) received radiation therapy: 7% in the period 1994-1998 compared to 62% after 1999 (p<0.01). Patients (60%) of 50 years or younger were treated with mastectomy compared to 44% in patients aged 50-69 years and 50% in patients of 70 years and older (p<0.01). The rate in use of radiation therapy after breast-conserving surgery was comparable to both age groups. CONCLUSION: This study shows variability in the treatment of DCIS in a geographically defined region. Approximately half of all patients were treated with mastectomy and 19% underwent an axillary staging procedure; this may represent aggressive, unwarranted treatment. In contrast, 38% of patients treated with breast-conserving surgery were not treated with radiation therapy after 1999, which may represent under-treatment.

Epidemiology and treatment of extramammary Paget disease in the Netherlands.

AIM: To determine the incidence of EMPD and to describe its epidemiology, treatment, survival and the risk of developing other malignancies. METHOD: All cases of EMPD, diagnosed between 1989 and 2001, were selected from the Netherlands Cancer Registry. RESULTS: In total, 178 cases of invasive and 48 cases of in situ EMPD had been registered. The overall relative 5-year survival for invasive tumours was 72%. Most patients with invasive as well as in situ cancer underwent surgery. Other malignancies were found in 32% of patients with invasive EMPD and 35% of patients with in situ EMPD. Patients had an increased risk of developing a second primary cancer (standardized incidence ratio: 1.7; 95% confidence interval 1.2-2.4). The most frequent localizations of the other cancers were the colorectum, the prostate, the breast and the extragenital skin. CONCLUSIONS: For EMPD, which is a rare disease in the Netherlands, there are no clear diagnostic and treatment guidelines. The prognosis is fairly good. A thorough search for other tumours is recommended for these patients.

[Trends in the incidence and death from cancer from 1989-2003 in The Netherlands]. / Trends in incidentie van en sterfte aan kanker in de periode 1989-2003 in Nederland.

OBJECTIVE: To provide insight into the changing nature and size of the cancer burden within The Netherlands. DESIGN: Retrospective. METHOD: Data on incidence and death relating to various forms of cancer are calculated on the basis of registered data concerning the incidence (Netherlands Cancer Registration; NCR) of and death (Statistics Netherlands) from cancer in the Netherlands from 1989 until 2003. RESULTS: From the start in 1989 up to 2003, more than one million new cases of cancer were registered with the NCR. The total number of new patients with a primary tumour increased from 56,335 in 1989 to 73,188 in 2003 (30%). The most frequently occurring tumours in 2003 were of the breast, colon, lung and prostate. The age standardized incidence rate for males and females combined, increased from 381 per 100,000 in 1989 to 400 per 100,000 person years in 2003 (+5%). There was an increase in breast, prostate, skin and oesophagus cancer, and also lung cancer in females. Major decreases were seen in lung cancer in males, as well as stomach, ovary and gallbladder cancer. The number of cancer deaths in the Netherlands increased from 35,420 in 1989 to 38,454 in 2003 (+8%). The age and sex standardized mortality rate declined from 234 per 100,000 in 1989 to 201 per 100,000 in 2003 (-14%). CONCLUSION: Despite a slight increase in the incidence of cancer and an increase in mortality from lung cancer (in females), oesophageal cancer and melanomas, the death rate from cancer has dropped considerably. The changes in incidence and mortality may be explained by changes in lifestyle in the 1970s and 80s, in particular use of tobacco and alcohol. Also early detection and screening programmes have resulted in an increase in the incidence of tumours with a better prognosis, which has led to a decrease in mortality. The downward trend in mortality was also influenced by treatment-improving prognoses.

Trends in incidence of and mortality from cancer in The Netherlands in the period 1989-1998.

This paper summarises the population-based major trends in cancer incidence and mortality in the period 1989-1998 in The Netherlands. Trends of the European age-adjusted incidence and mortality rates were estimated by the Estimated Annual Percentage Change (EAPC) method. Increases in incidence were found for cancer of the breast and lung for females. For males, an increase was observed for cancer of the prostate, colon, rectum and testis. In both groups, oesophageal and pharyngeal cancer increased, but that of stomach and gallbladder cancer decreased. The main increases in mortality were found for pharyngeal cancer in males, lung in females and oesophageal cancer in both sexes. Decreases were shown for stomach cancer for both sexes and lung cancer for males. Trends in incidence may be a result of changes in behaviour, smoking habits in preceding decades are related to the increase in lung cancer for females, and early detection, screening programmes increased the incidence for breast and prostate cancers. Decreases in mortality may be related to more successful treatment of leukaemia, Hodgkin's lymphoma, colorectal and testicular cancers. Primary prevention of cancer remains important.

Age-specific differences in treatment and survival of patients with cervical cancer in the southeast of The Netherlands, 1986-1996.

Age at diagnosis has been proven to be an important determinant of the choice of initial treatment for several sites of cancer. Elderly patients are more likely to receive no treatment or less intensive treatment modalities. This study analysed the influence of age on treatment choice and survival in patients diagnosed with cervical cancer. This population-based study used data on 1176 new cases of invasive cervical cancer diagnosed in the period of 1986-1996 from three regional cancer registries in the Netherlands. All available information on treatment and survival (on 1 January 1998) was recorded. Relative survival rates were calculated according to the Hakulinen method. Relative risks (RR) for excess mortality due to the diagnosis of cervical cancer were calculated with a regression model for relative survival rates. Only 5% of the patients aged 70 years and older (n=224) were diagnosed with stage IA disease, compared with 11 and 30% of the patients aged 50-69 years and 49 years and younger, respectively. Almost 50% of the 70+ patients with stage IB-IIA were treated with radiotherapy as a single treatment modality, whereas 64% of the patients aged < or =49 years were treated with surgery alone. In all age groups, treatment for advanced stage disease (stage > or =IIB) was radiotherapy alone. No treatment was given to 10% of the patients aged 70 years and older, 5% of those aged 50-69 years and 1% of those aged 49 years and younger. Five-year relative survival was 69% (95% Confidence Interval (CI): 66-72%) and differed significantly (P=0.001) with age (70+ years: 49%; 50-69 years 58%; < or =49 years: 81%). Multivariate analyses on a subset of patients showed that age was not an independent prognostic factor, whereas stage and treatment modality were very important prognostic factors. Although elderly cancer patients were sometimes treated differently from younger patients, this was in accordance with the guidelines. Relative survival rates differed significantly by age. The multivariate analyses on the subset of patients also revealed that excess mortality increased with age. However, when adjustment was made for stage and treatment, this difference disappeared. The influence of treatment on survival is likely to be due to the selection of patients based on other characteristics, such as tumour volume, comorbidity and performance status.

Influence of age, comorbidity and performance status on the choice of treatment for patients with non-small cell lung cancer; results of a population-based study.

BACKGROUND: In the Netherlands in 1997, 43% of patients with newly diagnosed lung cancer were over 70. Large age-specific differences in treatment exist. We examined whether age, comorbidity, performance status and pulmonary function influenced treatment. PATIENTS AND METHODS: Data on patients with newly diagnosed non-small cell lung cancer (N = 803) were obtained: comorbidity, performance status, pulmonary function (FEV1) and initial treatment. Age-specific differences in treatment according to the guidelines were examined. Odds ratios were calculated by means of logistic regression analyses. RESULTS: 82% with stage I or II disease received treatment according to the guidelines; this applied to 48% with stage IIIA disease and to 54% with stage IIIB disease. For all stages, this proportion decreased with increasing age. In stage IV disease, 36% did not receive any treatment; this applied to 52% of the elderly patients (75+ years). Multivariate analyses showed associations between comorbidity and treatment choice, but none with performance status. Age of 75+ years appeared to be the most important factor for not receiving treatment according to guidelines. CONCLUSION: A substantial proportion of elderly patients with non-small cell lung cancer did not receive standard treatment. Performance status and comorbidity seldom formed the underlying reason. Calendar rather than biological age seemed to play the most important role in choice of treatment for patients with non-small cell lung cancer.

Models predicting non-sentinel node involvement also predict for regional recurrence in breast cancer patients without axillary treatment.

BACKGROUND: Non-SN prediction models are frequently used in clinical decision making to identify patients that may not need axillary treatment, but these models still need to be validated by follow-up data. Our purpose was the validation of non-sentinel node (SN) prediction models in predicting regional recurrences in patients without axillary treatment. METHODS: We followed a cohort of 486 women with favorable primary tumor characteristics and pN0(i+)(sn) or pN1mi(sn) for median 4.5 years. None of the patients underwent axillary treatment. Based on four published non-SN prediction models, the threshold allowing separation into low versus high-risk on non-SN involvement was set at 10%. RESULTS: Overall 5-year regional recurrence rate was 3.0% (SE, ±0.1%). Using the Tenon scoring system, 438 low-risk patients had a 5-year regional recurrence rate of 2.3% (±0.8%), and 48 high-risk patients a recurrence rate of 10.1% (±0.4%). The MSKCC nomogram identified 300 low-risk patients with a recurrence rate of 2.8% (±1.1%), versus 166 high-risk patients with a rate of 3.4% (±0.5%) (20 patients not assessable). The Stanford nomogram identified 21 high-risk patients without recurrence, and 465 low-risk patients with a 3.2% (±0.9%) recurrence rate. A Dutch model discriminated between 384 low-risk patients with a recurrence rate of 2.2% (±0.8%) and 102 high-risk patients with a rate of 6.3% (±2.9%). CONCLUSION: The Tenon scoring system outperformed the other models as it identified the largest subgroup of patients with low recurrence rate. In patients resembling our cohort we would recommend axillary treatment if they had a Tenon score above 3.5.

[Aftercare in oncology--greater role for the general practitioner]. / Nacontrole oncologie--grotere rol voor de huisarts.

Patients who undergo curative treatment for cancer continue to be medically monitored for a number of years. Scheduled aftercare, mainly aimed at early detection of locoregional cancer recurrences, distant metastases and secondary primary tumours, takes place chiefly in the second line, but is expected to shift to the first line. Figures from the Nijmegen Continuous Morbidity Registration show that an average (Dutch) general practitioner, caring for about 2500 patients, has in his practice 90 patients who have or have had cancer. This number will increase due to the increasing prevalence of cancer. In addition, extra consultations for each cancer patient will increase the demand for GP care.

Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases.

BACKGROUND: The prognostic relevance of isolated tumor cells and micrometastases in lymph nodes from patients with breast cancer has become a major issue since the introduction of the sentinel lymph node procedure. We conducted a systematic review of this issue. METHODS: Studies published from January 1, 1977, until August 11, 2008, were identified by use of MEDLINE, EMBASE, and the Cochrane Library. A total of 58 studies (total number of patients = 297,533) were included and divided into three categories according to the method for pathological assessment of the lymph nodes: cohort studies with single-section pathological examination of axillary lymph nodes (n = 285,638 patients), occult metastases studies with retrospective examination of negative lymph nodes by step sectioning and/or immunohistochemistry (n = 7740 patients), and sentinel lymph node biopsy studies with intensified work-up of the sentinel but not of the nonsentinel lymph nodes (n = 4155 patients). We used random-effects meta-analyses to calculate pooled estimates of the relative risks (RRs) of 5- and 10-year disease recurrence and death and the multivariably corrected pooled hazard ratio (HR) of overall survival of the cohort studies. RESULTS: In the cohort studies, the presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes was associated with poorer overall survival (pooled HR of death = 1.44, 95% confidence interval [CI] = 1.29 to 1.62). In the occult metastases studies, the presence (vs the absence) of occult metastases was associated with poorer 5-year disease-free survival (pooled RR = 1.55, 95% CI = 1.32 to 1.82) and overall survival (pooled RR = 1.45, 95% CI = 1.11 to 1.88), although these endpoints were not consistently assessed in multivariable analyses. Sentinel lymph node biopsy studies were limited by small patient groups and short follow-up. CONCLUSION: The presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes detected on single-section examination was associated with poorer disease-free and overall survival.

On the rising trends of incidence and prognosis for breast cancer patients diagnosed 1975-2004: a long-term population-based study in southeastern Netherlands.

BACKGROUND: Much progress has been made in the early diagnosis and treatment of breast cancer. We have assessed the changing burden of this disease, by means of a comprehensive description of trends in incidence, survival, and mortality. METHODS: Data on breast cancer patients diagnosed between 1975 and 2004 (n = 26,464) registered in the population-based Eindhoven Cancer Registry were investigated. RESULTS: Incidence for patients aged below 40 and 40-49 has increased by 2.1% and 2.4% annually, since 1995 (p = 0.08 and p = 0.001, respectively). Mortality decreased in all age groups, but most markedly among women aged 50-69 (-1.5% yearly since 1985, p = 0.14). The proportion of stage I tumors increased from 25% to 39%, that of advanced stages (III & IV) decreased from 30% (1975-1984) to 13% in 1995-2004, and the proportion of in situ tumors increased from 1.5% to 10%. Adjuvant systemic treatment was administered to 15% of patients in 1975-1984 vs. 49% in 1995-2004. Relative 10-year survival rates for women aged 50-69 (period analysis) increased from 53% to 75% between 1975 and 2004. The best prognosis was observed for women aged 45-54. Women younger than 35 had a particularly poor prognosis. CONCLUSION: The observed improvement in survival of breast cancer patients during the last three decades is impressive. The peak in breast cancer incidence is not yet in sight considering the recent trends in exposure to known risk factors and improved diagnosis. The combination of increasing incidence and improved survival rates implies that the number of prevalent cases will continue to increase considerably in the next 10 years.

Significant decrease of adenocarcinoma in situ not reflected in cervical adenocarcinoma incidence in the Netherlands 1989-2003.

Over the period 1989-2003, the incidence of cervical adenocarcinoma (n=1615) was stable whereas that of cervical adenocarcinoma in situ (n=1884) significantly decreased (P=0.008), mainly caused by adenocarcinoma in situ lesions with a concurrent squamous dysplasia.

Decreased rates of advanced breast cancer due to mammography screening in The Netherlands.

The effect of the implementation of the Dutch breast cancer screening programme during 1990-1997 on the incidence rates of breast cancer, particularly advanced breast cancer, was analysed according to stage at diagnosis in seven regions, where no screening took place before 1990. The Netherlands Cancer Registry provided detailed data on breast cancer incidence in 1989-1997 by tumour stage, age and region. Annual age-adjusted incidence rates of all breast cancers and advanced cancers, defined as large tumours T2+ with lymph node and/or distant metastases, were compared with rates in 1989. In general, breast cancer incidence rose strongly in the early 1990s, especially in the age category 50-69 years (estimated annual percentage change (EAPC) 4.25; 95% CI 1.70, 6.86). The increase was mainly due to the increase in small T1 cancers and ductal carcinoma in situ. However, in women aged 50-69, advanced cancer incidence rates showed a significant decline by 12.1% in 1997 compared with 1989 (EAPC -2.14, 95% CI -3.47, -0.80), followed by a breast cancer mortality reduction of similar size after approximately 2 years. We confirm that breast cancer screening initially leads to a temporary strong increase in the breast cancer incidence, which is followed by a significant decrease in advanced diseases in the women invited for screening. It is evident that breast cancer screening contributes to a reduction in advanced breast cancers and breast cancer mortality.