J.A.A.M. van Dijck

Increased risk of concurrent primary malignancies in patients diagnosed with a primary malignant epithelial ovarian tumor

Ovarian cancer and second malignant neoplasms are found to occur rather frequently in the same patient. From a clinical perspective, it is important to have quantitative information on concurrent malignancies in the same year of diagnosis of the epithelial ovarian cancer. In this population-based study, we used data from the Netherlands Nationwide Network for Registry of histo- and cytopathology (PALGA) and the Netherlands Cancer Registry (NCR). Data of the ovarian cancer as well as data on previous or later cancers were obtained. Age-specific cancer rates from the NCR were used to calculate expected numbers of cancer. Between 1987 and 1993, histopathology reports were identified of 4577 patients with primary epithelial malignant or primary borderline malignant ovarian cancers and its longitudinal data. As the database may lack detailed information on histopathology, a recent sample of 789 patients diagnosed with ovarian cancer in 1996–2003 was comprehensively studied as well. In the eventual data analysis of 5366 patients, 244 cases (4.5%) of concurrent primary malignancy were reported in the same year that the malignant epithelial ovarian tumor had been diagnosed against 51 expected. The observed vs expected ratio was 4.8 and the 95% confidence interval (CI) (4.3–5.5). For cancer of the uterus/endometrium the observed vs expected ratio was 62.3 (95% CI 52.5–73.5). For skin, breast, colorectal, urinary bladder, renal and cervical cancer the ratio was also larger than unity. The elevated risk of concurrent cancer may lead to clinical screening protocols. The findings on endometrial cancer may prompt research on common etiologies and biomarkers.

No supportive evidence for clinical benefit of routine follow-up in ovarian cancer: a Dutch multicenter study.

Introduction: Routine follow-up is standard medical practice in ovarian cancer patients treated with curative intent. However, no strong evidence exists indicating that prognosis is improved. The objective of this study was to evaluate the routine follow-up schedule for ovarian cancer patients regarding the adherence to the Dutch protocol, the detection of recurrences, and the follow-ups impact on overall survival. Methods: All 579 consecutive patients diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube cancer in 4 Dutch hospitals between 1996 and 2006 were selected. Only patients in complete clinical remission after primary treatment were studied. Compliance to the Dutch follow-up guideline was assessed in a random sample of 68 patients. Of the 127 patients with recurrence, the mode of recurrence detection was addressed. Survival time since primary treatment was calculated using the Kaplan-Meier method. Results: The patients received more follow-up visits than was recommended according to the guideline. The cumulative 5-year risk of recurrence was 55% (95% confidence interval [CI], 43%-67%). The survival of patients with recurrent ovarian cancer detected asymptomatically at a routine visit (n = 51) tended to be better compared with patients with symptomatic detection at a routine (n = 31) or diagnosed after an interval visit (n = 31). The median survival times were 44 (95% CI, 38-64), 29 (95% CI, 21-38), and 33 months (95% CI, 19-61), respectively (P = 0.08). The median time from primary treatment to recurrence was similar for the 3 groups: 14, 10, and 11 months, respectively (P = 0.26). Conclusions: Follow-up in line with (inter)national guidelines yields a seemingly longer life expectancy if the recurrence was detected asymptomatically. However, this result is expected to be explained by differences in tumor biology and length-time bias.

Micrometastases and isolated tumor cells: relevant and robust or rubbish? (MIRROR): preliminary results of the MIRROR study from the Dutch breast cancer trialists' group (BOOG).

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #23 Background The sentinel lymph node procedure (SNP) has largely replaced axillary lymph node dissection (ALND) in patients with early breast cancer (BC). Intensified examination of the sentinel node (SN) results in the detection of isolated tumor cells (ITCs) and micrometastases, whereas its relevance is still debated. This retrospective cohort study is the first study on this topic which includes only patients who underwent a SNP, with central review of all SN slides, and with separate analyses for the impact of administration of adjuvant systemic therapy. Methods Patients operated for BC in all Dutch hospitals in the years 1998-2005, having favourable tumor characteristics (> 35 year; tumor size 1-3 cm and differentiation grade I-II OR tumor size ≤ 1 cm irrespective of grade), having undergone a SNP with pN0(i-), pN0(i+), or pN1mi as final N-stage were selected. Patients were classified in cohort I in case of pN0(i-) and no adjuvant systemic therapy (AST), in cohort II in case of pN0(i+)/pN1mi and no AST, and in cohort III in case of pN0(i+)/pN1mi with AST. SNs were centrally reviewed and restaged according to 6th TNM classification. The 5-year disease-free survival (DFS) was analysed for the 3 different cohorts. Results So far, data are available for 1,744 of the 3,240 selected patients (cohort I n=935; cohort II n=340, cohort III n=469) with a median follow-up of 5.5 years. At diagnosis median age was 58, 56 and 56 years (p < 0.01) and median tumor size was 1.2, 1.4 and 1.5 cm (p < 0.0001). Differentiation grade and hormone receptor status were equally distributed among the three cohorts. Adjuvant systemic therapy in cohort III consisted of chemotherapy (10%), hormonal therapy (63%), or both (27%). The 5-yr DFS is 84% in cohort I, 73% in cohort II, and 86% in cohort III (p = 0.003 cohort I vs II; p < 0.0001 cohort II vs III). Correction for baseline characteristics did not lead to a relevant change in the results. Conclusion BC patients with ITCs or micrometastases as final N-stage after SNP have a significantly worse 5-yr DFS as compared to patients having no ITCs or micrometastases, independent of primary tumor characteristics. Adjuvant systemic therapy significantly improves the 5-yr DFS in the group of patients with ITCs or micrometastases in the lymph node(s). At the meeting, updated analyses will be available for the entire MIRROR study population. Support: The Netherlands organization for health research and development (ZonMw) and all Dutch CCCs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 23.

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.

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.

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

ABSTRACT 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 17β-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.

Cost-effectiveness of adjuvant systemic therapy in early-stage breast cancer patients with isolated tumor cells or micrometastases in regional lymph nodes.

614 Background: The MIRROR study has shown a negative prognostic impact of isolated tumor cells and micrometastases in regional lymph nodes in early-stage breast cancer patients who had not received adjuvant systemic therapy (endocrine and/or chemotherapy) compared to those who had received adjuvant therapy. The goal of the present study was to evaluate whether administering AST in those patients is cost-effective. Methods: The primary objective of this cost-effectiveness analysis was to determine the incremental cost-effectiveness ratio (ICER), expressed as the investment necessary to prevent one percent of events after 5 years of follow-up. The median costs of the adjuvant and nonadjuvant therapy cohort of the MIRROR study were compared using a log regression taking into account possible confounders. The costs of every treatment delivered for primary breast cancer, follow-up, and recurrence of disease were included in the analyses. The 5- year disease free survival was assessed using Cox regression anal...

Abstract PD06-04: Relevant Impact of Central Pathology Review on Nodal Classification, but Not on the Association of Small Nodal Metastases with Breast Cancer Outcome. Results from the Dutch MIRROR Study

Background: Previously, we reported that isolated tumor cells, pN0(i+), or micrometastases, pN1mi, were associated with a reduced 5-year disease-free survival (DFS) rate among patients with favorable early-stage breast cancer who did not receive adjuvant systemic therapy (AST) (de Boer et al, NEJM 2009). In patients with pN0(i+) or pN1mi who received AST, DFS was improved. Patients were classified by N-status as determined after central pathology review and restaged according to the 6 th AJCC classification. In real life, however, treatment decisions are based on the pathology reports performed by local pathologists. Therefore, in the present study we addressed the role of the central pathology review. Methods: In the MIRROR study, a total of 2707 patients were included. Involved women were operated for breast cancer in a(ny) Dutch hospital in 1998-2005, had favorable characteristics (tumor size 1-3 cm and differentiation grade I-II OR tumor size 1 cm irrespective of grade) and had undergone a sentinel node procedure with pN0(i+) or pN1(mi) as final N-status. A control group with low-risk node-negative disease was randomly selected from the years 2000 and 2001. We assessed the difference between the original N-status and N-status after central review. Further, in patients who had not received AST (n=1712), 5-year DFS was assessed according to the original N-status as well as the review N-status. Results: Of 856 patients with pN0 after central review, 0.4% patients were originally staged as pN0(i+). Of 819 patients with reviewed pN0(i+), 24% patients originally had pN0 and 20% patients pN1 mi. And, of 1032 patients with pN1mi after review, 3% patients had originally pN0 and 15% patients pN0(i+). Overall, central review changed the N-classification thereby in 20% of patients. In patients who did not receive AST, the 5-year DFS rates of cohorts based on central pathology review were 86% for pN0, 77% for pN0(i+) and 76% for pN1mi (P Conclusion: Central pathology review changed the N-classification in 20% of patients. On a population level the association of isolated tumor cells and micrometastases with breast cancer outcome remained unchanged. However, on an individual patient level, the upstaging of pN0 patients may be of clinical relevance. Quality control of pathology departments should therefore also include nodal staging of breast (and perhaps other) cancers. Support: The Netherlands organization for health research and development (ZonMw) and the Dutch Breast Cancer TrialistsGroup (BOOG) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-04.