Vcg Tjan-Heijnen

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.

Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer: an EORTC phase II study (EORTC 08958)☆

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naïve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

Variation in management of early breast cancer in the Netherlands, 2003–2006

BACKGROUND To describe variation in staging and primary treatment by hospital characteristics including type and volume and region in patients with early breast cancer (BC) in the Netherlands, 2003-2006 after completion of national guidelines in 2002. METHODS All patients newly diagnosed with invasive BC in 2003-2006 and recorded in the Netherlands Cancer Registry were included (n = 51 354). Multivariable logistic regression analyses examined the influence of patient and hospital characteristics, also by region, on type of breast surgery, axillary lymph node dissection (ALND), sentinel node procedure (SNP), and adjuvant irradiation and/or systemic treatment. RESULTS Patients <40 years more often underwent breast conserving surgery (BCS) in general hospitals (OR 1.4 (95%CI 1.1-1.5)) than in teaching and academic hospitals, whereas patients of 40-69 years less often received BCS in an academic hospital (OR 0.9 (95%CI 0.8-1.0)) than in teaching hospitals. Patients with pT1-2N0 cancer more often underwent primary ALND in a general hospital than in a larger teaching or academic hospital. Type of hospital did not seem to affect utilization of adjuvant systemic therapy, but patient age and tumour size and grade did. Over time, patients more often received SNP, BCS, and adjuvant systemic therapy, primary ALND being on the decline, but with substantial regional variation between geographic regions. CONCLUSION With detailed evidence-based national guidelines since 2002 the considerable regional and hospital variation in staging procedures and primary treatment among newly diagnosed patients with early breast cancer in the Netherlands decreased markedly, suggesting the presence of late adaptors rather than specific hospital characteristics.

Considering early detection of relapsed ovarian cancer: a review of the literature.

Introduction: Patients treated for ovarian cancer with curative intent receive an intensive follow-up program in the years after treatment. However, the aimed improved survival through early detection of recurrence is subject to debate. Theoretically, the survival benefit depends on the lead time and the preclinical detection rate and on the effectiveness of recurrence treatment. This systematic review aimed at determining the effectiveness of early detection of recurrent ovarian cancer. Methods: A systematic literature search in PubMed, EMBASE, MEDLINE, and the Cochrane Library was performed for articles published in 1985 to 2009 in English, German, or Dutch, excluding editorials, letters, and case reports. Results: In total, 67 articles were included. Of 4 observational studies and 1 randomized controlled trial, only 1 observational study reported a better survival for patients who attended routine follow-up compared with those who did not. The sensitivity of cancer antigen 125 for a preclinical recurrence, based on 38 articles using 35 U/mL as a cutoff level, was 65%, with a median lead time of 3 months (range, 1-7 months). Seven studies showed that, on average, 67% (ranging from 20% to 80%) of the 798 relapsed patients had no clinical symptoms when recurrent ovarian cancer was diagnosed. Conclusions: Routine follow-up may detect 2 of 3 recurrences asymptomatically with a lead time of 3 months. Recurrence treatment may extend survival by several months, but published studies did not show a survival advantage of early detection by routine follow-up examinations. Therefore, the content and aims of routine follow-up should be reconsidered, whereas routine cancer antigen 125 testing with the aim to improve life expectancy should be omitted.

Small but significant excess mortality compared with the general population for long-term survivors of breast cancer in the Netherlands

BACKGROUND Coinciding with the relatively good and improving prognosis for patients with stage I-III breast cancer, late recurrences, new primary tumours and late side-effects of treatment may occur. We gained insight into prognosis for long-term breast cancer survivors. PATIENTS AND METHODS Data on all 205 827 females aged 15-89 diagnosed with stage I-III breast cancer during 1989-2008 were derived from the Netherlands Cancer Registry. Conditional 5-year relative survival was calculated for every subsequent year from diagnosis up to 15 years. RESULTS For stage I, conditional 5-year relative survival remained ~95% up to 15 years after diagnosis (a stable 5-year excess mortality rate of 5%). For stage II, excess mortality remained 10% for those aged 15-44 or 45-59 and 15% for those aged 60-74. For stage III, excess mortality decreased from 35% at diagnosis to 10% at 15 years for those aged 15-44 or 45-59, and from ~40% to 30% for those aged ≥60. CONCLUSIONS Patients with stage I or II breast cancer had a (very) good long-term prognosis, albeit exhibiting a small but significant excess mortality at least up to 15 years after diagnosis. Improvements albeit from a lower level were mainly seen for patients who had been diagnosed with stage III disease. Caregivers can use this information to better inform (especially disease-free) cancer survivors about their actual prognosis.

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.

Treatment and survival of patients with non-small cell lung cancer Stage IIIA diagnosed in 1989–1994: a study in the region of the Comprehensive Cancer Centre East, The Netherlands

The purpose of this study was to gain insight into the treatment policy and survival of patients with non-small cell lung cancer (NSCLC) clinical stage IIIA in daily practice. We selected 212 patients, who had been diagnosed between 1989 and 1994 and registered by the Cancer Registry, Comprehensive Cancer Centre East (CCCE). Diagnostic tests comprised chest X-ray and bronchoscopy in all cases but one, computed tomography in 89%, mediastinoscopy in 55% and conventional tomography of the chest in 16%. NSCLC had been verified histologically in 88% and cytologically in 12%. The initial treatment for the primary tumor had been surgery alone in 13% of the patients, surgery plus radiotherapy in 8%, radiotherapy alone in 56%, chemotherapy in 1% (three patients, one in addition to surgery); 22% received none of these treatments. Median survival of the 212 patients was 9.4 months (95% confidence interval 8.3-11.0 months). Overall survival rates after 1, 2 and 3 years were 41, 17 and 8%, respectively. Three-year survival of the patients who had undergone surgery, surgery plus radiotherapy, radiotherapy alone and no treatment was 18, 19, 6 and 4%, respectively. Treatment was an independent prognostic factor (multivariate Coxs proportional hazards analysis adjusted for sub-stage, age, number of co-morbid diseases and hospital). In the same model, the Hazard rate ratio for one hospital relative to the five others was 1.9 (95% confidence interval 1.2-2.8). Surgery (whether or not in combination with radiotherapy) independently gave the best results. In conclusion, policies varied between hospitals, although the variation in overall survival was small except at one hospital. New regional management guidelines are in preparation. Physicians will be encouraged to follow these guidelines, both with regard to diagnostic tests and to treatment policies, as our study showed that differences in policy might lead to differences in survival.

Is the sentinel lymph node pathology protocol in breast cancer patients associated with the risk of regional recurrence

BACKGROUND Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN) in breast cancer patients. Previously, we reported that ultra-staging led to more axillary lymph node dissections (ALND). The question was, whether ultra-staging is effective in reducing the risk of regional relapse. METHODS From January 2002 to July 2003, 541 patients from 4 hospitals were prospectively registered when they underwent a SN biopsy. In hospitals A, B, and C, 3 levels of the SN were examined pathologically, whereas in hospital D at least 7 additional levels were examined. Patients with a positive SN, including isolated tumor cells, underwent an ALND. This analysis focuses on the 341 patients with a negative SN. Primary endpoint was 5-year regional recurrence rate. RESULTS In hospital D 34% of the patients had a negative SN as compared to 71% in hospitals A, B, and C combined (p < 0.001). At 5 years follow-up, 9 (2.6%) patients had developed a regional lymph node relapse. In hospital D none of the patients had a regional recurrence, as compared to 9 (2.9%) cases of recurrence in hospitals A, B, and C. CONCLUSION The less intensified SN pathology protocol appeared to be associated with a slightly increased risk of regional recurrence. The absolute risk was still less than 3%, and does not seem to justify the intensified SN pathology protocol of hospital D.

Abstract OT2-1-03: The Z11 design for breast cancer patients undergoing a mastectomy

Background: The diagnostic work-up and treatment of axillary lymph nodes in breast cancer patients is an ongoing topic of research. The ACOSOG-Z0011 study demonstrated no additional value of complementary axillary lymph node dissection (cALND) in case of limited axillary sentinel lymph node (SLN) metastases in breast cancer patients undergoing breast conserving therapy1. It is questionable whether these results can be applied to patients undergoing a mastectomy2. Trial design: A prospective non-inferiority randomized multicenter trial was designed. Breast cancer patients with cT1-2N0 disease treated with mastectomy and limited axillary SLN metastases will be randomized for follow-up versus complementary axillary treatment. To assess the Quality of Life and morbidity benefits of this experimental treatment, 3 validated questionnaires will be used: QLQ-C30, QLQ-BR 23 and Lymph-ICF3-5. Eligibility criteria: – Women with histological confirmed cT1-2 invasive unilateral breast carcinoma – Clinical node negative: no palpable nodes in physical examination and the axillary ultrasound without signs of lymph node metastases (cyto-/histology if indicated) – Sentinel lymph node biopsy must contain at least one and a maximum of 3 (micro)metastases – Neoadjuvant systemic therapy is allowed Specific aims: Primary endpoint is the axillary recurrence rate. The number of delayed axillary dissections will be registered. Secondary endpoints are distant-disease free survival, overall survival, local recurrence, morbidity and Quality of Life. Statistical methods: Based on 5-year axillary recurrence free survival rate, a failure rate of 0.98 among controls and a true failure rate of 0.96 for study subjects are considered acceptable. Overall, 1114 patients will be included to be able to reject the null hypothesis that the failure rate for experimental and control subjects is inferior by at least 5% (D = −5%) with probability of 0.8 and alpha of 5%. Present accrual and target accrual: This study is expected to start in late 2012 after approval by the Ethical Medical Committee. References 1. Giuliano, A.E., et al., Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA, 2011. 305(6): p. 569–75. 2. Morrow, M. and A.E. Giuliano, To cut is to cure: can we really apply Z11 in practice? Ann Surg Oncol, 2011. 18(9): p. 2413–5. 3. Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 1993. 85(5): p. 365–76. 4. Sprangers, M.A., et al., The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol, 1996. 14(10): p. 2756–68. 5. Devoogdt, N., et al., Lymphoedema Functioning, Disability and Health questionnaire (Lymph-ICF): reliability and validity. Phys Ther, 2011. 91(6): p. 944–57. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-1-03.