Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Employment and social benefits up to 10 years after breast cancer diagnosis: a population-based study.

BACKGROUND: Little is known about employment outcomes after breast cancer (BC) beyond the first years after treatment. METHODS: Employment outcomes were compared with a general population comparison group (N=91 593) up to 10 years after BC for 26 120 patients, diagnosed before age 55 between 2000-2005, with income and social benefits data from Statistics Netherlands. Treatment effects were studied in 14 916 patients, with information on BC recurrences and new cancer events. RESULTS: BC survivors experienced higher risk of losing paid employment (Hazard Ratio (HR): 1.6, 95% Confidence Interval (95% CI) 1.4-1.8) or any work-related event up to 5-7 years (HR 1.5, 95% CI 1.3-1.6) and of receiving disability benefits up to 10 years after diagnosis (HR 2.0, 95% CI 1.6-2.5), with higher risks for younger patients. Axillary lymph node dissection increased risk of disability benefits (HR 1.5, 95% CI 1.4-1.7) or losing paid employment (HR 1.3, 95% CI 1.2-1.5) during the first 5 years of follow-up. Risk of disability benefits was increased among patients receiving mastectomy and radiotherapy (HR 1.2; 95% CI 1.1-1.3) and after chemotherapy (HR 1.7; 95% CI 1.5-1.9) during the first 5 years after diagnosis. CONCLUSIONS: BC treatment at least partly explains the increased risk of adverse employment outcomes up to 10 years after BC.

Cause-specific excess mortality in patients treated for cancer of the oral cavity and oropharynx: A population-based study.

PURPOSE: To assess cause-specific mortality in a large population-based cohort of 14,393 patients treated for squamous cell carcinoma of the oral cavity (OC) or oropharynx (OP) in The Netherlands between 1989 and 2006. PATIENTS AND METHODS: Causes of death were obtained for 94.7% of 9620 patients who had died up to January 1, 2009. We assessed standardized mortality ratios (SMR) and absolute excess mortality (AEM), comparing observed cause-specific mortality with expected mortality for our cohort based on general population mortality rates. RESULTS: Median survival was 3.9 years. Overall, the study population experienced a 6-fold higher (95% Confidence Interval (95% CI) 5.9-6.1) mortality risk compared with the general population. After three years, 41% of OP and 29% of OC patients had died due to cancer of the oral cavity and pharynx. Additionally, OC and OP patients experienced high excess mortality from esophageal (SMR 10.6 and 17.9) and lung cancer (SMR 4.6 and 6.3). With regard to non-cancer deaths, the highest AEMs were due to diseases of the circulatory system, with OC patients experiencing an AEM of 11.3 per 10,000 person-years for ischemic heart disease. OP patients experienced excess mortality due to pneumonia (AEM 22.1 per 10,000 person-years). The risk of death due to diseases of the digestive system was for OP and OC patients where about equal (AEM 28.7 and 23.80, respectively). The SMR for death due to pneumonia was more than two times higher (4.4 vs. 1.7) for OP patients than for OC patients (P<0.001). From 15 years after diagnosis, second tumors located outside the head and neck region accounted for most of the excess mortality. CONCLUSIONS: Excess mortality in OC and OP patients appears to be dominated by effects of heavy tobacco and alcohol use with high AEM due to second tumors, respiratory, cardiovascular and gastrointestinal diseases. Patients with OP experienced more than two times higher risk of death due to pneumonia than OC patients. Therefore, awareness of this potential complication should be raised along with development of prevention strategies.

The epidemiology of head and neck squamous cell carcinoma in The Netherlands during the era of HPV-related oropharyngeal squamous cell carcinoma. Is there really evidence for a change?

BACKGROUND: Several recent studies have shown that incidence of oropharyngeal carcinomas is rising in the Western World. This increase has been attributed to changes in the etiology of oropharyngeal carcinomas with a growing role for infections with Human Papilloma viruses. This nationwide study evaluates and compares trends in incidence, clinical behavior and tumor characteristics of oropharyngeal and oral squamous cell cancer. METHODS: This study comprised all 16,480 patients with primary squamous cell carcinoma of the oral tongue (OTSCC), oral cavity excluding oral tongue (OCSCC), and oropharynx (OPSCC) diagnosed from 1989 through 2008 in The Netherlands. We assessed trends in age-standardized incidence, second cancer risk and subsite specific relative survival (RS) over time. RESULTS: Incidence of OTSCC and OPSCC in males and incidence of all subsites in females increased significantly from 1989 through 2008. In males increases in incidence were largely restricted to the 50-64 year age group (estimated annual percentage change 2.2% and 3.2% for OTSCC and OPSCC, respectively), while in females incidence increased for most age groups. The incidence of OCSCC (excl. oral tongue) and OPSCC before 50 years of age decreased. Patients with OPSCC showed the poorest prognosis with a relative survival of 41.6% after 5 years and 29.4% after 10 years (P<0.001) over the entire period 1989-2008. However survival increased substantially for OPSCC patients over time (5-year RS of 37.2% in 1989-1993 to 47.6% in 2004-2008, P<0.001). CONCLUSION: Although incidence of OPSCC did increase since 1989, especially in females, similar increases were seen for OCSCC (excl. oral tongue) and OTSCC. Our study does not appear to support that HPV is the main contributor to a rising incidence of OPSCC as the effects of changes in smoking and alcohol use cannot be discounted.

Melanoma risk after ovarian stimulation for in vitro fertilization.

STUDY QUESTION: Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? SUMMARY ANSWER: Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. WHAT IS KNOWN ALREADY: Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. STUDY DESIGN, SIZE, DURATION: In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). LIMITATIONS, REASONS FOR CAUTION: Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. STUDY FUNDING/COMPETING INTEREST: This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival.

Outcomes of a population-based series of early breast cancer patients with micrometastases and isolated tumour cells in axillary lymph nodes.

BACKGROUND: Axillary lymph node staging is traditionally important to provide prognostic information to guide further treatment. However, the relevance of isolated tumour cells (ITC) or micrometastases in axillary nodes and the need for adjuvant treatment remain uncertain. PATIENTS AND METHODS: Data from 18 370 patients with pT1-2 breast cancer with pN0, pN0i+ or pN1mi were analysed. The primary end point was 5-year disease-free survival (locoregional recurrence, distant metastases or contralateral breast cancer). RESULTS: Five-year disease-free survival was 89.9% [95% confidence interval 89.5% to 90.4%]; and did not differ significantly between groups. After adjusting for prognostic factors (including treatment), patients with ITC had a comparable risk (hazard ratio = 1.12) as patients with node-negative disease, while patients with micrometastases had a 38% higher risk of recurrence. CONCLUSION(S): Patients with ITC and node-negative breast cancer appear to have similar prognosis, and those with micrometastases have a 38% higher risk of tumour recurrence. However, considering that disease-free survival is already high, we are reluctant to advise chemotherapy in all patients with ITC or micrometastases. In future, genomic tumour characteristics might predict the propensity of dissemination from the primary cancer better than the status of the axillary lymph nodes.

Risk and prognostic significance of metachronous contralateral testicular germ cell tumours.

BACKGROUND: Testicular germ cell tumour (TGCT) patients are at increased risk of developing a contralateral testicular germ cell tumour (CTGCT). It is unclear whether TGCT treatment affects CTGCT risk. METHODS: The risk of developing a metachronous CTGCT (a CTGCT diagnosed ≥6 months after a primary TGCT) and its impact on patient's prognosis was assessed in a nationwide cohort comprising 3749 TGCT patients treated in the Netherlands during 1965-1995. Standardised incidence ratios (SIRs), comparing CTGCT incidence with TGCT incidence in the general population, and cumulative CTGCT incidence were estimated and CTGCT risk factors assessed, accounting for competing risks. RESULTS: Median follow-up was 18.5 years. Seventy-seven metachronous CTGCTs were diagnosed. The SIR for metachronous CTGCTs was 17.6 (95% confidence interval (95% CI) 13.9-22.0). Standardised incidence ratios remained elevated for up to 20 years, while the 20-year cumulative incidence was 2.2% (95% CI 1.8-2.8%). Platinum-based chemotherapy was associated with a lower CTGCT risk among non-seminoma patients (hazard ratio 0.37, 95% CI 0.18-0.72). The CTGCT patients had a 2.3-fold (95% CI 1.3-4.1) increased risk to develop a subsequent non-TGCT cancer and, consequently, a 1.8-fold (95% CI 1.1-2.9) higher risk of death than patients without a CTGCT. CONCLUSION: The TGCT patients remain at increased risk of a CTGCT for up to 20 years. Treatment with platinum-based chemotherapy reduces this risk.

Safety and cost-effectiveness of shortening hospital follow-up after breast cancer treatment.

BACKGROUND: In the Netherlands, the first 5 years of follow-up after treatment for breast cancer are carried out in hospital with yearly mammography. After this, for patients aged over 60 years who have undergone mastectomy, there is a shift of care to the National Screening Programme (NSP) for mammography every 2 years. After breast-conserving therapy follow-up is perfomed by the general practitioner (GP), with mammography every second year and physical examination annually. The aim of this study was to evaluate the clinical effects and costs of four different strategies for follow-up after breast cancer treatment. METHODS: An extended and validated simulation model for breast cancer follow-up was used. The current guidelines for follow-up (baseline strategy) and three less intensive follow-up strategies were evaluated. The main outcome measure was the detection rate of small tumours (2 cm or smaller) and associated costs for each strategy. RESULTS: Shortening the follow-up time in hospital by shifting care to the NSP or GP after 2 years instead of 5 years of hospital follow-up, lowering the age of referral to the NSP or GP from 60 to 50 years, and termination of annual physical examination by the GP after hospital follow-up did not decrease the detection of small tumours. In addition, a substantial decrease in costs was observed with simplified follow-up. CONCLUSION: Decreasing hospital follow-up time, lowering the age of referral to the NSP or GP, and termination of annual physical examinations would lead to a substantial reduction in costs while maintaining the possibility of detecting small breast cancers.

A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study.

BACKGROUND: In ovarian cancer, cyclooxygenase-2 (COX-2) overexpression is prognostic for poor survival. We investigated the efficacy of celecoxib (C), a selective COX-2 inhibitor, added to docetaxel (Taxotere)/carboplatin (DC) in advanced ovarian cancer. PATIENTS AND METHODS: In a phase II, randomized study, 400 mg celecoxib b.i.d. was added to first-line DC treatment (DCC). Celecoxib was to be continued after DC termination up to 3 years. Study end points were tolerability, progression-free survival (PFS) and overall survival (OS). RESULTS: 151 of 196 eligible patients were diagnosed with stage IIIC/IV disease. Median follow-up for patients alive was 32.3 months. Celecoxib was used during a mean of 8.5 months. Twenty-three of 97 DCC patients stopped celecoxib prematurely, mainly due to skin reactions. Complete biochemical response was achieved in 51/78 DC patients (65%) versus 57/78 DCC patients (75%, not significant). In both study arms, median PFS was 14.3 months and median OS 34 months. COX-2 was expressed in 82% of 120 tumor samples retrospectively recovered. The PFS and OS of patients with intermediate/high COX-2 expression were similar to that in the other patients. CONCLUSION: Celecoxib did not influence PFS and OS, but interpretation of results is hampered by premature celecoxib discontinuation.

Breslow thickness in the Netherlands: a population-based study of 40 880 patients comparing young and elderly patients.

BACKGROUND: Melanoma incidence has increased rapidly in the last decades, and predictions show a continuing increase in the years to come. The aim of this study was to assess trends in melanoma incidence, Breslow thickness (BT), and melanoma survival among young and elderly patients in the Netherlands. METHODS: Patients diagnosed with invasive melanoma between 1994 and 2008 were selected from the Netherlands Cancer Registry. Incidence (per 100 000) over time was calculated for young (<65 years) and elderly patients (≥65 years). Distribution of BT for young and elderly males and females was assessed. Regression analysis of the log-transformed BT was used to assess changes over time. Relative survival was calculated as the ratio of observed survival to expected survival. RESULTS: Overall, 40 880 patients were included (42.3% male and 57.7% female). Melanoma incidence increased more rapidly among the elderly (5.4% estimated annual percentage change (EAPC), P<0.0001) than among younger patients (3.9% EAPC, P<0.0001). The overall BT declined significantly over time (P<0.001). Among younger patients, BT decreased for almost all locations. Among elderly males, BT decreased for melanomas in the head and neck region (P=0.001) and trunk (P<0.001), but did not decrease significantly for the other regions. Among elderly females, BT only decreased for melanomas at the trunk (P=0.01). The relative survival of elderly patients was worse compared with that of younger patients (P<0.001). CONCLUSION: Melanoma incidence increases more rapidly for elderly than for younger patients and the decline in BT is less prominent among elderly patients than among young patients. Campaigns in the Netherlands should focus more on early melanoma detection in the elderly.

Burden of testicular, paratesticular and extragonadal germ cell tumours in Europe.

We provide updated estimates of survival, incidence, complete prevalence, and proportion cured for patients with testicular/paratesticular and extragonadal germ cell cancers in Europe, grouped according to the new list of cancer types developed by RARECARE. We collected data, archived in European cancer registries, with vital status information available to 31st December 2003. We analysed 26,000 cases of testicular, paratesticular and extragonadal germ cell cancers diagnosed 1995-2002, estimating that about 15,600 new testicular/paratesticular and 630 new extragonadal cancer cases occurred per year in EU27, with annual incidence rates of 31.5/1,000,000 and 1.27/1,000,000, respectively. Slightly more than 436,000 persons were alive at the beginning of 2008 with a diagnosis of testicular/paratesticular cancer, and about 17,000 with a diagnosis of extragonadal germ cell cancer. Five-year relative survival was 96% for testicular/paratesticular cancer and 71% for extragonadal germ cell cancer; the proportions cured were 95% and 69%, respectively. We found limited variation in survival between European regions except for non-seminomatous testicular cancer, for which five-year relative survival ranged from 86% in Eastern Europe to 96% in Northern Europe. Survival for all cancer types considered decreased with increasing age at diagnosis. Further investigation is required to establish the real reasons for the lower survival in Eastern Europe. Considering the high prevalence of these highly curable cancers, it is important to monitor patients long-term, so as to quantify treatment-related risks and develop treatments having limited impact on quality of life.

Implementation of trastuzumab in conjunction with adjuvant chemotherapy in the treatment of non-metastatic breast cancer in the Netherlands.

Trastuzumab in conjunction with adjuvant chemotherapy markedly improves outcome. In the Netherlands, a national guideline was released in September 2005 stating that trastuzumab should be given in conjunction with adjuvant chemotherapy in women with HER2-positive breast cancer. Aim of this study was to identify the number of women with HER2-positive breast cancer and to evaluate the level of implementation of adjuvant trastuzumab in clinical practice nationwide. Women diagnosed with primary breast cancer between September 2005 and January 2007 were selected from the Netherlands Cancer Registry (NCR). HER2 status, adjuvant treatment and reasons to withhold trastuzumab were registered. 14,934 Breast cancer patients were diagnosed in this period of whom 1,928 (13%) had a HER2-positive tumour. Of all HER2-positive women receiving adjuvant chemotherapy, 66 (6%) did not receive trastuzumab. This percentage decreased from 10% at the time of introduction of the guideline to 4% in the study period September 2005-December 2006. Most common reasons to withhold trastuzumab were cardiovascular disease (29%) and patient refusal (21%). Of all HER2-positive patients who received adjuvant chemotherapy, 94% received trastuzumab. The implementation of trastuzumab in clinical practice was realized within 8 months after introduction of the new guideline.

Effect of hospital characteristics on outcome of patients with gastric cancer: a population based study in North-East Netherlands.

BACKGROUND: Surgical resection is an important factor in the curative treatment of gastric cancer. However a variety of aspects of surgical treatment that potentially influence outcome are still not well defined. This study aims to assess the influence of hospital type, referral pattern and proximal or distal location of the tumour on the ultimate survival. METHODS: From January 1994 to January 2007, a total of 5245 patients were diagnosed with gastric adenocarcinoma in the region of the Comprehensive Cancer Centre North-East Netherlands. Hospitals in this region were categorized into three types: teaching university (TU), teaching non-university (TNU), and non-teaching hospitals (NT). The influence of hospital type, referral for surgery and location of the tumour on the relative survival of operated patients was studied. RESULTS: Of the 5245 patients, 2334 patients underwent surgery. For operated patients, the 5-year relative survival was 42.5% for the TU versus 34.0% and 35.5% for respectively TNU and NT hospitals (p = 0.064), with no difference (p = 0.38) in relative survival (25.6-31.9%) in the proximal tumours. A significant difference was found between the hospitals in the 5-year relative survival in the distal tumours; 59.7% in the TU versus 36.4% in the TNU and 36% in the NT (p = 0.03 univariate), however this was not confirmed in the multivariate analysis (p = 0.184). High referral centres did not perform better as far as survival is concerned than low referral hospitals. In conclusion the hospital type in our region did not significantly influence outcome of surgery for gastric cancer.

Risk of third malignancies and death after a second malignancy in retinoblastoma survivors.

Retinoblastoma patients have a strongly increased risk of second malignancies, and survivors with a third or subsequent malignancy are increasingly observed. However, it has not been examined whether survivors who developed a second malignancy have a greater risk of a subsequent malignancy. On the basis of the Dutch retinoblastoma registry, the risk of a third malignancy was compared with cancer risk in the Dutch population. Cox model analysis with a time-dependent covariate was used to compare the subsequent malignancy risk and survival among patients with and without a second malignancy. Risk of a third malignancy was increased 8-fold compared with the general population. The hazard ratio (HR) of a third malignancy after a second malignancy was more than 7-fold increased compared to the risk of a second malignancy after retinoblastoma. Radiotherapy increased the risk 3-fold. A third malignancy was associated with worse survival compared with survival of patients only diagnosed with a second malignancy (HR=5.0). Survivors of retinoblastoma who already developed a second primary malignancy have an even higher risk of subsequent primary malignancies than retinoblastoma survivors without a second malignancy. Treating physicians and patients should be aware of this higher risk.

Long-term morbidity of adjuvant whole abdominal radiotherapy (WART) or chemotherapy for early stage ovarian cancer.

UNLABELLED: The aim of the study was to evaluate long-term toxicity of adjuvant treatment in early stage ovarian cancer survivors. Data from all patients treated in one hospital for early stage ovarian cancer diagnosed between 1980 and 1990 were collected using a structured data form. In 93 FIGO stages I and II patients, cytoreductive and staging surgery was performed; 15 received no adjuvant treatment (controls), 39 whole abdominal radiotherapy (WART) and 39 platin-based chemotherapy. Median age at diagnosis was 54 years (range 21-83 years). During follow-up, 49/93 (53%) patients have died with a median overall survival of 18.4 years (95% CI 12.8-23.9). In both the radiotherapy and the chemotherapy group, 50% of patients reported long-term side-effects (all grades) versus 13% of controls. Two patients in the WART group died from bowel complications. Secondary malignancies were observed in 16 patients. Of all patients alive at the last follow-up, 12/17 (71%) patients treated with radiotherapy and 11/18 (61%) treated with chemotherapy experienced long-term morbidity versus 2/9 (22%) controls (P=0.03). IN CONCLUSION: Long-term follow-up of early stage ovarian cancer patients showed lasting GI morbidity in the survivors treated with adjuvant radiotherapy, which has therefore become obsolete. Cisplatin-based chemotherapy caused peripheral neuropathy versus virtual absence of problems in the survivors of just surgery, emphasising the need for strict criteria before instigating adjuvant treatment.

Second primary tumours after a squamous cell carcinoma of the oral cavity or oropharynx using the cumulative incidence method.

The aim of this study was to define the incidence of second primary tumours (SPTs) after treatment of a first primary oral or oropharyngeal squamous cell carcinoma (SCC) and to define patient groups with an increased or decreased risk of developing SPT with adjustment for competing risks. Cancer registry data from 917 consecutive patients with primary oral or oropharyngeal SCC were reviewed. Outcomes considered were the incidence and location of the SPT. Cumulative incidence was assessed instead of cumulative risks for SPTs. 149 patients (16%) developed a metachronous SPT (median follow-up time 2.6 years). The 5-year and 10-year cumulative incidence was 13% (S.E. 1.2) and 21% (S.E. 1.7), respectively. Most SPT developed in the upper aerodigestive tract (n=65) and lungs (n=35). No statistically significant risk factors were identified when considering patient and index tumour characteristics. The advantage of this study was the large and homogeneous patient population and the correction for competing risks, resulting in a lower but more accurate estimation of the incidence of SPTs. Despite this lower, but still continuous risk, regular follow-up for over 10 years is indicated for all patients treated for cancer of the oral cavity and oropharynx.

Cancer in adolescents and young adults in north Netherlands (1989-2003): increased incidence, stable survival and high incidence of second primary tumours.

BACKGROUND: Lack of survival improvement in adolescents and young adults (AYA) with cancer has led to increased awareness of this young population. DESIGN: We carried out a population-based study of incidence and survival of primary tumours and second primary tumours in patients aged 12-24 in north Netherlands. Age-specific incidence rates per 100,000 and 3-year moving means were calculated. Factors associated with incidence and survival were assessed using a Poisson model, log-rank test and multivariate Cox proportional hazards analysis. RESULTS: From 1989 to 2003 a total of 1118 patients were diagnosed. The total age-specific incidence rates per 100,000 were as follows: males: 13.4 (12-15 years), 26.9 (16-19 years) and 27.5 (20-24 years) and females: 13.9, 20.7 and 20.7. Male : female ratio was 1.32. The overall estimated annual percentage change (EAPC) in incidence was 2.15% (P < 0.01). Five-year survival was 80.8% and did not improve during the study period. With median follow-up of 5.5 years (range 0.0-16.0) in our cohort the standardized incidence ratio (SIR) of second primary tumours was 30.55 (95% confidence interval = 19.96-44.76, P < 0.05). CONCLUSIONS: The total incidence of cancer in AYA increased (EAPC = 2.15%). Survival was unchanged. The SIR of a second primary tumour in this young cohort increased 31-fold. Further research is needed to study this increasing incidence and optimise treatment outcome in these young patients.

Pulmonary tumours in the Netherlands: focus on temporal trends in histology and stage and on rare tumours.

BACKGROUND: Recent temporal trends in histology and stage of pulmonary tumours in the Netherlands were studied. The incidence of rare pulmonary tumours was determined. METHODS: All tumours originating from the trachea, bronchus and lung recorded in the Netherlands Cancer Registry were included. Based on ICD-O morphology codes, five major subgroups were constructed: squamous carcinoma (SC), adenocarcinoma (AC), large cell (undifferentiated) carcinoma (LC), small cell lung cancer (SCLC) and other (including uncommon tumours). RESULTS: Between 1989 and 2003, 134,894 tumours were diagnosed. In men the age-adjusted incidence of SC and SCLC decreased, AC remained stable and LC increased. In women the incidence of all subgroups increased. Since 1996, a stage shift was observed with fewer patients in stage I and more patients in stage IV at diagnosis. This stage shift occurred equally in SC, AC and LC. In SC, fewer patients presented with stage IV disease than in AC and LC (25% vs 44% and 49% in 2003, respectively). The incidence of adenosquamous carcinoma decreased from 0.6 to 0.29/100 000 (p<0.001). The incidence of carcinoid tumours, sarcomatoid carcinomas and primary pulmonary sarcomas remained stable (0.44, 0.17 and 0.08/100 000, respectively). CONCLUSION: The incidence of smoking-related tumours decreased in men (especially SC and SCLC) and increased in women (all subgroups). More patients presented with stage IV disease. The incidence of non-smoking-related uncommon tumours remained constant.

Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer.

BACKGROUND: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. PATIENTS AND METHODS: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). RESULTS: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. CONCLUSIONS: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.