Marnix L.M. Lybeert

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial

BACKGROUND Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma. METHODS Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints. FINDINGS Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors. INTERPRETATION Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.

Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s Lymphoma

BACKGROUND Survivors of Hodgkins lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown. METHODS We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkins lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort. RESULTS With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30). CONCLUSIONS The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkins lymphoma. (Funded by the Dutch Cancer Society.).

Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for Endometrial Carcinoma

PURPOSE To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. PATIENTS AND METHODS The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. RESULTS 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). CONCLUSIONS The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.

Quality of life among long-term non-Hodgkin lymphoma survivors : A population-based study

The objective of this population‐based study was to document the long‐term effects (5–15 years postdiagnosis) of non‐Hodgkin lymphoma and its treatment on health‐related quality of life (HRQL) and social problems.

The impact of treatment, socio-demographic and clinical characteristics on health-related quality of life among Hodgkin’s and non-Hodgkin’s lymphoma survivors: a systematic review

Cancer survivors are at risk of experiencing adverse physical and psychosocial effects of their cancer and its treatment. Both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL) survivors face problems that can affect their health-related quality of life (HRQoL). The authors systematically reviewed the literature on HRQoL among HL and NHL survivors. A PubMed and PsychINFO literature search for original articles published until May 2011 was performed. Twenty-four articles, which met the predefined inclusion criteria, were subjected to a quality checklist. HL survivors showed the most problems in (role) physical, social and cognitive functioning, general health, fatigue and financial problems. In addition, HL survivors treated with a combination of therapies, with older age and female sex reported worse HRQoL. NHL survivors showed the most problems in physical functioning, appetite loss, vitality and financial problems. Having had chemotherapy was negatively associated with HRQoL, but no differences in chemotherapy regimens were found. Furthermore, in NHL survivors not meeting public exercise guidelines, HRQoL is low but can be improved with more exercise. More research on the longitudinal comparison between HL and NHL survivors and healthy controls should be performed in order to better understand the long-term (side) effects of treatment on HRQoL and possibilities to alleviate these.

A high level of fatigue among long-term survivors of non-Hodgkin's lymphoma : Results from the longitudinal population-based PROFILES registry in the south of the Netherlands

The course of fatigue and quality of life in survivors of non-Hodgkin’s lymphoma is unknown. The aims of this study were, therefore, to assess fatigue and quality of life in patients with non-Hodgkin’s lymphoma following primary treatment, compare fatigue and quality of life in these patients with those of an age- and sex matched normative population to assess the severity of concerns and identify associations with fatigue of survivors who remained fatigued. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with non-Hodgkin’s lymphoma from 1999–2009. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Fatigue Assessment Scale were completed once by 824 survivors of non-Hodgkin’s lymphoma (80% response rate); 434 survivors completed these questionnaires again 1 year later. Survivors of non-Hodgkin’s lymphoma reported more clinically relevant fatigue up till 10 years post-diagnosis compared to a normative population (P<0.001). Mean fatigue scores remained fairly stable over time (T1: x ¯=28, SD=26; T2:=30, SD=27, P=0.14): 22–28% of survivors reported deterioration, 19–23% reported improvement and 44–54% reported constant fatigue. Survivors who reported constant fatigue were more often diagnosed with stage IV disease and had more comorbid diseases. They were additionally more often female and divorced. Having comorbidities and being without a partner were also associated with constant fatigue in the normative population. In conclusion, six out of every ten responding non-Hodgkin’s lymphoma survivors reported a high level of fatigue up till 10 years after diagnosis. Mean fatigue scores remained stable over time and survivors reporting constant fatigue more often had stage IV disease at diagnosis and comorbidities.

Health related quality of life and symptoms after pelvic lymphadenectomy or radiotherapy vs. no adjuvant regional treatment in early-stage endometrial carcinoma : A large population-based study

OBJECTIVES Routine lymphadenectomy (LA) in early stage endometrial cancer does not improve survival. However, in the absence of lymph node metastasis, radiotherapy (RT) could be withheld and hence could result in less morbidity. Our aim was to evaluate health related quality of life (HRQL) in endometrial cancer survivors that received routine pelvic LA without RT compared to no LA, but RT in the presence of risk factors. METHODS Stage I-II endometrial cancer survivors diagnosed between 1999 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC-QLQ-EN24. ANCOVA and multiple linear regression analyses were applied. RESULTS 742 (77%) of the endometrial cancer survivors returned a completed questionnaire. 377 (51%) had received no LA nor RT (LA-RT-), 198 (27%) had received LA+RT-, 153 (21%) LA-RT+ and 14 patients (2%) had received both. LA+ women reported as higher lymphedema symptom scores (25 vs. 20, p=0.04). Women who were treated with RT reported higher gastrointestinal symptom scores vs. those who did not (23 vs. 16, p=0.04). HRQL scales were comparable between all four treatment groups. CONCLUSION Despite distinct symptom patterns among women who received LA or RT, no clinically relevant differences in HRQL were observed when compared to women not receiving adjuvant therapy. Using LA to tailor adjuvant pelvic radiotherapy and prevent over-treatment in low-risk patients cannot be recommended.

T1 AND T2 carcinoma of the urinary bladder: Long term result with external, preoperative, or interstitial radiotherapy

Between January 1974 and December 1984, 273 consecutive patients with cancer of the urinary bladder, Stages T1 or T2, any N, M0, were referred to the radiotherapy department of the Catharina Hospital at Eindhoven, The Netherlands and 265 were treated in a non-randomized fashion according to one of the three following schedules: 137 patients (67 T1, 70 T2) received radiotherapy only; 96 (44 T1, 52 T2) had preoperative radiotherapy followed by cystectomy and diversion according to the Bricker technique in 94/96; 32 patients (13 T1, 19 T2) had low total dose (12 Gy median) external radiotherapy followed by an interstitial cesium implant. The external radiotherapy fields included the pelvic structures. Total dose was 64 Gy median in the radiotherapy-only group and 40 Gy median in the preoperative irradiated group. The median follow-up in survivors was 81 months (range: 15-203). Locoregional relapse was observed in 50% in the group treated by external radiotherapy alone versus 17% in the group treated by preoperative radiation plus surgery and 28% of the patients who received cesium implant. During follow-up, 106/137 (77%), 67/96 (70%) and 13/32 (41%) patients died. In the radiotherapy-alone group, 38 died from intercurrent diseases, 36 from bladder cancer, two from therapy-related complications and cause of death was unknown in 30 patients. In the preoperative radiation group, the figures were 17 for intercurrent deaths, 26 related to progressive bladder cancer, 14 died due to perioperative complications and cause of death was unknown in 10. Cause of death was intercurrent in six and due to bladder cancer in seven patients treated by cesium implant. Probability of survival (calculated from the date of histological diagnosis) for the whole group, with censoring death to intercurrent disease was 53% at 5 years (56% for T1; 51% for T2) and 41% (40% for T1; 43% for T2) at 10 years. No significant difference was observed between T1 and T2 (p = 0.76). Survival in the treatment subgroups was, for patients treated by external radiotherapy only: 50% at 5 years and 33% at 10 years; for patients treated by external radiotherapy and surgery: 49% at 5 years and 42% at 10 years; for patients treated by cesium implant: 76% at 5 years and 76% at 10 years. Survival of patients in the cesium implant group was significantly better than in the other groups (p = 0.0001). Following variables were analyzed using the Cox proportional hazards model: age, gender, T1 or T2 stage, grade, cesium implant or not, and surgery or not.(ABSTRACT TRUNCATED AT 400 WORDS)

Adherence to national guidelines for treatment and outcome of endometrial cancer stage I in relation to co-morbidity in southern Netherlands 1995–2008

BACKGROUND Endometrial cancer (EC) occurs more frequently amongst women over 60years old, who often also suffer from co-morbidity. Since treatment guidelines are derived from clinical trials that usually exclude such patients, nevertheless these guidelines are also applied for older EC patients. We assessed the independent influence of age and co-morbidity on treatment modalities and survival of patients with stage I EC in everyday clinical practice, thereby also examining the implementation of Dutch guidelines on treatment, since 2000. METHODS All 2099 stage I EC patients diagnosed between 1995 and 2008 in the southern Netherlands were registered in the ECR (Eindhoven Cancer Registry) were included for analysis of the influence of age and co-morbidity on treatment and survival. For co-morbidity we used a modified version of Charlsons list, uniquely recorded in the ECR since 1993. A subgroup analysis was performed of patients who should have received adjuvant radiotherapy based on the risk factors advised in the Dutch guidelines of 2000. We considered five periods (1995-97; 1989-2000; 2001-03; 2004-06; 2007-08). RESULTS Having two or more co-morbid conditions resulted in a significant reduction of receiving adjuvant radiotherapy (Odds Ratio: 0.6, 95% Confidence Interval (95% CI): 0.3-1.0)) but receiving adjuvant radiotherapy did not appear to improve survival. After adjustment for age, tumour stage, tumour grade, period of diagnosis and treatment, co-morbidity increased the risk of death, especially diabetes (Hazard Ratio (HR) for mortality: 2.9,95% CI: 2.2-4.0), a previous cancer (HR: 2.6, 95%CI: 1.9-3.7) and cardiovascular disease (HR: 2.3, 95%CI: 1.7-3.2). The combination of two or more co-morbid conditions resulted in a HR of 3.0 (95%CI: 2.2-3.9). CONCLUSION Co-morbidity decreased the likelihood of receiving adjuvant radiotherapy in patients with stage I EC qualifying to undergo this according to the Dutch guidelines of 2000. Whereas adjuvant radiotherapy did not seem to affect survival in those patients, co-morbidity significantly did.

An increased utilisation rate and better compliance to guidelines for primary radiotherapy for breast cancer from 1997 till 2008: A population-based study in the Netherlands

Only scarce data are available on the utilisation rate of primary radiotherapy (RT) for patients with breast cancer. In this study, we compared the use of primary RT for patients with stages I-III breast cancer in 4 of the 9 Dutch Comprehensive Cancer Centres, focussing specifically on time trends as well as age effects. From the population-based cancer registries, we selected all females diagnosed with breast cancer between 1997 and 2008 (N=65,966, about 50% of all Dutch breast cancer patients in this period). We observed an overall increase in the use of primary RT for breast cancer patients ranging from 55-61% in 1997 to 58-68% in 2008. This can be explained by a higher rate of breast-conserving surgery (BCS), which was followed by RT in 87-99% of cases, and a reduced rate of total mastectomy (TM) which was followed by RT in 26-47% of cases. Increasing age was associated with a reduced use of RT, especially for those above 75. Finally, we observed a decrease in time of observed regional variances in the use of RT after BCS as well as after TM (for stage III disease). These findings can be attributed to the development and implementation of the Dutch nationwide guidelines for treatment of breast cancer.