Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.

BACKGROUND: After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. METHODS: In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. FINDINGS: At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17-3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for VBT and 2.1% (0.8-5.8) for EBRT (HR 2.08, 0.71-6.09; p=0.17). 1.5% (0.5-4.5) versus 0.5% (0.1-3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32-29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1-13.4] vs 5.7% [3.3-9.9]; HR 1.32, 0.63-2.74; p=0.46). We recorded no differences in overall (84.8% [95% CI 79.3-90.3] vs 79.6% [71.2-88.0]; HR 1.17, 0.69-1.98; p=0.57) or disease-free survival (82.7% [76.9-88.6] vs 78.1% [69.7-86.5]; HR 1.09, 0.66-1.78; p=0.74). Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215] vs 53.8% [112/208]). INTERPRETATION: VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. FUNDING: Dutch Cancer Society.

Adjuvant radiotherapy in patients with vulvar cancer and one intra capsular lymph node metastasis is not beneficial.

AIM OF THE STUDY: The aim of the study was to analyze the benefit from adjuvant radiotherapy in patients with vulvar cancer and a single positive node without extra capsular spread. MATERIALS AND METHODS: The study population comprised data of 75 patients with vulvar cancer and one lymph node metastasis. The patients were treated in three different university centers in Amsterdam, Groningen and Rotterdam between 1984 and 2005. RESULTS: Out of 75 patients, 31 (41%) were treated with adjuvant radiotherapy. Both disease-free survival (DFS) and disease-specific survival (DSS) were comparable between the groups who did and who did not receive adjuvant radiotherapy (HR 0.98, 95% CI 0.45-2.14, p=0.97 and HR=1.02, 95% CI 0.42-2.47, p=0.96). CONCLUSION: We could not demonstrate any beneficial effect of adjuvant radiotherapy in the group of patients with one intra capsular metastasis.

Total pelvic exenteration for primary and recurrent malignancies.

INTRODUCTION: Complete resection is the most important prognostic factor in surgery for pelvic tumors. In locally advanced and recurrent pelvic malignancies, radical margins are sometimes difficult to obtain because of close relation to or growth in adjacent organs/structures. Total pelvic exenteration (TPE) is an exenterative operation for these advanced tumors and involves en bloc resection of the rectum, bladder, and internal genital organs (prostate/seminal vesicles or uterus, ovaries and/or vagina). METHODS: Between 1994 and 2008, a TPE was performed in 69 patients with pelvic cancer; 48 with rectal cancer (32 primary and 16 recurrent), 14 with cervical cancer (1 primary and 13 recurrent), 5 with sarcoma (3 primary and 2 recurrent), 1 with primary vaginal, and 1 with recurrent endometrial carcinoma. Ten patients were treated with neoadjuvant chemotherapy and 66 patients with preoperative radiotherapy to induce down-staging. Eighteen patients received IORT because of an incomplete or marginal complete resection. RESULTS: The median follow-up was 43 (range, 1-196) months. Median duration of surgery was 448 (range, 300-670) minutes, median blood loss was 6,300 (range, 750-21,000) ml, and hospitalization was 17 (range, 4-65) days. Overall major and minor complication rates were 34% and 57%, respectively. The in-hospital mortality rate was 1%. A complete resection was possible in 75% of all patients, a microscopically incomplete resection (R1) in 16%, and a macroscopically incomplete resection (R2) in 9%. Five-year local control for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 89%, 38%, and 64%, respectively. Overall survival after 5 years for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 66%, 8%, and 45%. CONCLUSIONS: Total pelvic exenteration is accompanied with considerable morbidity, but good local control and acceptable overall survival justifies the use of this extensive surgical technique in most patients, especially patients with primary locally advanced rectal cancer and recurrent cervical cancer.

A comparison of quality of life between vulvar cancer patients after sentinel lymph node procedure only and inguinofemoral lymphadenectomy.

OBJECTIVES: The SLN-procedure has been introduced in vulvar cancer treatment to reduce morbidity and thereby improve quality of life. Aim of this study was to compare quality of life in vulvar cancer patients who were treated with a SLN-procedure only to those who underwent inguinofemoral lymphadenectomy. Moreover, it was evaluated what patients would advise relatives on the application of the SLN-procedure in light of possible false negative results. METHODS: Patients who participated in the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) were invited to fill out three questionnaires: the EORTC QLQ-C30, a vulvar specific questionnaire and a questionnaire about the opinion of patients on new treatment options. Patients who only underwent SLN-procedure were compared to those who subsequently underwent inguinofemoral lymphadenectomy because of a positive SLN. RESULTS: With a response rate of 85%, 35 patients after the SLN-procedure and 27 patients after inguinofemoral lymphadenectomy filled out the questionnaires. No difference in overall quality of life was observed between the two groups. The major difference was the increase in complaints of lymphedema of the legs after inguinofemoral lymphadenectomy. The majority of patients would advise the SLN-procedure to relatives. Patients after inguinofemoral lymphadenectomy were more reserved concerning the acceptable false negative rate of a new diagnostic procedure. CONCLUSIONS: Patients who underwent the SLN-procedure report less treatment related morbidity compared to those who underwent inguinofemoral lymphadenectomy. However, this did not influence overall quality of life. Furthermore, patients who underwent inguinofemoral lymphadenectomy are more reserved in advising the SLN-procedure to relatives.

The prediction of progression-free and overall survival in women with an advanced stage of epithelial ovarian carcinoma.

OBJECTIVE: Prognosis in women with ovarian cancer mainly depends on International Federation of Gynecology and Obstetrics stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free survival (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study was to determine predictors of PFS and OS in women with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. DESIGN: Retrospective observational study. SETTING: Two teaching hospitals and one university hospital in the south-western part of the Netherlands. POPULATION: Women with advanced stage EOC. METHODS: All women who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy between January 1998 and October 2004 were identified. To investigate independent predictors of PFS and OS, a Cox' proportional hazard model was used. Nomograms were generated with the identified predictive parameters. MAIN OUTCOME MEASURES: The primary outcome measure was OS and the secondary outcome measures were response and PFS. RESULTS: A total of 118 women entered the study protocol. Median PFS and OS were 15 and 44 months, respectively. Preoperative platelet count (P = 0.007), and residual disease <1 cm (P = 0.004) predicted PFS with a optimism corrected c-statistic of 0.63. Predictive parameters for OS were preoperative haemoglobin serum concentration (P = 0.012), preoperative platelet counts (P = 0.031) and residual disease <1 cm (P = 0.028) with a optimism corrected c-statistic of 0.67. CONCLUSION: PFS could be predicted by postoperative residual disease and preoperative platelet counts, whereas residual disease, preoperative platelet counts and preoperative haemoglobin serum concentration were predictive for OS. The proposed nomograms need to be externally validated.

[My mother is also a physician]. / Mijn moeder is ook dokter.

When the mother of the authoress started her medical education in 1949, 15% ofthe students were female. When the authoress followed in her footsteps 27 years later, about 30% of the students were female. In 2008, marking the 75th anniversary of the Dutch Association of Medical Women, the figure has risen to 66%. When the authoress began studying medicine, her mother, then 45, decided to specialise in microbiology. Her father, a teaching neurologist, increased his contribution to housekeeping so that his wife could realise her career move. It is sad that nowadays examples like this are still needed. Even when women outnumber men in medicine, the sexes are not represented equally in higher positions. The life of young female physicians is complicated as they combine work and home and struggle to divide time and attention among both areas. There is no easy solution, but historic examples of female physicians are a source of inspiration.

Cervical cancer in Bangladesh: community perceptions of cervical cancer and cervical cancer screening.

We investigated the awareness of, and the attitude towards screening for, cervical cancer in Bangladesh. We performed a qualitative study using focus group discussions (FGD). The framework approach to qualitative analysis was used. The study was performed in the catchment areas of Addin Hospital, Jessore, Southern Bangladesh (peri-urban) and LAMB hospital, Parbatipur, North West Bangladesh (rural). A total of 220 men, women and adolescents participated in 28 FGDs. Awareness of cervical cancer was widespread. Knowledge about causes was often inadequate. The perceived consequences of cervical cancer were numerous and awareness of the need for cervical cancer treatment was present. Barriers to accessing care include: low priority for seeking help for symptoms, limited availability of health services and cost. Most women were unaware of the possibility of screening via speculum examination, which was considered acceptable to women (and men), as long as the examination was done by a female healthcare provider in an environment with sufficient privacy. In conclusion, adequate gynaecological services are not available or accessible for most women in rural and peri-urban Bangladesh. However, awareness of cervical cancer is widespread. Screening for cervical cancer in these communities is acceptable if done by a female healthcare provider under conditions with sufficient privacy.

Work ability and return-to-work in cancer patients.

The extent to which self-assessed work ability collected during treatment can predict return-to-work in cancer patients is unknown. In this prospective study, we consecutively included employed cancer patients who underwent treatment with curative intent at 6 months following the first day of sick leave. Work ability data (scores 0-10), clinical and sociodemographic data were collected at 6 months, while return-to-work was measured at 6, 12 and 18 months. Most of the 195 patients had been diagnosed with breast cancer (26%), cancer of the female genitals (22%) or genitourological cancer (22%). Mean current work ability scores improved significantly over time from 4.6 at 6 months to 6.3 and 6.7 at 12 and 18 months, respectively. Patients with haematological cancers and those who received chemotherapy showed the lowest work ability scores, while patients with cancer of urogenital tract or with gastrointestinal cancer had the highest scores. Work ability at 6 months strongly predicted return-to-work at 18 months, after correction for the influence of age and treatment (hazard ratio=1.37, CI 1.27-1.48). We conclude that self-assessed work ability is an important factor in the return-to-work process of cancer patients independent of age and clinical factors.

Sentinel node procedure in vulvar squamous cell carcinoma: a histomorphologic review of 32 cases. The significance of anucleate structures on immunohistochemistry.

The sentinel lymph node (SLN) procedure is used in our institute in the setting of an observational multicenter study investigating the reliability of the sentinel node procedure in vulvar carcinoma (GROINSS-V: The Groningen International Study on Sentinel Nodes in Vulvar Cancer). One of our patients had a groin recurrence where the SLN had been reported as negative. After reviewing this SLN, it contained several anucleate, keratin-positive structures on immunohistochemistry, and in the same area on hematoxylin and eosin coloring, one single cell with a nucleus interpreted as a tumor cell. Our objective was to assess how frequently these anucleate structures occur and whether such nodes should be regarded as positive. The sentinel nodes from 32 patients with early-stage vulvar squamous cell carcinoma were reviewed. Seventy-seven SLN's were identified. In ten patients, the SLN was positive and a bilateral inguinofemoral lymph node dissection was subsequently performed. In two of these ten patients, both with a macrometastasis on SLN, further metastatic disease was present in the dissection specimen. Anucleate keratin-positive structures were seen on immunohistochemistry in 14 SLN's (18%), usually along with metastasis or single tumor cells, but in five nodes this was the only abnormality (mean follow-up period of 26.28 months). Anucleate keratin-positive structures are a common finding in immunohistochemical examination of SLN's. Our findings suggest that they are of no clinical significance and the SLN should be regarded as negative. When an atypical cell with a nucleus is present, the SLN should be classified as positive and further management should be accordingly.

Mammography: interobserver variability in breast density assessment.

Our objective was to determine the interobserver variability of breast density assessment according to the Breast Imaging Reporting and Data System (BI-RADS) and to examine potential associations between breast density and risk factors for breast cancer. Four experienced breast radiologists received instructions regarding the use of BI-RADS and they assessed 57 mammograms into BI-RADS density categories of 1-4. The weighted kappa values for breast density between pairs of observers were 0.84 (A, B) (almost perfect agreement); 0.75 (A, C), 0.74 (A, D), 0.71 (B, C), 0.77 (B, D), 0.65 (C, D) (substantial agreement). The weighted overall kappa, measured by the intraclass correlation coefficient (ICC), was 0.77 (95% CI: 0.69-0.85). Body mass index was inversely associated with high breast density. In conclusion, overall interobserver agreement in mammographic interpretation of breast density is substantial and therefore, the BI-RADS classification for breast density is useful for standardization in a multicentre study.

The incidence of parametrial tumor involvement in select patients with early cervix cancer is too low to justify parametrectomy.

OBJECTIVE: To determine the incidence of parametrial involvement in a select group of patients with early cervical cancer. METHODS: We retrospectively reviewed the records of patients with cervical cancer and a maximum tumor diameter of 2 cm, infiltration depth<10 mm and negative pelvic lymph nodes who underwent a radical hysterectomy in two university hospitals. In addition, the literature was reviewed. RESULTS: 103 patients were identified in our databases that met the abovementioned criteria. In two of these patients (1.94%), parametrial involvement was found. Both patients had LVSI. Literature review revealed 696 patients described in three studies that satisfied the selection criteria. Three (0.43%) of these patients had parametrial involvement. In patients with early stage cervical carcinoma, tumor size<2 cm, infiltration depth<10 mm, negative pelvic lymph nodes and absent LVSI the risk of parametrial involvement is 0.63%. CONCLUSION: Because of a very low risk on parametrial involvement, patients who fulfil strict selection criteria could be candidates for conization and pelvic lymphadenectomy instead of more extensive surgery. Morbidity and pregnancy complications may decrease while it is unlikely that survival will be compromised.

Preoperative predictors for residual tumor after surgery in patients with ovarian carcinoma.

OBJECTIVES: Suboptimal debulking (>1 cm residual tumor) results in poor survival rates for patients with an advanced stage of ovarian cancer. The purpose of this study was to develop a prediction model, based on simple preoperative parameters, for patients with an advanced stage of ovarian cancer who are at risk of suboptimal cytoreduction despite maximal surgical effort. METHODS: Retrospective analysis of 187 consecutive patients with a suspected clinical diagnosis of advanced-stage ovarian cancer undergoing upfront debulking between January 1998 and December 2003. Preoperative parameters were Karnofsky performance status, ascites and serum concentrations of CA 125, hemoglobin, albumin, LDH and blood platelets. The main outcome parameter was residual tumor >1 cm. Univariate and multivariate logistic regression was employed for testing possible prediction models. A clinically applicable graphic model (nomogram) for this prediction was to be developed. RESULTS: Serum concentrations of CA 125 and blood platelets in the group with residual tumor >1 cm were higher in comparison to the optimally cytoreduced group (p < 0.0001 and <0.01, respectively). Serum albumin and hemoglobin levels were lower in the group with residual tumor (p < 0.0001 and <0.05, respectively). The frequency of preoperative ascites was higher in the group with residual tumor (p < 0.0005). The prediction model, consisting of CA 125 and albumin, for remaining with residual tumor showed an area under the receiver operating characteristics curve of 0.79. A nomogram for probability of residual tumor >1 cm based on serum levels of CA 125 and albumin was established. CONCLUSION: Postoperative residual tumor despite maximal surgical effort can be predicted by preoperative CA 125 and serum albumin levels. With a nomogram based on these two parameters, probability of postoperative residual tumor in each individual patient can be predicted. This proposed nomogram may be valuable in daily routine practice for counseling and to select treatment modality.

"Cutaneous-type" angiosarcoma arising in a mature cystic teratoma of the ovary.

Benign and malignant somatic tumours arising in mature cystic teratomas of the ovary are a rare but recognised phenomenon. Squamous cell carcinoma is the most common somatic malignancy arising in ovarian teratomas, although many other types of tumour have been described. An angiosarcoma with "cutaneous" type typical features arising in a dermoid cyst of the ovary is reported. Vascular tumours have only rarely been described as secondary somatic tumours in ovarian teratomas. The diagnostic features and complications of such tumours are described.

Pitfalls in the sentinel lymph node procedure in vulvar cancer.

OBJECTIVES: There is an increasing interest among gynecologic oncologists to implement the sentinel lymph node (SLN) procedure in vulvar cancer patients in clinical practice. However, the safety of this promising method of staging still has to be proven in a randomized trial. MATERIALS AND METHODS: Two vulvar cancer patients are reported to illustrate pitfalls in the sentinel lymph node procedure. RESULTS: The phenomena of bypassing the sentinel lymph node and confusion about the number of removed sentinel lymph nodes are presented and discussed. CONCLUSION: Gynecological oncologists who perform the sentinel lymph node procedure in vulvar cancer patients should perform this technique by following a strict protocol and within the protection of a clinical trial.

Cancer, fatigue and the return of patients to work-a prospective cohort study.

Fatigue is a highly prevalent and debilitating symptom in cancer survivors. The aim of this study was to assess the impact of fatigue and other cancer-related symptoms on the return to work of cancer survivors. A prospective inception cohort study with 12 months of follow-up was initiated. At 6 months following the first day of sick leave, levels of fatigue, depression, sleep problems, physical complaints, cognitive dysfunction and psychological distress were assessed, in addition to clinical, sociodemographic and work-related factors. Data were obtained from one academic hospital and two general hospitals in the Netherlands. 235 patients who had a primary diagnosis of cancer and underwent treatment with curative intent were included. The rate of return to work was measured at 6, 12 and 18 months. Hazard ratios (HRs) for the duration of sick leave up to 18 months following the first day of sick leave were calculated. The rate of return to work increased from 24% at 6 months to 64% at 18 months following the first day of sick leave. Fatigue, diagnosis, treatment type, age, gender, depression, physical complaints and workload were all related to the time taken to return to work. Fatigue scores were also strongly related to diagnosis, physical complaints, and depression scores. Fatigue at 6 months predicted a longer sick leave with a hazard ratio of 0.71 (95% Confidence Interval (C.I.) 0.59-0.85), adjusted for diagnosis, treatment type, age and gender. In a multivariate Cox regression analysis, diagnosis, treatment, age, physical complaints and workload remained the only significant predictors of duration of the sick leave. 64% of cancer survivors returned to work within 18 months. Fatigue levels predicted the return to work. This was independent of the diagnosis and treatment, but not of other cancer-related symptoms. Better management of cancer-related symptoms is therefore needed to facilitate the return to work of cancer patients.

Pregnancy after EMA/CO for gestational trophoblastic disease: a report from The Netherlands.

OBJECTIVE: To investigate whether a desire for pregnancy changed after etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA/CO) treatment for gestational trophoblastic disease and whether the incidence of infertility and adverse pregnancy outcome differed from the general population. DESIGN: A cohort study was performed. Data were collected from hospital records and questionnaires. SETTING: The study was carried out in referral hospitals in The Netherlands. POPULATION: All women registered by the Dutch Working Party on Trophoblastic Disease and treated with EMA/CO were included. METHODS: A questionnaire was sent to all surviving patients treated with EMA/CO from 1986 until 1997. Women who underwent a hysterectomy were excluded from the study. MAIN OUTCOME MEASURE: Pregnancy outcome and pregnancy wish after chemotherapy. RESULTS: Fifty patients were treated with EMA/CO. In 86%, a complete remission was achieved. A questionnaire was sent to 33 patients. Response rate was 82% (27/33). After EMA/CO, 18 of the patients experienced a regular menstrual cycle. Three patients had an amenorrhoea. Fourteen patients had a pregnancy wish. Twelve patients conceived; 21 pregnancies occurred. Sixteen pregnancies were term deliveries. Two pregnancies ended in a miscarriage and two congenitally abnormal children were delivered prematurely. CONCLUSION: After EMA/CO, 86% of women with a pregnancy wish achieved pregnancy. However, women can be so anxious about a new pregnancy that they refrain from it. A causative relation between the two congenitally abnormal children and EMA/CO cannot be determined because of the small sample. The rate of miscarriages is not higher than in the general population. We can reassure patients that pregnancy after EMA/CO has a high probability of success and a favourable outcome. To diminish the fear of getting pregnant in some patients, psychosocial care should be considered in addition to medical care.

What doctors and patients think about false-negative sentinel lymph nodes in vulvar cancer.

The sentinel lymph node procedure is a relatively new, minimally-invasive method for the assessment of nodal status in malignancies such as breast cancer, cutaneous melanoma and vulvar cancer. Although highly accurate, this new method is inevitably associated with a certain false-negative rate, possibly leading to worse survival in a small subset of patients. The clinical implementation of the sentinel lymph node procedure is therefore a matter of ongoing debate, especially among doctors. The aim of this study was to assess opinions on the acceptable false-negative rate of the sentinel lymph node procedure in patients with vulvar cancer, who in the past had undergone standard routine radical vulvectomy and complete inguinofemoral lymphadenectomy (and frequently experienced complications), and in gynecologists treating patients with vulvar cancer. Structured questionnaires were sent to both patients and gynecologists. The patients had been treated for vulvar cancer between 1985 and 1993, and were all in complete remission with a median follow-up of 118 months (range: 76-185). Questions to the patients dealt with experienced side-effects of the standard treatment and opinion on the acceptable false-negative rate of the sentinel lymph node procedure. The response rate among patients was 91% (106/117). Forty per cent of the patients experienced one or more infections in the legs (cellulitis) and 49% of the patients still experience either severe pain and/or severe lymphedema in the legs. Sixty-six per cent of the patients preferred complete inguinofemoral lymphadenectomy in preference to a 5% false-negative rate of the sentinel lymph node procedure of 5%. Their preference was not related to age or the side-effects they had experienced. The response rate among gynecologists was 80% (80/100), of whom 60% were willing to accept a 5-20% false-negative rate of the sentinel lymph node procedure. While gynecologists may consider the sentinel lymph node procedure to be a promising diagnostic tool, the majority of vulvar cancer patients, who have undergone complete inguinofemoral lymphadenectomy in the past and have frequently experienced complications, would not advise introduction of this technique because they do not want to take any risk of missing a lymph node metastasis.