Journal
Real-life treatment patterns and time to next treatment among patients with ovarian cancer in the pre-PARP inhibitor era: the OCRWE-Finland Study
Background: As the treatment landscape for advanced ovarian cancer (OC) evolves, it is important to understand patient outcomes in real-world clinical practice. OCRWE-Finland was an observational cohort study investigating OC outcomes, including treatment patterns, time to next treatment 1 (TTNT1), overall survival and healthcare resource utilisation, in Finland during the pre-PARPi era. Materials and methods: Patients included in OCRWE-Finland were diagnosed with OC between 2014 and 2019. Here, we report treatment patterns and TTNT1 outcomes (as a surrogate for progression-free survival) for patients in the high-grade serous ovarian carcinoma (HGSOC) cohort. Results: In OCRWE-Finland, there were 867 patients with HGSOC. Of the 811 patients who received first-line treatment, the most common regimen was surgery and adjuvant chemotherapy (53%), and 227 patients also received first-line bevacizumab. Median TTNT1 among 623 patients with stage III/IV disease was 19 months (95% confidence interval, 18–21 months), with no difference between patients with stage III or IV disease (p = 0.24). The presence versus absence of visible residual disease post-debulking surgery was associated with shorter TTNT1 among patients with stage III tumours (p = 0.031) but showed no impact for stage IV tumours (p = 0.55). First-line versus no first-line bevacizumab was associated with shorter TTNT1 among stages I–IV (p < 0.0001) but did not affect patients with stage III/IV tumours (p = 0.45). Interpretation: In the pre-PARPi era, prognosis for advanced OC was poor, particularly for patients with stage III tumours and visible residual disease or stage IV tumours regardless of the presence of residual disease. The increasing use of PARPis will hopefully help address the need for effective treatments in advanced OC.
Safe to save blood in ovarian cancer surgery – time to change transfusion habits
Background: Patients with advanced ovarian cancer (AOC) undergoing surgery are often subjected to red blood cell (RBC) transfusions. Both anemia and RBC transfusion are associated with increased morbidity. The aim was to evaluate patient recovery after the implementation of patient blood management (PBM) strategies. Methods: This retrospective cohort study included 354 patients with AOC undergoing surgery at Skane University Hospital Lund, Sweden, between January 2016 and December 2021. The gradual implementation of PBM strategies included restrictive RBC transfusion, tranexamic acid as standard medication before laparotomies and intravenous iron administered to patients with iron deficiency. Severe complications were defined as Clavien-Dindo (CD) grade ≥ 3a. Logistic and linear regression analyses were used to evaluate the differences between three consecutive periods. Results: After the implementation of new strategies, 52% of the patients had at least one transfusion compared to 83% at baseline (p < 0.001). There was no difference in the rate of severe complications (CD ≥ 3a) between the groups, adjusted odds ratio 0.55 (95% CI 0.26–1.17). The mean difference in hemoglobin before chemotherapy was -1.32 g/L (95% CI -3.04 to -0.22) when adjusted for blood loss and days from surgery to chemotherapy. The length of stay (LOS) decreased from 8.5 days to 7.5 days (p 0.002). Interpretation: The number of patients transfused were reduced by 31%. Despite a slight increase in anemia rate, severe complications (CD ≥ 3a) remained stable. The LOS was reduced, and chemotherapy was given without delay, indicating that PBM is feasible and without causing major severe effects on short-term recovery.
Implementing MyChoice® CDx HRD testing for the Nordics: lessons from 2021 to 2023
Background: Assessment of homologous recombinant deficient (HRD) phenotypes is key for managing Poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. To accommodate the need for a validated HRD platform and enhance targeted treatment of ovarian cancer patients, a Nordic core facility for the myChoice® CDx platform was established in Denmark. Materials and methods: Comparative calculations and statistics are based on information from test requisitions and results (Genome Instability Score [GIS], BRCA status and combined HRD status) obtained from ovarian and breast cancer samples submitted for HRD-testing by myChoice® CDx through the Nordic core facility in the 2-year period. Results: Copenhagen University Hospital received 1,948 requisitions during the 2-year period. Conclusive results were obtained in 89% of the tests, while 7% were inconclusive due to the lack of GIS and 4% were not able to be analysed. Comparing the conclusive HRD status results across countries, Sweden had the highest percentage of HRD positives (38%) compared to Denmark, Norway, and Finland (28–32%). Interpretation: The myChoice® CDx Nordic core facility has been well received among the Nordic countries and provides new insights on the influence of national guidelines on HRD testing. Overall, we experienced an efficient turnaround time and a high fraction of conclusive results. Interestingly, prior somatic BRCA testing is redundant when assessing HRD status through myChoice® CDx test since somatic BRCA screening is already a significant component of the myChoice® CDx test. Thus, it should be considered to omit prior somatic BRCA testing to ensure a rationalised HRD diagnostic flow optimised for clinical use.
Impact of parity on the incidence of ovarian cancer subtypes: a population-based case–control study
Parity is known to have a protective effect as regards ovarian cancer, but its effect on the different histological subtypes of ovarian cancer is not well known. The impact of parity on the incidence of ovarian cancer subtypes was studied. All Finnish women diagnosed 1994-2013 with ovarian cancer for the first time were included. Altogether, 5412 cases of ovarian cancer were identified in the Finnish Cancer Registry and stratified according to morphology into serous, mucinous, endometrioid, clear cell and others. Five age-matched controls were randomly selected for each case from the Finnish National Population Registry. Data on postmenopausal hormonal therapy were derived from the Registry of Prescribed drugs and used as cofactors. Multivariate conditional logistic regression for matched case-control data was used to examine the associations between parity parameters and ovarian cancer risk. Parous women had lower risk than nulliparous women in getting ovarian cancer of any type under age of 55 years. The odds ratio (OR) for serous cancer was 0.65 (95% confidence interval 0.56-0.77), for mucinous cancer 0.66 (0.52-0.83), for endometrioid cancer 0.52 (0.40-0.68), for clear-cell cancer 0.30 (0.19-0.46) and for other types 0.59 (0.43-0.80). In women aged 55 or older, the respective ORs were 0.86 (0.75-0.99), 0.78 (0.57-1.07), 0.61 (0.47-0.79), 0.44 (0.29-0.66) and 0.74 (0.57-0.95), adjusted for hormone therapy. Number of childbirths was associated with a trend toward reduction of risk, especially in serous and clear-cell cancers. Higher age at first birth was associated with higher risk of clear-cell cancer but otherwise age at first or last birth did not have an impact on the incidence of cancer subtypes. Childbirths decrease the risk of all histologic subtypes of epithelial ovarian cancer in women in premenopausal and postmenopausal age.
The trajectory of conditional, recurrence-free, and long-term survival in a complete 10-year cohort of patients with advanced ovarian cancer
Background: The prognosis in advanced ovarian cancer is generally poor since the majority experience recurrence. Nevertheless, there is a chance of cure and very long-term survival may be achieved. However, traditional survival metrics do not account for the dynamic changes in prognosis over time. Our objectives were to examine conditional, very long-term and recurrence-free survival, in addition risk-factors for recurrence. Methods: In this observational study, all patients diagnosed with advanced ovarian cancer between 2009 and 2018 in the Stockholm/Gotland region, Sweden, were identified in the Swedish Quality Registry of Gynecologic Cancer. Conditional and recurrence-free survival were estimated with the Kaplan Meier method. The association between predefined clinical factors and hazard of death was analysed with Cox regression yielding hazard ratio (HR) with 95% confidence interval (CI). Results: A total of 888 patients were analysed of which 87.0% (n = 740) experienced a recurrence and 8.5 % (n = 76) were alive > 10 years. The 5-year conditional survival increased from 33.0% (95% CI: 30–36) in patients who had survived 1 year to 57.0% (95% CI: 50–63) in patients who had already survived 5 years. The median recurrence-free survival was 18 months (95% CI: 16–19). Risk factors associated with recurrence included any residual tumour (> 10 mm; HR: 2.15; 95% CI: 1.65 to 2.80) and evidence of disease at end of first line treatment (HR: 2.40; 95% CI: 1.97 to 2.93; p < 0.001). Interpretation: Conditional survival improves significantly with time survived following an advanced ovarian cancer diagnosis. Most patients experience relapse within 1 year after completing first-line treatment, nevertheless long-term survival is possible.
Co-occurrence of symptoms after radiochemotherapy in locally advanced cervix cancer patients: a cluster analysis
State of the art combined radiochemotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) has shown improved disease control and survival as well as a significant reduction of organ related morbidity. However, LACC cancer survivors are still experiencing a spectrum of symptoms. The aim of this study was to identify co-occurring symptoms in cervix cancer survivors by using patient-reported outcome and physician assessed morbidity. EMBRACE I is a multicenter prospective observational study with 1416 LACC patients (2008-2015). Information on physician-assessed morbidity and patient-reported outcome was assessed at baseline and at regular follow-ups up with the CTCAE v.3 and EORTC-C30/CX24, respectively. Patients with at least 2 years of follow-up were included and data from 3 months to 2 years was used in the analysis. Factor analysis was used on both EORTC and CTCAE data with symptoms and follow-ups as observations. The extracted factors represent clusters of symptoms. Subsequently, regression models were built to investigate associations between the symptom clusters and QOL. The analysis included 742 patients. Despite the differences in the definition of physician-assessed and patient-reported symptoms, similar clusters are identified by the two assessment methods. Three main organ-related clusters are recognized for urinary, gastro-intestinal and vaginal morbidity. Furthermore, a general symptoms cluster where fatigue, pain, insomnia, neuropathy, and hot flashes have large weights is found. Lastly, a cluster with nausea, vomit and lack of appetite is also identified. The general, gastrointestinal and nausea clusters show significant associations with general QOL. This analysis on both PRO and physician-assessed morbidity found a cluster associated with general symptoms and organ-related symptom clusters (urinary, gastrointestinal, vaginal). This shows that LACC survivors experience a variety of co-occurring symptoms. Our analysis also shows that the cluster of general symptoms is associated with a decrease in QOL.
Script-based automatic radiotherapy planning for cervical cancer
This study aimed to develop fully automated script-based radiotherapy treatment plans for cervical cancer patients, and evaluate them against clinically accepted plans, as validation before clinical implementation. In this retrospective planning study, treatment plans for 25 locally advanced cervical cancer (LACC) patients with up to three dose levels were included. Fully automated plans were created using an in-house developed Python script in RayStation, and compared to clinically accepted manually made plans. Quantitatively, relevant dose statistics were compared, and average dose volume histograms (DVHs) were analyzed. Qualitatively, a blinded plan comparison was conducted between the clinical and automatic plans. The accuracy of treatment plan delivery was verified with the Delta4 Phantom+. The quantitative evaluation showed that target coverage was acceptable for all the automatic and clinical plans. The automatic plans were significantly more conformal than the clinical plans; median of 1.03 vs. 1.12. Mean doses to almost all organs at risk (OARs) were reduced in the automatic plans, with a median reduction of between 0.6 Gy and 1.9 Gy. In the blinded plan comparison, the automatic plans were the preferred plans or of equal quality as the clinical plans in 99% of the cases. In addition, plan delivery was excellent, with a mean gamma passing rate of 99.8%. Complete script-based plans were generated in 30-45 min; about four to ten times faster than manually made plans. The automatic plans had acceptable target coverage, lower doses to almost all OARs, more conformal dose distributions, and were predominantly preferred by the clinicians. Based on these results, our institution has implemented the script for clinical use.
Prevalence of human papillomavirus (HPV) types 16 and 18 in cervical cancer in Stockholm, Sweden during 2019–2023 compared to 2003–2008
The prevalence of different HPV types, especially HPV16 and 18 in cervical cancer in patients diagnosed 2019-2023 in Stockholm was compared to corresponding data from 2003-2008 before the introduction of HPV vaccination in Sweden. Cervical cancer samples from 125 patients diagnosed 2019-2023 in Stockholm were analysed for 27 HPV types by multiplex assay and the HPV type prevalence data was compared to data obtained in 154 cervical samples from 2003-2008. Patient median age was higher 2019-2023 compared to 2003-2008 (55-years vs. 42-years, The joint prevalence of HPV16 and 18 in SCC and ADC tended to be slightly lower in 2019-2023 as compared to 2003-2008, but the difference was not statistically significant.
Clinical outcomes using a 3D printed tandem-needle-template and the EMBRACE-II planning aims for image guided adaptive brachytherapy in locally advanced cervical cancer
Extensive local disease or narrow vagina may compromise brachytherapy (BT) in patients with cervical cancer. This is the first study to analyze long-term outcomes of using 3D printed vaginal tandem-needle templates (3DP TNT) for transvaginal insertion of needles in parallel (P) or parallel and oblique (P&O) direction to the tandem. All patients treated with BT using 3DP TNT from 2015-2020 were included. Decision to use a 3DP TNT and preplanning were made after 4-5 weeks of external beam radiotherapy, based on gynecological examination and MRI with a tandem-ring applicator 101 patients (median age of 63 years) were included: 49 with P needles only and 52 with P&O needles. Personalized TNT was used in 19 patients in the P&O group. Performance status (WHO) was > 0 in 48%. FIGO 3DP TNT for BT in cervical cancer provides successful management of very extensive local disease and/or unfavorable anatomy with the possibility for treatment individualization.
CBCT-based deformable dose accumulation of external beam radiotherapy in cervical cancer
Oncological management of pregnancy-associated cancers: analysis from the French CALG (Cancer Associé à La Grossesse) network
The influence of bevacizumab on the costs of ovarian cancer treatment in routine clinical practice
Surgery performed later in the week is associated with failure to achieve complete radical surgical resection in advanced ovarian cancer
Retrospective validation of coverage probability based simultaneous integrated nodal boost in locally advanced cervical cancer: a mono-institutional analysis
Treatment outcomes and the role of surgery in gestational trophoblastic neoplasia: a population-based cohort study
Background and purpose: Cure rates of gestational trophoblastic neoplasia (GTN) are excellent, however the surgical interventions in disease management are not well described. The primary aim of this study was to investigate the incidence and types of surgical procedures used for management of GTN and to report treatment outcomes in a population-based cohort. The secondary aim was to assess the impact of hysterectomy on time to human chorionic gonadotropin (hCG)-normalisation in low-risk GTN. Material and methods: Medical records of all patients treated for GTN at Karolinska University Hospital, Stockholm, Sweden between 1994 and 2020 were screened for treatment outcomes, types of surgical procedures and complications. Regression models were used to assess if hysterectomy affected time to complete remission in low-risk GTN. Results and interpretation: Over the 27-year study period, 185 patients with GTN were included. The primary complete remission rate was 98.4% and relapse rate 3.2%. Sixty-four patients (34.6%) underwent at least one surgical procedure; 39/154 (25.3%) of low-risk patients, 17/23 (73.9%) of high-risk patients and all (100%) patients with placental site or epithelioid trophoblastic tumour. No severe complications (Clavien-Dindo ≥3) were observed. Seven of 74 procedures (9.5%) were complicated by bleeding >1,000 mL or surgical site infection. Therapeutic hysterectomy significantly shortened time to hCG-normalisation in the low-risk group (48 vs 74 days, p = 0.002). This population-based study confirms the excellent cure rates and low relapse rates for GTN. Surgery plays an important role in the management of GTN with low risk of complications. Hysterectomy shortens time to hCG normalisation.
ARAP1 is an independent prognostic biomarker in older women with ovarian high-grade serous adenocarcinoma receiving first-line platinum-based antineoplastic therapy
The PROMova study comparing active and passive use of patient-reported outcome measures in ovarian cancer follow-up: effect on patient-perceived involvement, satisfaction with care, and usefulness
Patients with ovarian cancer often experience substantial health problems and side effects resulting in reduced quality of life (QoL). Different models of using patient-reported outcome measures (PROMs) during follow-up may improve the quality of care. This national, multicenter observational study investigated the effect of active use of PROMs on patient-perceived involvement, satisfaction with care, unmet needs, and QoL during follow-up of ovarian cancer. Ovarian cancer patients were recruited at the end of primary treatment at eight centers in Denmark. During 18 months of follow-up patients repeatedly completed European Organization for Research and Treatment of Cancer (EORTC) questionnaires covering health related QoL and symptoms. At the sites using PROMs actively (ACT), the clinician had access to an overview of the patient's scores during the clinical encounter. Clinicians using PROMs passively were alerted in case of severe development of symptoms. Following each encounter, patients evaluated their health service experience by completing the CollaboRATE scale of involvement in decision making, the Patient Experience Questionnaire, and ad hoc questions covering patient-perceived usefulness of the PROMs. A total of 223 patients were enrolled, i.e., 168 (75.3%) at five sites using ACT and 53 (23.8%) at three sites using them passively. We found no statistically significant difference in involvement in the decision making, satisfaction with care, unmet needs, and QoL between the two groups. The majority of patients found it useful to complete the PROMs, although it did not seem to significantly support them in raising issues with the oncologist. Active use of PROMs did not improve patients' experience of involvement in follow-up care as compared to passive use.
Societal costs of ovarian cancer in a population-based cohort – a cost of illness analysis
The societal cost associated with ovarian cancer (OC) is not well known. Increasing costs for new treatments and/or the impact of organizational changes motivates these costs to be described and communicated. This study aims to evaluate the cost of illness of OC in a population-based cohort. All patients diagnosed with ovarian, fallopian tube, primary peritoneal cancer, and serous cancer of undesignated primary site (UPS) in 2011-2012 were followed for six years. Direct costs, i.e., costs for health care expenditures, were gathered from the regional healthcare database. Information on indirect costs, i.e., costs of loss of production due to sick leave, was retrieved from Statistics Sweden. Sub-group analyses were conducted regarding stage, income levels, residential area, and diagnosis. The cost of illness for all stages during the six years of follow-up was €201,086 per patient, where indirect costs constituted 43.7%. The mean cost of illness per year per patient for all stages was €33,514. Direct costs were higher in advanced stages compared to early stages for every year from diagnosis. During the first two years, there were no differences in indirect costs between early and advanced stages. However, during the third year there was a difference with higher indirect costs in advanced stages. There was no difference in direct costs depending on income levels. Regarding residential area, there was a difference in the outpatient cost during the index and second year with higher costs when chemotherapy and follow-up were provided at county hospitals, compared to at the tertiary hospital. Indirect costs constituted a large part of the cost of illness over 6 years from diagnosis. This could indicate that even though treatment costs can be expected to rise with the introduction of new therapies, the societal cost may decrease when survival increase.
Nonepithelial ovarian cancer – the current clinical practice in the Nordic countries. Survey from the surgical subcommittee of the Nordic society of gynecological oncology (NSGO)
Nonepithelial ovarian cancer (NEOC) represents a wide variety of rare tumors. They are often diagnosed at an early stage and have a good prognosis compared to epithelial ovarian cancer. In the Nordic countries, the total annual number of patients diagnosed with ovarian cancer, Fallopian tube cancer or primary peritoneal carcinoma (hereafter ovarian cancer) was 2281 in 2014-2018, of which 3-10% were NEOC. International guidelines for diagnosis, treatment and follow-up have been developed. We present the results of a survey, aiming at clarifying current clinical practice in the Nordic countries. Between 09.2020 and 02.2021 a 33-question electronic survey was distributed to 22 hospitals in Finland, Sweden, Norway, Iceland and Denmark Twenty-one (95,4%) centers completed the survey. A total of 155 annual new NEOC cases treated in the Nordic countries were reported, corresponding to approximately 7% of all ovarian cancer cases. Most centers measured some or all of the recommended biomarkers routinely. Vaginal ultrasound and computed tomography (CT) were the preferred imaging modalities. The majority of centers conducted multidisciplinary team (MDT) meetings. The primary reported treatment was surgery. In 65% of centers, lymph node dissection was only performed in cases with suspicious lymph nodes. Surveillance was usually offered > four years. Despite, the presence of clinical European guidelines, variation in the current clinical practice amongst participating centers adhering to national guidelines was observed. Prospective clinical national research programs are sparse, and an enhanced cooperation in the Nordic countries toward development of a Nordic guideline and database is highly warranted and a prerequisite for future research, preferably in cooperation with the larger international groups.
Ovarian tumor frozen section, a multidisciplinary affair
Ovarian Cancer (OC) constitute the eighth most common cancers among women worldwide. Surgery remains the cornerstone in the management of OC. Intraoperative frozen section (FS) diagnosis is widely used to decide the surgery course. We aimed to assess the reliability of intraoperative FS diagnosis for treatment planning of patients with suspected OC from a multidisciplinary perspective. The clinical consequences of reclassification and the multidisciplinary management of the therapy plan, is the secondary aim of this study. To our knowledge, this information is sparely investigated. A single-center, retrospective population-based study of patients who underwent surgery for suspected OC between 2018 and 2020. Histopathological outcomes were classified as benign, borderline, or malignant. The FS diagnosis was the diagnostic test, and the final histopathology report was the gold standard. Diagnostic capability for treatment planning was assessed, and modifications made possible by overall clinical knowledge were discussed. A total of 358 patients were identified, of whom 187 were included in the FS group. Overall accuracy was 89.8%, and 19 patients were reclassified; the malignancy grade of 15 tumors was underestimated. Prevalence, sensitivity, specificity, positive predictive value, and negative predictive value for invasive malignancies on FS were 54.0% (CI 46.6-61.3%), 88.1% (CI 80.2-93.7%), 98.8% (CI 93.7-99.9%), 98.9% (CI 92.7-99.8%), and 87.6% (CI 80.6-92.4%), respectively. Tumors incorrectly graded by FS tended to be of borderline-related. The reliability of the FS methodology was an accurate test to help perform appropriate surgery and plan swift oncological treatment. FS is a reliable method to diagnose invasive malignancies and benign pathology. The communication between the pathologist, surgeon, and medical oncologist is highly important for both intraoperative decision-making and postoperative patient care.
Brain metastases in patients with ovarian cancer
Brain metastasis (BM) are uncommon among women with epithelial ovarian cancer (EOC). The frequency, risk factors and clinical repercussions of BM in these patients are not well described. We retrospectively evaluated EOC patients treated at our center from 2002 to 2020 and assessed their clinical parameters, risk for BM development and association with overall survival (OS). This cohort has a known high frequency of BRCA mutation carriers ( Among 1035 EOC patients, 29 (2.8%) were diagnosed with BM. The prevalence of BM are rare among EOC patients. However, the risk is three-fold higher among patients with
Management of low-grade cervical cytology in young women. Cohort study from Denmark
Cytology findings of atypical squamous cells of unknown significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) are common among women under 30, but evidence on best management strategy is insufficient. We therefore investigated how different management strategies used in Denmark influenced biopsy rates and detection of cervical intraepithelial neoplasia (CIN). Register-based cohort study including Danish women aged less than 30 years and born 1980-95, with ASCUS/LSIL as their first abnormal cervical cytology in 2008-16. Rates and relative risks (RR) of biopsy and detection of CIN3+, CIN2 and < CIN2 during two years follow-up were compared between women referred directly to colposcopy after ASCUS/LSIL or undergoing additional testing, including mRNA or DNA test for high risk HPV or repeat cytology. 19,946 women with ASCUS and 19,825 with LSIL were included in the study of whom 92% had adequate information about follow-up. Among women referred directly to biopsy, CIN3+ was detected among 21%, CIN2 in 17%, while 62% had < CIN2. Repeating cytology after 6 months reduced the biopsy rate to 44% of which 53% had < CIN2. Biopsy rates with HPV test were 67% for DNA test, 77% with 14-type mRNA test and 58% with 5-type mRNA test. The detection of CIN3+ was somewhat higher, between 13% and 14% for the three HPV tests vs. 11% with repeat cytology. However, the detection of < CIN2 (not indicating treatment) also increased with RR 2.11 (95% CI 2.01-2.21) for 14-type mRNA test, 1.35 (95% CI 1.29-1.41) for 5-type mRNA test, and 1.86 (95% CI 1.76-1.97) with HPV DNA test. The choice of management strategy influences both the detection rate for severe lesions (CIN3+) and the proportion of women followed up for potentially insignificant findings.
Toward PET/MRI as one-stop shop for radiotherapy planning in cervical cancer patients
Radiotherapy (RT) planning for cervical cancer patients entails the acquisition of both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Further, molecular imaging by Positron Emission Tomography (PET) could contribute to target volume delineation as well as treatment response monitoring. The objective of this study was to investigate the feasibility of a PET/MRI-only RT planning workflow of patients with cervical cancer. This includes attenuation correction (AC) of MRI hardware and dedicated positioning equipment as well as evaluating MRI-derived synthetic CT (sCT) of the pelvic region for positioning verification and dose calculation to enable a PET/MRI-only setup. 16 patients underwent PET/MRI using a dedicated RT setup after the routine CT (or PET/CT), including eight pilot patients and eight cervical cancer patients who were subsequently referred for RT. Data from 18 patients with gynecological cancer were added for training a deep convolutional neural network to generate sCT from Dixon MRI. The mean absolute difference between the dose distributions calculated on sCT and a reference CT was measured in the RT target volume and organs at risk. PET AC by sCT and a reference CT were compared in the tumor volume. All patients completed the examination. sCT was inferred for each patient in less than 5 s. The dosimetric analysis of the sCT-based dose planning showed a mean absolute error (MAE) of 0.17 ± 0.12 Gy inside the planning target volumes (PTV). PET images reconstructed with sCT and CT had no significant difference in quantification for all patients. These results suggest that multiparametric PET/MRI can be successfully integrated as a one-stop-shop in the RT workflow of patients with cervical cancer.
Adherence to international recommendations in the governance and organisation of Nordic cervical cancer screening programmes
Screening has been the primary reason for the decline in the incidence and mortality of cervical cancer in the Nordic countries since the beginning of screening in the 1960s. Recently, the incidence of cervical cancer has increased in the Nordic countries indicating the need to look closely at possibilities for further improvement in screening. This article provides an overview of cervical cancer screening programmes in the Nordic countries and whether the programmes adhere to international recommendations. Relevant and unambiguous screening recommendations were extracted from applicable literature and classified into legal framework, governance, organisation, and monitoring and evaluation. The up-to-date status of screening programmes and adherence to selected recommendations was gathered from official documentation and co-authors representing cervical cancer screening programmes in all the Nordic countries. A total of 168 recommendations were extracted and 54 of them were considered to be unambiguous and relevant. Forty-nine recommendations were included after synthesising similar recommendations. All Nordic countries adhere to recommendations related to legal framework, but adherence was lower with recommendations related to governance and organisation of screening. Monitoring and evaluation are also areas where adherence to recommendations could be improved. The Nordic cervical cancer screening programmes have substantially decreased cancer burden despite not fully adhering to many of the recommendations. The presented gaps in adherence suggest that there is room for improvement in the screening programmes. Establishing clearer governance structures would still increase the ability to manage changes such as implementing HPV testing as the primary screening method or modifying the programme when HPV vaccinated cohorts of women enter the target age for screening.
Automatic segmentation of pelvic organs-at-risk using a fusion network model based on limited training samples
Increase of cervical cancer incidence in Sweden in relation to screening history: population cohort study
Coverage probability planning for simultaneously integrated boosts of inguinal lymph nodes in vulvar cancer
Strategies for minimizing irradiation of organs at risk (OARs) from pathological inguinal lymph node (PILN) boosting are needed to minimize the risk of morbidity. Coverage probability (CovP) is a conformal planning strategy for simultaneously integrated boost (SIB). Our aim was to investigate if SIB of PILN using CovP can be delivered safely in vulvar cancer. Ten consecutive patients treated with definitive radiotherapy (RT) including SIB of PILN and with daily cone beam CT (CBCT) were included. Dose prescription was 51.2/32 fx to the elective target and 64 Gy/32 fx to the gross disease at the vulva and to positive lymph nodes (LN). PILN were contoured on both planning CT and MRI (GTV-N) and combined to form ITV-N. Each PILN GTV-N was contoured on every third CBCT, in total 11 CBCT for each patient. OARs were subcutaneous tissue (SC), inguinal vessels, skin rim, bowel, and body contour. Three plans were created for every patient: A) Standard CT-based planning; PTV-N based on GTV-N Thirty-five PILNs were boosted. There was no significant difference in accumulated GTV-N D98% between the three plans. CovP delivered a higher mean dose to the GTV-N D50% and D2% ( SIB of PILN in vulvar cancer based on CovP and a 5 mm PTV margin does not compromise target coverage during RT and reduces the dose to normal tissues in the groin.
Inguino-femoral radiotherapy in vulvar squamous cell carcinoma: clues to revised indications in patients with only one intracapsular lymph node metastasis
Hypoxic gene expression is a prognostic factor for disease free survival in a cohort of locally advanced squamous cell cancer of the uterine cervix
Tumour hypoxia in locally advanced squamous cervical cancer (LACC) has been shown to be of substantial prognostic importance. The aims of the present study were therefore to investigate if hypoxia could be identified by a newly validated hypoxic gene expression classifier and used as a prognostic factor for disease free survival (DFS). Paraffin embedded biopsies were obtained from 190 patients with LACC with squamous cell carcinoma treated 2005-2016 with chemo-radiation and image guided adaptive brachytherapy. Analysis of hypoxia was successful in 183 patients (96%). Hypoxic classification of tumours into 'more' or 'less' hypoxic was based on 15 genes using the same method as in a prospective head and neck cancer trial (NCT02661152). HPV was genotyped using INNO-LiPA. Local tumour invasion was evaluated by the T-score. Primary endpoint was DFS analysed by Kaplan-Meier and Cox regression. Events were death of any cause, persistent disease, or recurrence. The FIGO Hypoxic gene expression is a prominent prognostic factor for DFS in LACC with SCC histology and should be considered for treatment stratification in clinical trials.
A practical method to improve the performance of knowledge-based VMAT planning for endometrial and cervical cancer
The aim of this work was to demonstrate a practical and effective method to improve the performance of RapidPlan (RP) model. 203 consecutive clinical VMAT plans (P For closed-loop validation, the difference of D The practical method of incorporating plan data of better-sparing OARs from both the clinical VMAT plans and the re-optimized plans could further improve the performance of the RP model.
Phase 1/2 trial evaluating the effectiveness and safety of dose-adapted Hypofractionated pelvic radiotherapy for Advanced Cervical cancers INeligible for ChemoTherapy (HYACINCT)
The standard treatment for locally advanced cervical cancer (LACC) is concurrent chemoradiation (CRT) followed by brachytherapy (BRT). The addition of chemotherapy (ChT) to radiotherapy (RT) is associated with a 7.5% improvement in overall survival but with more grade 3-4 acute toxicities (16.4% vs 4.9%, CRT vs RT alone). The risk-benefit ratio could be less favorable in advanced disease with renal dysfunction secondary to tumor-related hydronephrosis; borderline cardiac function; and frail patients. RT alone followed by BRT achieves long-term locoregional control <62%. Hypofractionated RT (HF-RT) using older techniques result in comparable disease control and low late toxicity rates (4-8%). Dose-adapted HF-RT using intensity-modulated RT with nodal simultaneous integrated boost (nSIB) could improve tumor control and toxicity, when ChT is contraindicated. The HYACINCT study is a two-phase study to determine the effectiveness and safety of HF-RT with nSIB in LACC when ChT is contraindicated. Phase 1 is a dose-escalation study using standard 3 + 3 design, to determine the maximum tolerated dose (MTD) for nSIB in combination with pelvic HF-RT (2.67 Gy x 15 fractions). Phase 2 is a single-arm clinical trial using Simon's two-stage design, to assess the efficacy of HF-RT with nSIB in terms of tumor response. Adult women with biopsy-proven, untreated LACC, with contraindication to ChT will be included in this trial. For the phase 1, the primary endpoint is dose-limiting toxicity (DLT), or any grade ?3 acute or sub-acute toxicity. The dose level at which incidence of DLT is ?33% is defined as the maximum tolerance dose (MTD). For the phase 2, the primary endpoint is complete response at 3 months post-treatment. Secondary outcomes are progression-free and overall survival, acute and late toxicity, and patient-reported outcomes (EPIC, EORTCQLQ C30 + CX24, PGIC, PCIS). Trial registration: NCT05210270.
SystematiC nurse-led cONsultations based oN Electronic patient-reported outcome among women with ovarian- or endometrial Cancer during chemoTherapy – protocol for the CONNECT study
The wait time to primary surgery in endometrial cancer – impact on survival and predictive factors: a population-based SweGCG study
Poor survival rates in different cancer types are sometimes blamed on diagnostic and treatment delays, and it has been suggested that such delays might be related to sociodemographic factors such as education and ethnicity. We examined associations of the wait time from diagnosis to surgery and survival in endometrial cancer (EC) and explored patient and tumour factors influencing the wait time. In this historical population-based cohort study, The Swedish Quality Registry for Gynaecologic Cancer (SQRGC) was used to identify EC patients who underwent primary surgery between 2010 and 2018. Factors associated with a wait time > 32 d were analysed with logistic regression. The 32-d time point was defined in accordance with the Swedish Standardisation Cancer Care programme. Adjusted Poisson regression analyses were used to analyse excess mortality rate ratio (EMRR). Out of 7366 women, 5535 waited > 32 d for surgery and 1098 > 70 d. The overall median wait time was 44 d. The factors most strongly associated with a wait time > 32 d were surgery at a university hospital (adjusted odds ratio [OR] 1.34, 95% confidence interval [CI] 1.08-1.66) followed by country of birth (OR 1.31, 95% CI 1.10-1.55) and year of diagnosis. There were no associations between wait time and histology or age. A wait time < 15 d was associated with higher mortality (adjusted EMRR 2.29,95% CI 1.36-3.84) whereas no negative survival impact was seen with a wait time of 70 d. Age, tumour stage, histology and risk group were highly associated with survival, whereas education, country of origin and hospital level did not have any impact on survival. Surgery within the first two weeks after EC diagnosis was associated with worsened survival. A prolonged wait time did not seem to have any significant adverse effect on prognosis.HighlightsSurgery within the first two weeks after diagnosis of endometrial cancer (EC) was associated with poorer survival.A prolonged wait time to surgery did not worsen prognosis.Delay in time to surgery was associated with sociodemographic factors.
Struma ovarii with synchronous ascites and elevated CA125 level: a retrospective cohort study
Benign struma ovarii (SO) with synchronous ascites and elevated CA125 level is extremely rare that the incidence, clinical characteristics, and risk factors remain unclear. We conducted a retrospective study of patients with SO treated in our hospital between 1980 and 2022. Logistic regression was used to identify potential risk factors for SO patients presenting with ascites and elevated CA125 levels. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of the identified risk factors. A total of 21 patients with synchronous ascites and elevated CA125 levels were identified in 229 patients with SO, the crude incidence rate was 9.17%, and four patients (1.75%) had pseudo-Meigs' syndrome. Ascites were completely involuted within 1 month postoperatively and the serum CA125 level decreased to normal between 3 d and 6 weeks after surgery. Multivariate logistic regression showed that age ≥49 years (OR 3.71, 95% CI 1.29 - 10.64, Less than one-tenth of patients with SO would present ascites and elevated CA125 levels, while age ≥49 years, tumor sizes ≥10 cm, and the presence of proliferative SO were the risk factors.
Radiologically enlarged cardiophrenic lymph nodes and CA-125 in relation to diaphragmatic carcinomatosis, surgical outcome, and overall survival in advanced ovarian cancer
We primarily aimed to determine whether the presence of enlarged cardiophrenic lymph nodes (CPLNs), visualized by computed tomography (CT), and CA-125 can be used to assess diaphragmatic carcinomatosis and residual disease (RD) in advanced ovarian cancer (AOC) patients treated with upfront surgery. The secondary aim was to determine the prognostic role of CT-CPLNs in overall survival (OS). A single-center, retrospective, population-based study was conducted of patients who underwent surgery for AOC from January 1, 2014-December 31, 2018. Suspicious CT-CPLNs were defined as having a short axis ≥5 mm. The median survival and rate of survival were calculated with the Kaplan-Meier method using multivariate Cox regression analyses, including comparisons of complete cytoreductive surgery (CCS; defined as the complete removal of all intra-abdominal tumor) versus noncomplete cytoreductive surgery (non-CCS) and analyses related to CT-CPLN status and preoperative CA-125 values. We included 208 patients. CT-CPLNs correlated with both diaphragmatic carcinomatosis (OR 3.59, 95% CI 1.81-7.16, Enlarged CPLNs on CT scans and CA-125 levels correlate with diaphragmatic carcinomatosis and RD at the end of the surgery. The strongest prognostic factor for OS remains CCS, regardless of the CT-CPLN status.
HE4 in the evaluation of tumor load and prognostic stratification of high grade serous ovarian carcinoma
Human epididymis protein 4 (HE4) is a validated, complementary biomarker to cancer antigen 125 (CA125) for high grade serous ovarian carcinoma (HGSC). Currently, there are insufficient data on the utility of longitudinal HE4 measurement during HGSC treatment and follow up. We set to provide a comprehensive analysis on the kinetics and prognostic performance of HE4 with serial measurements during HGSC treatment and follow up. This prospective study included 143 patients with advanced HGSC (ClinicalTrials.gov identifier: NCT01276574). Serum CA125 and HE4 were measured at baseline, before each cycle of chemotherapy and during follow up until first progression. Baseline biomarker values were compared to the tumor load assessed during surgery and to residual disease. Biomarker nadir values and concentrations at progression were correlated to survival. The baseline HE4 concentration distinguished patients with a high tumor load from patients with a low tumor load assessed during surgery ( HE4 is a feasible biomarker in the treatment monitoring and prognostic stratification of patients with HGSC. Specifically, the serum level of HE4 at first relapse was associated with the survival of patients and it may be a useful complementary tool in the selection of second line treatments. This is to the best of our knowledge the first time this finding has been reported.
Treatment of vulvar cancer recurrence with electrochemotherapy: a case-control study
Background: Electrochemotherapy (ECT) is a combined treatment method based on electroporation and simultaneous chemotherapy. In cases where radiotherapy has previously been used, surgery is often the only treatment option for vulvar cancer recurrence with potential resection of clitoris, vagina, urethra or anal sphincter. The unique advantage of ECT is its selectivity for cancer cells while sparing the surrounding healthy tissue. The aim of the study was to compare the ECT treatment of vulvar cancer recurrence for non-palliative purposes with surgical treatment. Materials and methods: Eleven patients with single vulvar cancer recurrence were treated with ECT and followed up for 12 months. As a control group, 15 patients with single vulvar cancer recurrence were treated with wide local excision. The following data were collected, analyzed and compared: Age, body mass index, comorbidities, histological type, location and size of vulvar cancer recurrence, treatment history, details of procedures and hospital stay. Results: The probability curves for local tumor control did not differ between the ECT group and the surgical group (p = 0.694). The mean hospital stay and the mean duration of procedure were statistically significantly shorter in the ECT group (p < 0.001). There were no statistically significant differences between the ECT and surgical groups in terms of mean body mass index, associated diseases, previous treatments, presence of lichen sclerosus, p16 status, gradus, anatomical site of the tumor, and type of anesthesia. Conclusion: In this case-control study, treatment of vulvar cancer recurrence with ECT for non-palliative purposes was comparable to surgical treatment in terms of effectiveness. The results need to be confirmed in larger randomized trials.
Lynch syndrome screening in colorectal and endometrial cancers in Iceland
Background and purpose: Screening for Lynch syndrome (LS) with mismatch repair (MMR) protein immunohistochemistry (IHC) in all patients with newly diagnosed colorectal (CRC) and endometrial cancer (EC) was implemented in Iceland in 2017. The aim of the study is to assess the accuracy of screening in 2020–2022 and compare it to 2017–2019 when screening was initiated. Patients/materials and methods: All patients diagnosed with CRC and EC according to the Icelandic Cancer Registry in 2020–2022 were included. Screening results were crossmatched with a genotyping database from deCODE to calculate sensitivity and specificity for LS detection. Results: In 2020–2022, 429 of 522 (82%) diagnosed CRCs were stained and 90 of 106 (85%) ECs, compared to 74% of CRCs and 82% of ECs in 2017–2019. The screening protocol was followed in 90% of cases for CRCs and 95% of cases for ECs compared to 89% and 68% during 2017–2019. The sensitivity of IHC as a screening method for LS was 70% and specificity 88% with a positive and negative predictive value of 8.4% and 99.4%, respectively. Interpretation: Three LS cases were missed with MMR IHC (1 MSH6 and 2 PMS2 carriers), it is possible these patients had sporadic cancers unrelated to their LS carrier status. MSH6 and PMS2 deficiency strongly predicts LS in Iceland.
The false-negative rate of sentinel lymph node biopsy and its related factors in early-stage cervical cancer: a systematic review and meta-analysis
Background and purpose: The objective of this systematic review and meta-analysis was to evaluate the false-negative rate (FNR) of sentinel lymph node biopsy (SLNB) performed in patients with early-stage cervical cancer (ECC), and to study the risk factors affecting FNR.Material and methods: We searched three databases (Embase, MEDLINE, and Cochrane Central Library) for articles published in the last decade from January 2014 to September 2024. Publications on patients with ECC who underwent SLNB, with information on the FNR of SLNB, were included. The QUADAS-2 tool was used to assess the risk of bias and the clinical applicability of the included studies. The FNR and associated factors were synthesized using random-effects meta-analysis and meta-regression.Results: A total of 49 eligible studies with a low to moderate risk of bias were included in the final analysis. The overall FNR was 10.9% (95 CI: 6.0–16.7). No significant differences in FNR were found for different reference standards or tumor diameters (< 2 cm vs. ≥ 2 cm). However, different tracers (e.g. methylene blue [MB], carbon nanoparticle [CNP], indocyanine green [ICG], and Technetium-99m [Tc-99m] combined with other tracers) appear to account for the different FNRs. In the meta-regression analysis, we found that the proportion of SLNs located in the obturator area was significantly negatively associated with FNR (coefficient = −0.88, p = 0.04). Interpretation: The overall FNR of SLNB for ECC was approximately 10.9%. Factors that tended to reduce the FNR included using a low-volume metastatic detection technique, having a tumor diameter of < 2 cm, employing specific tracer regimens, and identifying more than one lymph node in the obturator fossa. Registration: PROSPERO (CRD42024608411)
The clinical utility of circulating human papillomavirus across squamous cell carcinomas
Background and purpose: The similarities in biology, treatment regimens and outcome between the different human papillomavirus (HPV) associated squamous cell carcinomas (SCCs) allow for extrapolation of results generated from one SC tumor type to another. In HPV associated cancers, HPV is integrated into the tumor genome and can consequently be detected in the circulating fragments of the tumor DNA. Thus, measurement of HPV in the plasma is a surrogate for circulating tumor DNA (ctDNA) and holds promise as a clinically relevant biomarker in HPV associated cancers. With the present overview we aim to present the status of circulating HPV studies in SCCs, the clinical potential and the gaps of knowledge, with the overall aim to facilitate the next steps into clinically relevant prospective trials. Material and methods: We reviewed the literature and presented the data for each tumor type as well as analyses of the clinical utility across the SCC. Results and interpretation: A total of 41 studies were identified in cervical, head and neck and anal SCC and we discuss the common signals from the results across the different tumor sites. Our results not only confirm the strong clinical potential but also emphasize an urgent need to coordinate studies to allow for relevant sample sizes and statistical validations.
Tolerability, safety and feasibility of metformin combined with chemoradiotherapy in patients with locally advanced cervical cancer: A phase II, randomized study
Background and purpose: Locally advanced cervical cancer is treated with chemoradiotherapy. The treatment-related morbidity is high. Tumor hypoxia has prognostic impact and represents a valid, interventional target. This phase II study investigated efficacy of the antidiabetic drug metformin to modify hypoxia according to established biomarkers. Preliminary results including tolerability, safety and feasibility are reported here. Patients and methods: Patients were included in a 1:1 randomized, open-label design, comparing standard chemoradiotherapy ± metformin. Metformin 850 mg twice daily was administered 1 week before and during chemoradiotherapy. Magnetic resonance images (MRI) and tumor biopsies were collected at baseline, after 1 week of metformin treatment, and at brachytherapy for biomarker assessments. Tolerability and safety were determined by treatment completion rates and frequency of adverse events (AEs). Safety was further evaluated by possible increase in MRI-based hypoxia during the first week of metformin. Feasibility was determined by proportion of completed study interventions and imaging and biopsy procedures. Results: In total, 18 and 23 patients were allocated to the intervention and control arm, respectively. Eighteen and 15 patients completed metformin treatment for 1 and 5 weeks. Frequency of AEs ≥ grade 3 was not significantly different between study arms. Most AEs were gastrointestinal toxicities. Tumors with increase in hypoxia during the first week were all below the defined safety limit. A total of 98% of scheduled MR series and biopsies were collected with satisfactory quality. Interpretation: Addition of metformin to chemoradiotherapy is tolerable and safe. Serial sampling of MRI and tumor biopsies for hypoxia biomarker assessment is feasible.
Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma
Ovarian carcinoma is the eighth most common cause of cancer death in women worldwide. The disease is predominantly diagnosed at a late stage. This contributes to high recurrence rates, eventually leading to the development of treatment-resistant disease. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor and regulator of growth factor signaling. LRIG1 levels have not been investigated in human plasma previously. A quantitative LRIG1-specific single molecule array assay was developed and validated. LRIG1 levels were quantified in plasma samples from 486 patients with suspicious ovarian masses. Among women with ovarian carcinoma, LRIG1 levels were significantly elevated compared to women with benign or borderline type tumors. High LRIG1 plasma levels were associated with worse overall survival and shorter disease-free survival both in the group of all malignant cases and among the stage 3 cases only. LRIG1 was an independent prognostic factor in patients with stage 3 ovarian carcinoma. LRIG1 plasma levels were elevated in patients with ovarian carcinoma, and high levels were associated with poor prognosis, suggesting that LRIG1 might be an etiologic factor and a potentially useful biomarker in ovarian carcinoma.
L1CAM/CD171 expression in human tumors and its association with tumor phenotype
Background and purpose: L1CAM (CD171) is suggested to play a critical role in cancer. Because of its expression in only few normal tissues and its membranous nature, L1CAM is a promising drug target. Patient/material and methods: To clarify the role of L1CAM expression in different cancer types, a tissue microarray containing 20,079 samples from 135 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: Membranous L1CAM staining was found in 1,175 (9.1%) of 12,888 interpretable tumor samples, including 301 (2.3%) with weak, 569 (4.4%) with moderate, and 305 (2.4%) with strong positivity. 74 of 135 tumor entities showed L1CAM staining, and 36 tumor categories included at least one case with strong L1CAM staining. The frequency of L1CAM positivity was high in subtypes of neural and neuroendocrine neoplasms (up to 100%), endometrium carcinoma (24.1-31.3%), ovarian cancer (10.0-33.1%), cervical adenocarcinoma (9.1%), malignant melanoma (24.1-31.3%), malignant mesothelioma (16.7-20.8%), adenocarcinomas of the gastrointestinal and biliopancreatic tract (4.9-14.1%), and in urothelial tumors (up to 10.3%). High L1CAM expression was associated with invasive tumor growth (pTa vs. pT2-4) in urothelial carcinoma of the bladder (p<0.0001) and with mismatch repair deficiency in colorectal adenocarcinoma (p=0.0064). However, L1CAM staining was unrelated to tumor phenotype in seven other tumor entities. Interpretation: The results highlighted a small number of tumor entities that could be targeted by anti-L1CAM drugs, once these are proved to be sufficiently safe and efficient. L1CAM expression does not appear to confer an aggressive phenotype to affected cancer cells.
Feasibility and outcome of genomics-guided treatment selection in advanced cancer – the MEGALiT explorative clinical trial
Background: Precision cancer medicine (PCM) is key to advancing cancer treatment beyond the standard of care. We performed an explorative clinical trial, MEGALiT, to investigate the feasibility, safety, and clinical benefit of genomics-based PCM in advanced cancer. Methods: MEGALiT recruited adult patients with advanced solid tumors refractory to standard treatment. Tumor DNA from newly acquired biopsies or ctDNA were analyzed for alterations targetable with the PD-L1 inhibitor atezolizumab, the MEK inhibitor cobimetinib, the mTOR inhibitor everolimus, or the PARP-inhibitor niraparib. Any other ‘in study’ treatment was left to the discretion of the physician. Results: Outcome data are reported for 153 patients. The median age was 65 years and the most common diagnoses were colorectal, prostate, and ovarian cancer. The median time from study inclusion to the Molecular Tumor Board was 35 days for tumor sampling by biopsy and 21 days by ctDNA. Of the 44 patients allocated to a study drug, 38 started treatment. The median follow-up was 1.9 years. Of the patients on a study drug and evaluable for tumor response, 6% (2/32) had partial remission, and 25% (8/32) had disease control at 16 weeks. Median overall survival for patients starting a study drug was longer, 7.4 months, compared to 2.7 months for the 61 untreated patients (HR 0.43; log-rank p < 0.0001), but shorter than for the 50 patients receiving treatment of physician’s choice, 11.8 months (HR 0.55; log-rank p = 0.012). No significant procedure- or drug-related severe adverse events were observed. Interpretation: Genomics-guided treatment selection in advanced cancer is feasible and safe. However, evidence of patient benefit warrants further investigation.
Determining the effect of frailty on survival in advanced ovarian cancer: study protocol for a prospective multicentre national cohort study (FOLERO)
Background and purpose: There is an urgent need to improve patient-selection to surgical treatment in advanced ovarian cancer as our results showed that cytoreductive surgery was without effect or even detrimental in a yet unknown subgroup of women. With an ageing population, 30% of women with advanced ovarian cancer in Sweden are >75 years. Nevertheless, there are no recommendations on patient-selection, albeit treating an unselected population in a public and centralized health care setting. Little attention has been placed on frailty assessments in oncology, despite their potential to stratify the risk of adverse outcome and mortality. Consequently, we hypothesize that frailty is a predictor of poor survival. Patients and methods: In this Swedish multi-centre prospective cohort study, where the exposure is frailty, consecutive women with advanced ovarian cancer scheduled for surgery with curative intent are eligible for inclusion. Three different frailty instruments are evaluated preoperatively, blinded to the caregiver. The primary outcome is 2-year overall survival. With a fixed sample size of 450 patients, a two-sided α of 0.05 and β of 0.20, the study is powered to detect a difference in 2-year survival of 12.5% by frailty, assuming a 20% prevalence of frailty. The result of the study will have a direct impact on clinical management and patient-selection as the results are expected to have a high external validity. Total study-time is 5 years, with 3 years of accrual. All participating centres started accrual by September 2024. Presentation of data on primary outcome is expected 2029. Study registration: ClinicalTrials.gov NCT06298877
Quantifying the dosimetric impact of online daily adaptation for MR-guided RT in cervical cancer
Purpose: This study assessed the inter- and intra-fractional dosimetric impact of MR-Linac-based adaptive radiotherapy for cervical cancer (CC). Methods: A retrospective analysis of five node-negative, locally advanced cervical cancer patients treated under the MOMENTUM study (NCT04075305) using adapt-to-shape (ATS) on an Elekta Unity MR-Linac. Assessing the dosimetric impact of daily online adaptations: (1) comparing dose between daily adapted (MR-adapted) and non-adapted (MR-guided) plans, by quantifying dose differences relative to reference plans (by 2 and 5%) and evaluating adaptation frequency; (2) performing intra-fraction dose evaluations. Dose metrics for targets and organs at risk (OARs) were evaluated following EMBRACE II guidelines. Results: MR-adapted plans improved target coverage or reduced OAR dose in 82–100% of fractions at a 2% dose deviation (and in 25–84% at a 5% deviation), compared to MR-guided plans. Dose reductions for OARs ranged from 2 to 8% for D0.1%, 4.77–16.70% for V4000cGy and 2.10–14.00% for V3000cGy. Intra-fraction analysis showed that the difference between daily planned and delivered doses in all target structures was not clinically significant, ranging from 0.08 to 2.20%, except two fractions that experienced higher deviations (5%) in ITV45. Treatment was well-tolerated, with no Grade 2 or 3 toxicities reported. Interpretation: MR-guided plans required adaptation in 25–100% of the fractions when compared to MR-adapted plans. MR-adapted plans demonstrated enhanced target dose consistency and reduced OAR dose for all patients, highlighting the benefits of daily adaptation. Despite longer treatment times, dose accuracy was preserved. Toxicity results for MRgART in CC appear promising.
Prognostic factors and overall survival among patients with ovarian cancer in the pre-PARP inhibitor era: the OCRWE-Finland study
Background: Despite recent treatment advances in ovarian cancer (OC), more real-world evidence studies investigating patient outcomes are needed. OCRWE-Finland was an observational cohort study investigating OC outcomes in Finland during the pre-PARP inhibitor era. Patients: Patients were diagnosed with OC between 2014 and 2019 in Finland. This analysis reports baseline characteristics of all patients, patients with high-grade serous OC (HGSOC), and overall survival (OS) for patients with HGSOC. Results: Among 1,711 patients diagnosed with OC, 867 (51%) had HGSOC. The absence versus presence of visible residual disease post-debulking surgery was associated with improved OS for patients at stage III (n = 303; median: NR vs. 43 months; p = 0.005), but not stage IV (n = 118; median: 37 months vs. 40 months; p = 0.96). Bevacizumab treatment at any line at stages III/IV improved OS in the short-term only. Receiving versus not receiving bevacizumab at first-line for patients with visible residual disease post-debulking surgery was associated with improved OS at stage III (median: 48 months vs. 36 months; p = 0.003), but not stage IV (median: 42 months vs. 37 months; p = 0.26). Multivariate Cox regression analyses showed that stage IV at initial diagnosis and the presence of R2 classification post-debulking surgery resulted in poorer OS. Interpretation: In the pre-PARP inhibitor era, the absence versus presence of visible residual disease post-debulking surgery was associated with improved OS in stage III, but not stage IV HGSOC. First-line bevacizumab seemed to be beneficial in patients with stage III HGSOC and visible residual disease.
The effect of tinzaparin on biomarkers in FIGO stages III-IV ovarian cancer patients undergoing neoadjuvant chemotherapy – the TABANETOC trial: study protocol for a randomized clinical multicenter trial
Background: Tinzaparin, a low-molecular weight heparin (LMWH), has shown anti-neoplastic properties in animal models and in in vitro studies of human cancer cell lines. The reduction of CA-125 levels during neoadjuvant chemotherapy (NACT) in patients with epithelial ovarian cancer (EOC) co-varies with the prognosis; the larger the decrease in CA-125, the better the prognosis. Purpose: This study aims to evaluate the potential anti-neoplastic effects of tinzaparin by investigating changes in serum CA-125 levels in advanced EOC patients who receive NACT. Material and methods: This is an open randomized multicenter pilot trial. Forty patients with EOC selected to receive NACT will be randomized 1:1 to receive daily addition of tinzaparin or no tinzaparin. The processing and treatment of the patients will otherwise follow the recommendations in the Swedish National Guidelines for Ovarian Cancer. Before every cycle of chemotherapy, preoperatively, and 3 weeks after the last cycle of chemotherapy, a panel of biomarkers, including CA-125, will be measured. Patients: Inclusion criteria are women aged 18 years or older, World Health Organization performance status 0–1, histologically confirmed high-grade serous, endometrioid or clear cell EOC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV. In addition, a CA-125 level of ≥ 250 kIE/L at diagnosis. Exclusion criteria are contraindications to LMWH, ongoing or recent treatment with unfractionated heparin, LMWH, warfarin or non-vitamin K antagonist oral anticoagulants. Interpretation: This study will make an important contribution to the knowledge of the anti-neoplastic effects of tinzaparin in EOC patients and may thus guide the planning of a future study on the impact of tinzaparin on survival in EOC.
Association of body composition with toxicity to first-line chemotherapy and three-year survival in women with ovarian adenocarcinoma
This study aimed to evaluate the association of body composition with toxicity to first-line chemotherapy and three-year survival in women with ovarian adenocarcinoma. We enrolled, in a retrospective cohort, 239 women treated with carboplatin and paclitaxel between 2008 and 2017. Pretreatment computed tomography scans were used to quantify skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and subcutaneous adipose tissue index (SATI). Chemotherapy doses, related toxicities, potential drug-drug interactions (DDI), and clinical variables were collected from medical records. Outcomes were the number of adverse events Average age was 56.3 years and 35.1% had myopenia. Almost 33% had TIMT and 51.3% presented any grade 3 toxicity. Potential severe DDI occurred in 48.1% of the patients and 65.1% died three years after the first treatment. The SMD and SATI below the median were independent predictors for the number of adverse events Fewer amounts of SATI and low SMD were associated with the occurrence of toxicity to chemotherapy, and the low SMD increased the risk of death in the three years after oncologic treatment.
Clinical impact of BRCA2 mRNA expression in high-grade serous ovarian cancer: validation using the TCGA cohort
Blood natural killer cells during treatment in recurrent ovarian cancer
Recent research indicated favorable prognostic impact of intratumoral natural killer (NK) cells in ovarian carcinoma (OC). The role of NK cells during chemotherapy in OC is unknown. We investigated impact of NK cells in OC patients treated with palliative chemotherapy. Participants receiving palliative chemotherapy for recurrent OC ( Median OS in patients with low vs. high NK cell count at baseline was 7.1 months vs. 15.6 months ( A low blood NK cell count in recurrent metastatic ovarian cancer during chemotherapy is associated with unfavorable prognostic impact. Early increase in survival difference based on NK cell status suggests an association between NK cell count and treatment benefit.
Favorable prognostic impact of Natural Killer cells and T cells in high-grade serous ovarian carcinoma
Surgery performed later in the week is associated with inferior survival in advanced ovarian cancer
Complete macroscopic resection without any residual tumour after completion of surgery is a strong prognostic factor in advanced epithelial ovarian cancer (EOC). It has previously been reported that surgery performed later in the week is associated with failure to achieve complete macroscopic resection. Our objective was to examine if weekday of surgery influences oncologic outcome. This population-based observational study included 100% of all women diagnosed with advanced-stage invasive epithelial ovarian cancer between 2009-2011 and 2014-2016 in the Stockholm/Gotland County of Sweden. The association between weekday of surgery and survival was analysed with proportional hazards regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for predefined confounders. Out of 1066 identified women, 524 with advanced stage EOC treated with surgery were included in the final analysis. Surgery performed Wednesday to Thursday was associated with an increased hazard of death (HR 1.28, 95% CI 1.04-1.58, The increased mortality associated with surgery that is performed later in the week suggests that surgery for advanced ovarian cancer is best conducted early in the week.
Prospective randomised phase II trial evaluating adjuvant pelvic radiotherapy using either IMRT or 3-Dimensional planning for endometrial cancer
To compare the incidence of grade ≥2 gastrointestinal (GI) or genitourinary (GU) toxicity for patients undergoing 3DRT versus IMRT in the postoperative setting for endometrial cancer. Eligible patients were post-operatively randomly assigned to one of two parallel groups in a 1:1 ratio, to have their RT delivered using either a 3DRT technique or using IMRT. The prescription dose was 45 Gy in 25 fractions over 5 weeks followed by vaginal vault brachytherapy. Toxicity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0. Fisher's exact tests were used to test for associations between toxicity and arm. Differences in dosimetric parameters for patients with or without toxicity were tested using Mann-Whitney 84 patients with a median age of 62 were evaluable for primary outcome. The median follow-up was 52 months. 14 (35%) participants from the 3DRT arm and 15 (34%) from the IMRT arm experienced acute grade ≥2 GI toxicity with older patients having a statistically higher risk of grade ≥2 acute GI toxicity. 20 (50%) participants from the 3DRT arm and 25 (57%) from the IMRT arm experienced acute grade ≥2 GI or GU toxicity ( Although IMRT can reduce dose to normal tissue, in this study no benefit in acute GI or GU toxicity outcome was seen.
Combination of aneuploidy and high S-phase fraction indicates increased risk of relapse in stage I endometrioid endometrial carcinoma
Endometrioid endometrial carcinoma is a cancer type with generally excellent prognosis when diagnosed at an early stage, but there is a subset of patients with relapsing disease in spite of early diagnosis and surgical treatment. There is a need to find prognostic markers to identify these patients with increased risk of relapse. Depth of myometrial invasion, histological grade, and presence of lymphovascular invasion are known risk factors. DNA content (ploidy) and proliferation measured as S-phase fraction (SPF) have been discussed as prognostic markers but need additional evaluation. We evaluated relapse-free survival (RFS) with respect to ploidy and SPF, which was analyzed by flow cytometry on fresh tumor tissue, in a cohort of 1001 women treated for stage I endometrioid endometrial carcinoma in northern Sweden during the period of 1993-2010, with a median follow up time of 12.0 years. Data were obtained from historical records. In simple analysis, both aneuploidy and high SPF were associated to increased risk of relapse with hazard ratios (HR) 2.37 (95% CI 1.52-3.70) and 1.94 (95% CI 1.24-3.02), respectively. Our data also confirmed stage, tumor grade, and ploidy as independent prognostic markers in an age adjusted cox regression multivariable analysis but we did not find SPF to contribute to prognosis. However, the combination of aneuploidy and high SPF identified a group of patients with increased risk of relapse, HR 2.02 (95% CI 1.19-3.44). In this study, which is the largest study of ploidy and SPF in stage I endometrioid endometrial carcinoma using fresh frozen tissue, aneuploidy was shown to be an independent prognostic marker. Furthermore, the combination of aneuploidy and high SPF could be used to identify patients with increased risk of relapse.
Outcome and safety analysis of endometrial cancer patients treated with postoperative 3D-conformal radiotherapy or intensity modulated radiotherapy
We sought to analyze the toxicity rates and the treatment outcomes in endometrial cancer (EC) patients treated with postoperative three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The clinical data of 646 EC patients treated with postoperative adjuvant 3DCRT (265 patients, 41%) or with IMRT (381 patients, 59%) between April 2007 and August 2019 were retrospectively analyzed. The primary endpoints were treatment-related acute and late gastrointestinal (GI) and genitourinary (GU) toxicities. The secondary endpoints were LC and overall survival (OS) and disease-free survival (DFS). Median follow-up time was 37 months. The rates for acute GI and GU toxicities of any grade for the entire group were 55.6% and 46.8%, respectively. Acute grade ≥2 GI toxicity was significantly less in patients treated with IMRT compared to those treated with 3DCRT (11.0% vs. 19.2%, In this multicentric study involving one of largest patient population, we found that IMRT-treated EC patients showed comparable clinical outcomes but with a lower incidence of GI toxicities compared with those treated with 3DCRT.
Comparison of survival outcomes and effects of therapy between subtypes of high-grade endometrial cancer – a population-based study
Similarities in outcome between grade 3 endometrioid cancer and non-endometrioid histologies have been reported by a number of studies. Other reports, however, stated a significantly better prognosis for G3 endometrioid compared to type II histology. In this population-based study, we compared the outcome and treatment approaches of high-grade endometrial cancer patients with FIGO stages I-III depending on their histology. 284 high-grade endometrial cancer patients diagnosed between 1998 and 2015 were retrospectively analyzed. Overall survival (OS), recurrence-free survival (RFS), and recurrence rates were compared depending on histology. Type I G3 patients had a statistically significant OS advantage over women suffering from type II carcinoma (HR 1.527, 95%-CI 1.024-2.276; The prognosis of patients with type I G3 endometrial cancer patients seems to be significantly superior to patients with type II cancer and particularly carcinosarcoma. Systematic LND seemed to be beneficial in all of the three subtypes. The benefit of adjuvant treatment methods may differ between histologies.
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