Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume.

PURPOSE: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. METHODS: A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. RESULTS: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. CONCLUSION: Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging.

Radical vaginal trachelectomy: long-term oncologic and fertility outcomes in patients with early cervical cancer.

OBJECTIVE: Radical vaginal trachelectomy is a fertility-preserving treatment for patients with early cervical cancer. Despite encouraging oncologic and fertility outcomes, large studies on radical vaginal trachelectomy are lacking. METHOD: Demographic, histological, fertility, and follow-up data of consecutive patients who underwent radical vaginal trachelectomy between March 1995 and August 2021 were prospectively recorded and retrospectively analyzed. RESULTS: A total of 471 patients of median age 33 years (range 21-44) were included. 83% (n=390) were nulliparous women. Indications were International Federation of Gynecology and Oncology (FIGO, 2009) stages IA1 with lymphvascular space involvement (LVSI) in 43 (9%) patients, IA1 multifocal in 8 (2%), IA2 in 92 (20%), IB1 in 321 (68%), and IB2/IIA in 7 (1%) patients, respectively. LVSI was detected in 31% (n=146). Lymph node staging was performed in 151 patients (32%) by the sentinel node technique with a median of 7 (range 2-14) lymph nodes and in 320 (68%) by systematic lymphadenectomy with a median of 19 (range 10-59) lymph nodes harvested. Residual tumor was histologically confirmed in 29% (n=136). In total, 270 patients (62%) were seeking pregnancy of which 196 (73%) succeeded. There were 205 live births with a median fetal weight of 2345 g (range 680-4010 g). Pre-term delivery occurred in 94 pregnancies (46%). After a median follow-up of 159 months (range 2-312), recurrences were detected in 16 patients (3.4%) of which 43% occurred later than 5 years after radical vaginal trachelectomy. Ten patients (2.1%) died of disease (five more than 5 years after radical vaginal trachelectomy). Overall survival, disease-free survival, and cancer-specific survival were 97.5%, 96.2%, and 97.9%, respectively. CONCLUSION: Our study confirms oncologic safety of radical vaginal trachelectomy associated with a high chance for childbearing. High rate of pre-term delivery may be due to cervical volume loss. Our long-term oncologic data can serve as a benchmark for future modifications of fertility-sparing surgery.

Oncologic and Fertility Outcomes After Simple Trachelectomy in Women With Early Cervical Cancer.

STUDY OBJECTIVE: This study aimed to present our case series of patients with early-stage cervical cancer undergoing simple trachelectomy (ST). Currently, radical trachelectomy is considered the most appropriate fertility-preserving procedure for the treatment of early-stage cervical cancer. However, there is increasing debate on the appropriate radicality of the surgery to preserve oncologic safety. DESIGN: Descriptive retrospective analysis of patient records and evaluation of questionnaires. SETTING: 2 gynecologic oncologic centers, surgeries performed by one surgical team. PATIENTS: 36 women with early-stage cervical cancer undergoing ST. INTERVENTIONS: Laparoscopic assisted simple vaginal trachelectomy. MEASUREMENTS: Demographic, histologic, fertility, and follow-up data of all patients who underwent ST between April 2007 and July 2021 were prospectively recorded and retrospectively analyzed. MAIN RESULTS: A total of 36 women (mean age: 28 years) underwent ST of whom 81% were nulliparous. Indications for ST were multifocal International Federation of Gynecology and Obstetrics stage IA1 (n = 30), stage IA1 L1 (n = 1), stage IA2 (n = 2), and stage IB1 (n = 3). Mandatory staging procedure was laparoscopic pelvic lymphadenectomy, including bilateral sentinel biopsy in 92% of the cases and systematic in 8%. Residual tumor was histologically confirmed in 8 specimens (22%); 18 women (50%) were seeking parenthood, and 13 succeeded (72%). There were 16 live births, all on term, with a median fetal weight of 3110 grams (2330-4420). One patient had a medical abortion owing to fetal congenital malformation. One pregnancy is ongoing. After a median follow-up of 91.5 months (9-174), all women are alive with no evidence of disease. CONCLUSION: ST represents a de-escalation compared with radical trachelectomy and provides excellent oncologic results with an outstanding fertility rate and obstetric outcome for patients with early cervical cancer. However, clear indications for this tailored fertility-preserving surgery have to be defined in well-designed trials.

[The COVID-pandemic and specialist training in Head and Neck oncology: A Survey among Physicians]. / Die COVID-19-Pandemie und ihr Einfluss auf die ärztliche Weiterbildung in der Kopf-Hals-Onkologie.

OBJECTIVE: The COVID-19 pandemic has had a profound impact on the healthcare system and medical education. In this publication, the influence of the pandemic on the education of physicians active in Head and Neck oncology was examined using a survey. METHODS: A survey comprising 53 questions was conducted to gather data on work settings, daily activities, team events, and educational aspects during the pandemic. A total of 497 oncologists participated, including 131 individuals working in the field of Head and Neck oncology. This subgroup consisted of 99 (75.6%) radiation oncologists, 10 (7.6%) maxillofacial specialists, and 22 (16.8%) otolaryngologists. RESULTS: Nearly half of the participants reported experiencing increased clinical burden, which resulted in reduced engagement in scientific activities. Digital platforms became the predominant mode of continuing education, albeit with reduced accessibility. The pandemic significantly impacted clinical training that involved direct patient interaction. On the other hand, positive effects were observed in terms of cost and availability for external educational events such as conferences. CONCLUSION: The findings highlight the detrimental effects of the COVID-19 pandemic on various aspects of medical education. While digitalization has accelerated in response, many physicians expressed a lack of professional interaction. Developing alternative digital learning platforms can provide a means to better cope with similar situations in the future. However, the importance of personal contact with colleagues and supervisors should not be overlooked when considering the quality of teaching.

Toxicity of dose-escalated radiotherapy up to 84 Gy for prostate cancer.

PURPOSE: The outcome of radiotherapy (RT) for prostate cancer (PCA) depends on the delivered dose. While the evidence for dose-escalated RT up to 80 gray (Gy) is well established, there have been only few studies examining dose escalation above 80 Gy. We initiated the present study to assess the safety of dose escalation up to 84 Gy. METHODS: In our retrospective analysis, we included patients who received dose-escalated RT for PCA at our institution between 2016 and 2021. We evaluated acute genitourinary (GU) and gastrointestinal (GI) toxicity as well as late GU and GI toxicity. RESULTS: A total of 86 patients could be evaluated, of whom 24 patients had received 80 Gy and 62 patients 84 Gy (35 without pelvic and 27 with pelvic radiotherapy). Regarding acute toxicities, no > grade 2 adverse events occurred. Acute GU/GI toxicity of grade 2 occurred in 12.5%/12.5% of patients treated with 80 Gy, in 25.7%/14.3% of patients treated with 84 Gy to the prostate only, and in 51.9%/12.9% of patients treated with 84 Gy and the pelvis included. Late GU/GI toxicity of grade ≥ 2 occurred in 4.2%/8.3% of patients treated with 80 Gy, in 7.1%/3.6% of patients treated with 84 Gy prostate only, and in 18.2%/0% of patients treated with 84 Gy pelvis included (log-rank test p = 0.358). CONCLUSION: We demonstrated that dose-escalated RT for PCA up to 84 Gy is feasible and safe without a significant increase in acute toxicity. Further follow-up is needed to assess late toxicity and survival.

Teaching in radiation oncology: now and 2025-results of a focus group with medical students.

PURPOSE: In Germany, the new Licensing Regulations for Physicians 2025 (Ärztliche Approbationsordnung, ÄApprO) define a binding legal framework on the basis of which medical faculties modernize their curricula. Since 2015, the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) formulates competencies and learning objectives to be achieved in the course of studies as curriculum orientation for the medical faculties. In addition, about 80% of the areas of a new core curriculum are to be made compulsory. A needs analysis in the target group of students has not yet taken place for the subject of radiation therapy (RT) or radiation oncology (RO). This study therefore surveys the experiences and requirements of students regarding medical education in RT. METHODS: Qualitative single-center study using a semistructured in-depth focus group with 11 medical students (20-26 years; 6 female, 5 male) was conducted. Brainstorming sessions were conducted in small groups and individually; oral contributions were recorded, transcribed, and analyzed using qualitative content analysis according to Mayring. Results were compared with the content of the future curriculum and reviewed for congruence with current expert recommendations of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). RESULTS: The plans to develop a longitudinal and practice-oriented curriculum was positively received by students. Specifically, students wanted to introduce the basics of RT as an early link to practice in preclinical teaching units. The necessary acquisition of communicative skills should also be taught by lecturers in RO. Methodologically, regular digital survey tools for self-monitoring, discussion rooms, and problem-based learning were named. In the perception of students, the subject appears underrepresented in relation to its relevance in the multimodal therapy of oncological diseases. CONCLUSION: Results of the needs analysis for the subject of RT are consistent with ÄApprO, NKLM, and DEGRO. Moreover, they complement them and should be considered in the curriculum development of Masterplan Medical Education 2020 (Masterplan Medizinstudium 2020). The results contribute to high-quality and target-group-oriented medical training in the subject of RT, increased visibility, and thus early bonding of future physicians to RO in Germany.

Impact of the COVID-19 pandemic on training conditions and education in oncologic disciplines: a survey-based analysis.

PURPOSE: The COVID-19 pandemic has led to changes in global health care. Medical societies had to update guidelines and enhance new services such as video consultations. Cancer treatment had to be modified. The aim of this study is to ensure optimal care for cancer patients with the help of high-quality training even in times of crisis. We therefore conducted a nationwide survey of physicians in training in oncological disciplines during the pandemic to assess the impact on their education. METHODS: The survey was sent to tumour centres, hospitals, specialist societies, and working and junior research groups and distributed via newsletters and homepages. Interim results and a call for participation were published as a poster (DEGRO) [26] and in the German Cancer Society (DKG) journal FORUM [42]. The survey contained 53 questions on conditions of education and training and on clinical and scientific work. Statistics were carried out with LimeSurvey and SPSS (IBM Corp., Armonk, NY, USA). RESULTS: Between February and November 2022, 450 participants answered the survey, with radio-oncologists being the largest group (28%). Most colleagues (63%) had access to digital training methods. Virtual sessions were rated as a good alternative, especially as multidisciplinary meetings (54%) as well as in-house and external training programs (48%, 47%). The time spent by training supervisors on education was rated as less than before the pandemic by 57%. Half of all participants perceived communication (54%), motivation (44%) and atmosphere (50%) in the team as bad. The participants felt strongly burdened by extra work (55%) and by a changed team atmosphere (49%). One third felt a change in the quality of training during the pandemic and rated it as negative (35%). According to 37% of the participants, this had little influence on their own quality of work. Additional subgroup analyses revealed significant differences in gender, specialty and education level. CONCLUSION: In order to improve oncology training in times of crisis, access to digital training options and meetings should be ensured. Participants wish for regular team meetings in person to enable good team spirit, compensation for overtime work and sufficient time for training supervisors for discussion and feedback.

Fertility sparing therapy in women with lymph node negative cervical cancer >2cm - oncologic and fertility outcomes of neoadjuvant chemotherapy followed by radical vaginal trachelectomy.

OBJECTIVE: Simple or radical trachelectomy are accepted fertility sparing therapies for patients diagnosed with cervical cancer ≤2 cm. In patients with larger tumors a fertility sparing concept is considered experimental. The aim of our study is to present oncological and fertility outcomes of laparoscopic pelvic lymphadenectomy followed by neoadjuvant chemotherapy and subsequent radical vaginal trachelectomy. These procedures were performed in two centers in patients diagnosed with cervical cancer of diameter >2 cm. METHOD: We retrospectively analyzed the demographic, histological, fertility and follow-up data of all patients with cervical cancer assessed as stage IB2, IB3 or IIA1 under the International Federation of Gynecology and Obstetrics (FIGO) 2018 system. These patients had undergone pelvic lymphadenectomy, followed by neoadjuvant chemotherapy and radical vaginal trachelectomy between February 2006 and June 2020 at Charité University Berlin and Asklepios Hospital, Hamburg. RESULTS: A total of 31 patients (mean age 29.5 years, range; 26-40) underwent neoadjuvant chemotherapy followed by radical vaginal trachelectomy in case of proven tumor-free lymph nodes. Twenty-six (84%) of these patients were nulliparous. Across all 31 patients, the initial tumor stages were FIGO 2018 stage IB2 (n=27), IB3 (n=3) and IIA1 (n=1).Lymphadenectomy was completed in all but one patient (sentinel) with a median of 33 (range; 11-47) pelvic lymph nodes. The neoadjuvant chemotherapy regimen was two cycles of paclitaxel, ifosfamide and cisplatin in 17 patients; three cycles of paclitaxel, ifosfamide and cisplatin in eight patients; two cycles of paclitaxel and cisplatin in four patients; two cylces cisplatin monoagent in one patient; and two cycles of paclitaxel and cisplatin followed by two cycles of paclitaxel, ifosfamide and cisplatin in one patient. Residual tumor was histologically confirmed in 17 specimens (55%). The median residual tumor size following neoadjuvant chemotherapy was 12 mm (range; 1-60). Fertility could be preserved in 27 patients (87%); two patients underwent adjuvant chemoradiation after radical vaginal trachelectomy due to high-risk histological features; two other patients underwent radical hysterectomy with adjuvant chemoradiation therapy following neoadjuvant chemotherapy. Of 18 (67%) patients seeking motherhood, 13 became pregnant (72%). There were 12 live births in 10 women, with a median fetal weight of 2490 grams (range; 1640-3560) and five miscarriages. After a median follow-up of 94.5 months (range; 6-183) three recurrences (11.1%) were detected, one patient (3.7%) died of the disease. CONCLUSION: Neoadjuvant chemotherapy followed by radical vaginal trachelectomy may be offered to patients seeking motherhood with cervical cancer >2 cm and histopathologically tumor-free lymph nodes, the rate of healthy baby pregnancy on discharge was 10/18 women (55%). This fertility-preserving strategy is associated with higher recurrence and death compared with what was published in the literature for women undergoing radical vaginal trachelectomy for tumors up to 2 cm.

Exercise interventions for adults with cancer receiving radiation therapy alone.

BACKGROUND: Radiation therapy (RT) is given to about half of all people with cancer. RT alone is used to treat various cancers at different stages. Although it is a local treatment, systemic symptoms may occur. Cancer- or treatment-related side effects can lead to a reduction in physical activity, physical performance, and quality of life (QoL). The literature suggests that physical exercise can reduce the risk of various side effects of cancer and cancer treatments, cancer-specific mortality, recurrence of cancer, and all-cause mortality. OBJECTIVES: To evaluate the benefits and harms of exercise plus standard care compared with standard care alone in adults with cancer receiving RT alone. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), CINAHL, conference proceedings and trial registries up to 26 October 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled people who were receiving RT without adjuvant systemic treatment for any type or stage of cancer. We considered any type of exercise intervention, defined as a planned, structured, repetitive, objective-oriented physical activity programme in addition to standard care. We excluded exercise interventions that involved physiotherapy alone, relaxation programmes, and multimodal approaches that combined exercise with other non-standard interventions such as nutritional restriction. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the GRADE approach for assessing the certainty of the evidence. Our primary outcome was fatigue and the secondary outcomes were QoL, physical performance, psychosocial effects, overall survival, return to work, anthropometric measurements, and adverse events. MAIN RESULTS: Database searching identified 5875 records, of which 430 were duplicates. We excluded 5324 records and the remaining 121 references were assessed for eligibility. We included three two-arm RCTs with 130 participants. Cancer types were breast and prostate cancer. Both treatment groups received the same standard care, but the exercise groups also participated in supervised exercise programmes several times per week while undergoing RT. Exercise interventions included warm-up, treadmill walking (in addition to cycling and stretching and strengthening exercises in one study), and cool-down. In some analysed endpoints (fatigue, physical performance, QoL), there were baseline differences between exercise and control groups. We were unable to pool the results of the different studies owing to substantial clinical heterogeneity. All three studies measured fatigue. Our analyses, presented below, showed that exercise may reduce fatigue (positive SMD values signify less fatigue; low certainty). • Standardised mean difference (SMD) 0.96, 95% confidence interval (CI) 0.27 to 1.64; 37 participants (fatigue measured with Brief Fatigue Inventory (BFI)) • SMD 2.42, 95% CI 1.71 to 3.13; 54 participants (fatigue measured with BFI) • SMD 1.44, 95% CI 0.46 to 2.42; 21 participants (fatigue measured with revised Piper Fatigue Scale) All three studies measured QoL, although one provided insufficient data for analysis. Our analyses, presented below, showed that exercise may have little or no effect on QoL (positive SMD values signify better QoL; low certainty). • SMD 0.40, 95% CI -0.26 to 1.05; 37 participants (QoL measured with Functional Assessment of Cancer Therapy-Prostate) • SMD 0.47, 95% CI -0.40 to 1.34; 21 participants (QoL measured with World Health Organization QoL questionnaire (WHOQOL-BREF)) All three studies measured physical performance. Our analyses of two studies, presented below, showed that exercise may improve physical performance, but we are very unsure about the results (positive SMD values signify better physical performance; very low certainty) • SMD 1.25, 95% CI 0.54 to 1.97; 37 participants (shoulder mobility and pain measured on a visual analogue scale) • SMD⁠⁠⁠⁠⁠⁠ 3.13 (95% CI 2.32 to 3.95; 54 participants (physical performance measured with the six-minute walk test) Our analyses of data from the third study showed that exercise may have little or no effect on physical performance measured with the stand-and-sit test, but we are very unsure about the results (SMD 0.00, 95% CI -0.86 to 0.86, positive SMD values signify better physical performance; 21 participants; very low certainty). Two studies measured psychosocial effects. Our analyses (presented below) showed that exercise may have little or no effect on psychosocial effects, but we are very unsure about the results (positive SMD values signify better psychosocial well-being; very low certainty). • SMD 0.48, 95% CI -0.18 to 1.13; 37 participants (psychosocial effects measured on the WHOQOL-BREF social subscale) • SMD 0.29, 95% CI -0.57 to 1.15; 21 participants (psychosocial effects measured with the Beck Depression Inventory) Two studies recorded adverse events related to the exercise programmes and reported no events. We estimated the certainty of the evidence as very low. No studies reported adverse events unrelated to exercise. No studies reported the other outcomes we intended to analyse (overall survival, anthropometric measurements, return to work). AUTHORS' CONCLUSIONS: There is little evidence on the effects of exercise interventions in people with cancer who are receiving RT alone. While all included studies reported benefits for the exercise intervention groups in all assessed outcomes, our analyses did not consistently support this evidence. There was low-certainty evidence that exercise improved fatigue in all three studies. Regarding physical performance, our analysis showed very low-certainty evidence of a difference favouring exercise in two studies, and very low-certainty evidence of no difference in one study. We found very low-certainty evidence of little or no difference between the effects of exercise and no exercise on quality of life or psychosocial effects. We downgraded the certainty of the evidence for possible outcome reporting bias, imprecision due to small sample sizes in a small number of studies, and indirectness of outcomes. In summary, exercise may have some beneficial outcomes in people with cancer who are receiving RT alone, but the evidence supporting this statement is of low certainty. There is a need for high-quality research on this topic.

Volumetric modulated arc therapy versus intensity-modulated proton therapy in the irradiation of infra diaphragmatic Hodgkin Lymphoma in female patients.

PURPOSE: To investigate the role of infra diaphragmatic intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for female Hodgkin Lymphoma (HL) patients and to estimate the risk of secondary cancer and ovarian failure. METHODS: A comparative treatment planning study was performed on 14 patients, and the results were compared according to conventional dose-volume metrics. In addition, estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the bowel, the bladder and the rectum. For the ovaries, the risk of ovarian failure was estimated. RESULTS: The dosimetric findings demonstrate the equivalence between VMAT and IMPT in terms of target coverage. A statistically significant reduction of the mean and near-to-maximum doses was proven for the organs at risk. The EAR ratio estimated for IMPT to VMAT was 0.51 ± 0.32, 0.32 ± 0.35 and 0.05 ± 0.11 for the bowel, bladder and rectum, respectively. Concerning the risk of ovarian failure for the chronologic age ranging from 18 to 46 years, the expected net loss in fertility years ranged from 4.8 to 3.0 years for protons and 12.0 to 5.7 years for photons. CONCLUSION: This in-silico study confirmed the beneficial role of IMPT from a dosimetric point of view. Mathematical models suggested that the use of protons might be further advantageous due to the expected reduction of the risk of secondary cancer induction and its milder impact on the reduction of fertility.

PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.

Long-term results of robotic radiosurgery for non brachytherapy patients with cervical cancer.

BACKGROUND: Consolidation brachytherapy is a critical treatment component for cervical cancer patients undergoing primary chemoradiation. Some patients are unsuitable for brachytherapy for a variety of reasons. The use of alternatives (LINAC-based stereotactic radiosurgery or external beam boosts) compromise oncologic results in cervical cancer patients. Thus, we evaluated the value of brachytherapy-like doses prescriptions using robotic radiosurgery (CyberKnife®, CR, Acuuray, Sunnyvale, CA, USA). METHODS: From 06/2011 to 06/2015, 31 patients (median age 53 years; range 30-77 years) with histologically proven FIGO stages IB-IVB cervical cancer underwent primary chemoradiation. All patients were either not suitable for intracervical brachytherapy for a variety of reasons or refused the brachytherapy. To achieve an adequate dose within the tumor, a CK boost was applied after fiducial implantation. In 29 patients, a dose of either five times 6 Gy or five times 5 Gy was prescribed to the target volume. Two patients received three times 5 Gy. The target dose was prescribed to the 70% isodose. Treatment toxicity was documented once weekly regarding vaginal mucositis, bladder, and bowel irritation according to CTCAE v. 4.03. If possible 3 months after completion of treatment intracervical curettage was performed to exclude residual tumor and the patients were followed up clinically. Sparing of organs at risk (OAR) and outcome in terms of local control (LC), overall survival (OS), and progression-free survival (PFS) were assessed. RESULTS: Of the 31 patients, 30 have completed CK boost therapy. The median follow-up time was 40 months (range 5-84 months). General treatment tolerability was good. Except for 1 patient, who had diarrhea grade 3, no treatment related side effects above grade 2 were reported. Sparing of OAR was excellent. The 1­, 3­, and 5­year OS rates were 89, 60, and 57% respectively across all stages. Seven patients showed progression (28%), only two of them with local relapse (8%), resulting in an LC rate of 92% after 3 and 5 years. Mean PFS was 41 months (range 2-84 months). Patients with local recurrence had PFS of 5 and 8 months. Five patients developed distant metastases. Fifteen patients (48%) underwent intracervical curettage 3 months after completion of treatment of which 14 (93%) had complete pathologic response. CONCLUSION: Brachytherapy remains the standard of care for patients diagnosed with cervical cancer and indication for primary chemoradiation. In terms of local control, CyberKnife®-based boost concepts provide excellent local control. It can be an alternative for patients who cannot receive adequate brachytherapy. Distant relapse still remains a challenge in this context.

Knowledge-based intensity-modulated proton planning for gastroesophageal carcinoma.

PURPOSE: To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model, for optimisation of intensity-modulated proton therapy (IMPT) plans applied to patients with locally advanced carcinoma in the gastroesophageal junction. METHODS: A cohort of 60 patients was retrospectively selected; 45 were used to 'train' a dose-volume histogram predictive model; the remaining 15 provided independent validation. The performance of the RP model was benchmarked against manual optimisation. Quantitative assessment was based on several dose-volume metrics. RESULTS: Manual and RP-optimised IMPT plans resulted dosimetrically similar, and the planning dose-volume objectives were met for all structures. Concerning the validation set, the comparison of the manual vs RP-based plans, respectively, showed for the target (PTV): the homogeneity index was 6.3 ± 2.2 vs 5.9 ± 1.2, and V98% was 89.3 ± 2.9 vs 91.4 ± 2.2% (this was 97.2 ± 1.9 vs 98.8 ± 1.1 for the CTV). Regarding the organs at risk, no significant differences were reported for the combined lungs, the whole heart, the left anterior descending artery, the kidneys, the spleen and the spinal canal. The D0.1 cm3 for the left ventricle resulted in 40.3 ± 3.4 vs 39.7 ± 4.3 Gy(RBE). The mean dose to the liver was 3.4 ± 1.3 vs 3.6 ± 1.5 Gy(RBE). CONCLUSION: A narrow-scope knowledge-based RP model was trained and validated for IMPT delivery in locally advanced cancer of the gastroesophageal junction. The results demonstrate that RP can create models for effective IMPT. Furthermore, the equivalence between manual interactive and unattended RP-based optimisation could be displayed. The data also showed a high correlation between predicted and achieved doses in support of the valuable predictive power of the RP method.

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Managing patient flows in radiation oncology during the COVID-19 pandemic : Reworking existing treatment designs to prevent infections at a German hot spot area University Hospital.

PURPOSE: The described work aimed to avoid cancellations of indispensable treatments by implementing active patient flow management practices and optimizing infrastructure utilization in the radiation oncology department of a large university hospital and regional COVID-19 treatment center close to the first German SARS-CoV­2 hotspot region Heinsberg in order to prevent nosocomial infections in patients and personnel during the pandemic. PATIENTS AND METHODS: The study comprised year-to-date intervention analyses of in- and outpatient key procedures, machine occupancy, and no-show rates in calendar weeks 12 to 19 of 2019 and 2020 to evaluate effects of active patient flow management while monitoring nosocomial COVID-19 infections. RESULTS: Active patient flow management helped to maintain first-visit appointment compliance above 85.5%. A slight appointment reduction of 10.3% daily (p = 0.004) could still significantly increase downstream planning CT scheduling (p = 0.00001) and performance (p = 0.0001), resulting in an absolute 20.1% (p = 0.009) increment of CT performance while avoiding overbooking practices. Daily treatment start was significantly increased by an absolute value of 18.5% (p = 0.026). Hypofractionation and acceleration were significantly increased (p = 0.0043). Integrating strict testing guidelines, a distancing regimen for staff and patients, hygiene regulations, and precise appointment scheduling, no SARS-CoV­2 infection in 164 tested radiation oncology service inpatients was observed. CONCLUSION: In times of reduced medical infrastructure capacities and resources, controlling infrastructural time per patient as well as optimizing facility utilization and personnel workload during treatment evaluation, planning, and irradiation can help to improve appointment compliance and quality management. Avoiding recurrent and preventable exposure to healthcare infrastructure has potential health benefits and might avert cross infections during the pandemic. Active patient flow management in high-risk COVID-19 regions can help Radiation Oncologists to continue and initiate treatments safely, instead of cancelling and deferring indicated therapies.

Changes in the cervical microbiota of cervical cancer patients after primary radio-chemotherapy.

OBJECTIVE: Several recent studies have identified a potential interaction between the vaginal microbiota and gynecological cancers, but little is known about the cervical microbiota and its changes during cancer treatment. Therefore, the aim of the study was to evaluate the quantitative and qualitative changes of cervical microbiota in patients undergoing concurrent chemotherapy and radiation treatment for locally advanced cervical cancer. METHODS: Cervical cytobrush samples of 15 cervical patients undergoing chemoradiation treatment were collected 1 day before starting external beam radiation therapy and on the day of the last fraction of brachytherapy. After DNA extraction, 16S rRNA amplicon sequencing of the V3-V4 region was performed on the MiSeq platform, followed by data processing and statistical analyses concerning the alpha and beta diversity of 16 samples (7 samples were excluded because of incomplete sample sets). RESULTS: The amount of amplicon yield after polymerase chain reaction analysis in post-radiation samples was significantly lower compared with the baseline samples (pre 31.49±24.07 ng/µl; post 1.33±1.94 ng/µl; p=0.007). A comparison of pre-treatment and post-treatment samples did not show significant differences regarding beta diversity (weighted UniFrac). There was no significant difference in alpha diversity, which is used to characterize species diversity within a particular community and takes into account both number and abundance (Shannon Diversity Index pre-treatment samples: 2.167±0.7504 (95% CI 1.54 to 2.79); post-treatment samples: 1.97±0.43 (95% CI 1.61 to 2.33); p=0.38). Interindividual differences in patients could partly explain some variation of the samples (permutational multivariate analysis of variance). CONCLUSION: There was a strong reduction in cervical bacterial loads after chemoradiation. Neither alpha nor beta diversity varied significantly when baseline samples were compared with post-treatment samples.

Comparison of surgical and pathological parameters after laparoscopic transperitoneal pelvic/para-aortic lymphadenectomies.

OBJECTIVE: Lymphadenectomy is an integral part of surgical staging and treatment for patients with gynecologic malignancies. Since its introduction, laparoscopic lymphadenectomy has proved feasible, safe, and oncologically adequate compared with open surgery while morbidity is lower and hospital stay considerably shorter. The aim of this study was to examine if surgical outcomes may be improved after the initial learning curve is complete. METHODS: An analysis of 2535 laparoscopic pelvic and/or para-aortic lymphadenectomies was performed between July 1994 and March 2018 by one team of gynecologic oncology surgeons but with the consistent supervision of a consultant surgeon. Data were collected prospectively evaluating operative time, intra-operative and post-operative complications, number of lymph nodes, and body mass index (BMI). Previously published data of 650 patients treated after introduction of the method (period 1, 1994-2003) were compared with the latter 524 patients (period 2, 2014-2018). RESULTS: The median age of the 2535 patients was 43 years (IQR 34-57). The most common indication for pelvic and/or para-aortic lymphadenectomy was cervical cancer (n=1893). Operative time for para-aortic lymph node dissection was shorter in period 2 (68 vs 100 min, p<0.001). The number of harvested lymph nodes was increased for pelvic (19.2 (range 2-52) vs 21.9 (range 4-87)) and para-aortic lymphadenectomy (10.8 (range 1-52) vs 14.4 (range 4-64)), p<0.001. BMI did not have a significant influence on node count or operative time, with BMI ranging from 14.6 to 54.1 kg/m2. In contrast to period 1 (n=18, 2.9%), there were no intra-operative complications in period 2 (n=0, 0.0%, p<0.001) whereas post-operative complications were similar (n=35 (5.8%) in period 1; n=38 (7.6%) in period 2; p=0.32). CONCLUSION: In this large cohort of patients who underwent laparoscopic transperitoneal lymphadenectomy, lymph node count and peri-operative complications improved after the initial learning curve.

Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB-IVA: oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study.

OBJECTIVE: Revised staging of patients with locally advanced cervical cancer is based on clinical examination, imaging, and potential surgical findings. A known limitation of imaging techniques is an appreciable rate of understaging. In contrast, surgical staging may provide more accurate information on lymph node involvement. The aim of this prospective study was to evaluate the impact of pre-treatment surgical staging, including removal of bulky lymph nodes, on disease-free survival in patients with locally advanced cervical cancer. METHODS: Uterus-11 was a prospective international multicenter study including patients with locally advanced cervical cancer who were randomized 1:1 to surgical staging (experimental arm) or clinical staging (control arm) followed by primary platinum-based chemoradiation. Patients with histologically proven squamous cell carcinoma, adenocarcinoma, or adenosquamous cancer International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIB-IVA underwent gynecologic examination and pre-treatment imaging including abdominal computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). Patients had chest imaging (any of the following: X-ray, CT, or PET-CT). The primary endpoint was disease-free survival and the secondary endpoint was overall survival. An ad hoc analysis was performed after trial completion for cancer-specific survival. Randomization was conducted from February 2009 to August 2013. RESULTS: A total of 255 patients (surgical arm, n=130; clinical arm, n=125) with locally advanced cervical cancer were randomized. Of these, 240 patients were eligible for analysis. The two groups were comparable with respect to patient characteristics. The surgical approach was transperitoneal laparoscopy in most patients (96.6%). Laparoscopic staging led to upstaging in 39 of 120 (33%) patients. After a median follow-up of 90 months (range 1-123) in both arms, there was no difference in disease-free survival between the groups (p=0.084). For patients with FIGO stage IIB, surgical staging is superior to clinical staging with respect to disease-free survival (HR 0.51, 95% CI 0.30 to 0.86, p=0.011). In the post-hoc analysis, surgical staging was associated with better cancer-specific survival (HR 0.61, 95% CI 0.40 to 0.93, p=0.020). CONCLUSION: Our study did not show a difference in disease-free survival between surgical and clinical staging in patients with locally advanced cervical cancer. There was a significant benefit in disease-free survival for patients with FIGO stage IIB and, in a post-hoc analysis, a cancer-specific survival benefit in favor of laparoscopic staging. The high risk of distant metastases in both arms emphasizes the need for further evaluation.

Laparoscopic radical hysterectomy with transvaginal closure of vaginal cuff - a multicenter analysis.

OBJECTIVE: Laparoscopic/robotic radical hysterectomy has been historically considered oncologically equivalent to open radical hysterectomy for patients with early cervical cancer. However, a recent prospective randomized trial (Laparoscopic Approach to Cervical Cancer, LACC) has demonstrated significant inferiority of the minimally invasive approach. The aim of this study is to evaluate the oncologic outcomes of combined laparoscopic-vaginal radical hysterectomy. METHODS: Between August 1994 and December 2018, patients with invasive cervical cancer were treated using minimally-invasive surgery at the Universities of Jena, Charité Berlin (Campus CCM and CBF) and Cologne and Asklepios Clinic Hamburg. 389 patients with inclusion criteria identical to the LACC trial were identified. In contrast to the laparoscopic/robotic technique used in the LACC trial, all patients in our cohort underwent a combined transvaginal-laparoscopic approach without the use of any uterine manipulator. RESULTS: A total of 1952 consecutive patients with cervical cancer were included in the analysis. Initial International Federation of Gynecology and Obstetrics (FIGO) stage was IA1 lymphovascular space invasion (LVSI+), IA2 and IB1/IIA1 in 32 (8%), 43 (11%), and 314 (81%) patients, respectively, and histology was squamous cell in 263 (68%), adenocarcinoma in 117 (30%), and adenosquamous in 9 (2%) patients. Lymphovascular invasion was confirmed in 106 (27%) patients. The median number of lymph nodes was 24 (range 2-86). Lymph nodes were tumor-free in 379 (97%) patients. Following radical hysterectomy, 71 (18%) patients underwent adjuvant chemoradiation or radiation. After a median follow-up of 99 (range 1-288) months, the 3-, 4.5-, and 10-year disease-free survival rates were 96.8%, 95.8%, and 93.1 %, and the 3-, 4.5-, and 10-year overall survival rates were 98.5%, 97.8%, and 95.8%, respectively. Recurrence location was loco-regional in 50% of cases with recurrence (n=10). Interestingly, 9/20 recurrences occurred more than 39 months after surgery. CONCLUSION: The combined laparoscopic-vaginal technique for radical hysterectomy with avoidance of spillage and manipulation of tumor cells provides excellent oncologic outcome for patients with early cervical cancer. Our retrospective data suggest that laparoscopic-vaginal surgery may be oncologically safe and should be validated in further randomized trials.

Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.

BACKGROUND: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).