Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

The impact of COVID-19 on systemic anticancer treatment delivery in Scotland.

Understanding the impact of the COVID-19 pandemic on systemic anticancer therapy delivery (SACT) is crucial to appreciate the short- and long-term consequences for cancer patients and plan future care. Here, we report real-time national SACT delivery data from NHS Scotland. We demonstrate an initial rapid reduction in patient attendance of 28.7% with subsequent rapid recovery following service redesign. The smallest decrease was seen in breast cancer (19.7%), which also had the most rapid recovery and the largest decrease seen in colorectal cancer (43.4%). Regional variation in the magnitude of impact on SACT delivery was observed, but nadirs occurred at the same time and the rate of recovery was similar across all regions. This recovery reflected a coordinated national approach and associated patient and clinician support structures, which facilitated the creation of COVID-19-protected areas for SACT delivery in Scottish cancer centres enabling rapid sharing of successful and innovative strategies. The data show that these actions have limited the disadvantage to cancer patients.

Evaluating the Use of 18F-FDG PET CT for External Beam Radiotherapy Planning in Gynaecological Malignancies.

PURPOSE OF REVIEW: To evaluate the evidence for the use of fluorine-18-fluorodeoyglucose (18F-FDG) PET CT in external beam radiotherapy planning for treatment of gynaecological malignancies. RECENT FINDINGS: Our review confirms that the incorporation of 18F-FDG PET CT during radiotherapy planning may decrease inter-observer variability during target delineation. It can also provide useful functional information regarding the tumour, which may facilitate the development of techniques for dose escalation and 'dose painting' not only for primary disease, especially in cervical cancer, but also nodal metastasis. The utilisation of this functional modality in external beam radiotherapy planning, particularly in locally advanced cervical malignancy, is an exciting topic that warrants further prospective research. Perhaps the most valuable role may be the potential to deliver dose escalation to 18F-FDG PET CT avid targets previously limited by organ at risk constraints, now that we have significantly more advanced radiotherapy planning tools at our disposal.

Lymphovascular Space Invasion as a Risk Factor in Early Endometrial Cancer.

Management of early endometrial cancer is contentious these days with little agreement between oncologists as well as across MDTs or tumour boards and indeed across countries. This is because of the state of knowledge with regards to risk factors in early endometrial cancer; although we recognise risk factors affect outcome, we haven't yet been able to demonstrate that our treatments make a significant difference. We have reviewed available literature on LVSI and are able to demonstrate that it is an independent risk factor for nodal metastasis as well as distant recurrence. We need a randomised trial integrating grade and LVSI and testing therapeutic options of radiotherapy and chemotherapy. However, it is unlikely to see the light of day. Therefore, we are left with this knowledge of prognostic factors and it is our duty to integrate this into our decision-making during our multidisciplinary team meetings and make decisions tailored to individual patient circumstances.

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study.

PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

A review of recent developments in image-guided radiation therapy in cervix cancer.

Brachytherapy is an essential part of radiotherapy treatment for cervical cancer. Over the decades, it has evolved from manual loading of radium and caesium to remote after-loaders and from low-dose and medium-dose rates to high-dose rates. Over the past 10 years, 3D image-based Brachytherapy has evolved and established itself as the gold standard, improving local control and overall survival, and significantly reducing toxicity. In this article, we review some of the available literature on gynaecologic brachytherapy, more specifically on topics such as dose rates, high-dose-rate/pulsed-dose-rate (HDR/PDR) brachytherapy and image-based brachytherapy (IBBT), and present some of the evidence that establishes IBBT.

British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: Recommendations for practice.

Cervix cancer in many countries is declining and screening programmes and immunisation will reduce the incidence in the next few decades. This guideline attempts to cover management of invasive disease reflecting diagnosis and imaging including new imaging and sentinel lymph node biopsies. Smaller volume disease is usually managed surgically whereas advanced disease is treated with (chemo)- radiation. It also includes discussion of fertility sparing procedures. Practices are changing frequently for all aspects of care usually in attempts to reduce complications and improve quality of life. The management of advanced disease is treated by chemotherapy and the use of newer agents is also discussed. Other sections discuss specialist situations such as cancer in pregnancy, rare cervical tumours, late effects and supportive measures and fertility preserving approaches.

Dosimetric impact of organ at risk daily variation during prostate stereotactic ablative radiotherapy.

OBJECTIVE: Prostate stereotactic ablative radiotherapy (SABR) delivers large doses using a fast dose rate. This amplifies the effect geometric uncertainties have on normal tissue dose. The aim of this study was to determine whether the treatment dose-volume histogram (DVH) agrees with the planned dose to organs at risk (OAR). METHODS: 41 low-intermediate risk prostate cancer patients were treated with SABR using a linac based technique. Dose prescribed was 35 Gy in five fractions delivered on alternate days, planned using volumetric modulated arc therapy (VMAT) with 10X flattening filter free (FFF). On treatment, prostate was matched to fiducial markers on cone beam CT (CBCT). OAR were retrospectively delineated on 205 pre-treatment CBCT images. Daily CBCT contours were overlaid on the planning CT for dosimetric analysis. Verification plan used to evaluate the daily DVH for each structure. The daily doses received by OAR were recorded using the D%. RESULTS: The median rectum and bladder volumes at planning were 67.1 cm3 (interquartile range 56.4-78.2) and 164.4 cm3 (interquartile range 120.3-213.4) respectively. There was no statistically significant difference in median rectal volume at each of the five treatment scans compared to the planning scan (p = 0.99). This was also the case for median bladder volume (p = 0.79). The median dose received by rectum and bladder at each fraction was higher than planned, at the majority of dose levels. For rectum the increase ranged from 0.78-1.64Gy and for bladder 0.14-1.07Gy. The percentage of patients failing for rectum D35% < 18 Gy (p = 0.016), D10% < 28 Gy (p = 0.004), D5% < 32 Gy (p = 0.0001), D1% < 35 Gy (p = 0.0001) and bladder D1% < 35 Gy (p = 0.001) at treatment were all statistically significant. CONCLUSION: In this cohort of prostate SABR patients, we estimate the OAR treatment DVH was higher than planned. This was due to rectal and bladder organ variation. ADVANCES IN KNOWLEDGE: OAR variation in prostate SABR using a FFF technique, may cause the treatment DVH to be higher than planned.

Safety and feasibility of prostate stereotactic ablative radiotherapy using multimodality imaging and flattening filter free.

OBJECTIVE: To investigate feasibility and safety of stereotactic ablative radiotherapy in the management of prostate cancer while employing MR/CT fusion for delineation, fiducial marker seeds for positioning and Varian RapidArc with flattening filter free (FFF) delivery. METHODS: 41 patients were treated for low-intermediate risk prostate cancer with initial prostate-specific antigen of ≤20 ng ml-1, Gleason score 6-7. Patients had MR/CT fusion for delineation of prostate ±seminal vesicles. CT/MR fusion images were used for delineation and planned using flattening filter free modality. Verification on treatment was cone beam CT imaging with fiducial markers for matching. Patients had Radiation Therapy Oncology Group scoring for genitourinary and gastointestinal symptoms at baseline, week 4, 10 and 18. RESULTS: Clinically acceptable plans were achieved for all patients, all plans achieved the objective clinical target volume D99% ≥ 95%, and for planning target volume D95% ≥ 95%. Rectum dose constraints were met for 95.1% for V18 Gy ≤ 35%, 80% V28 Gy ≤ 10%. A total of 32 (78.0%) plans achieved all rectum dose constraints. Grade 1 acute genitourinary symptoms were 53.7% of patients at baseline, 90.2% [95% CI (76.8-97.3%)] (p = 0.0005) at treatment 5, falling to 78.0% (62.4-89.4%) at week 4, and 75.0% (58.8-87.3%) by week 10 and 52.5% (36.1-68.5%) (p = 1.00) at week 18. Acute gastrointestinal symptoms were 5% at baseline, 46.3% [95% CI (30.7-62.6%)] at treatment 5, week 4 43.9% [95% CI (28.5-60.3%)], week 10 25.0% (11.1-42.3%), and declined slightly by week 18 [-20.095% CI (12.7-41.2)] p = 0.039. Overall 75.6% (31/41) of patients experienced Grade 1-2 toxicity during or after treatment. CONCLUSION: This planning and delivery technique is feasible, safe and efficient. A homogeneous dose can be delivered to prostate with confidence, whilst limiting high dose to nearby structures. The use of this technology can be applied safely within further randomized study protocols. Advances in knowledge: Multimodality imaging for delineation and linac-based image-guided RT with FFF for the treatment of prostate stereotactic ablative radiotherapy.

Variability in prostate and seminal vesicle delineations defined on magnetic resonance images, a multi-observer, -center and -sequence study.

BACKGROUND: The use of magnetic resonance (MR) imaging as a part of preparation for radiotherapy is increasing. For delineation of the prostate several publications have shown decreased delineation variability using MR compared to computed tomography (CT). The purpose of the present work was to investigate the intra- and inter-physician delineation variability for prostate and seminal vesicles, and to investigate the influence of different MR sequence settings used clinically at the five centers participating in the study. METHODS: MR series from five centers, each providing five patients, were used. Two physicians from each center delineated the prostate and the seminal vesicles on each of the 25 image sets. The variability between the delineations was analyzed with respect to overall, intra- and inter-physician variability, and dependence between variability and origin of the MR images, i.e. the MR sequence used to acquire the data. RESULTS: The intra-physician variability in different directions was between 1.3 - 1.9 mm and 3 - 4 mm for the prostate and seminal vesicles respectively (1 std). The inter-physician variability for different directions were between 0.7 - 1.7 mm and approximately equal for the prostate and seminal vesicles. Large differences in variability were observed for individual patients, and also for individual imaging sequences used at the different centers. There was however no indication of decreased variability with higher field strength. CONCLUSION: The overall delineation variability is larger for the seminal vesicles compared to the prostate, due to a larger intra-physician variability. The imaging sequence appears to have a large influence on the variability, even for different variants of the T2-weighted spin-echo based sequences, which were used by all centers in the study.

Role of chemotherapy in the management of epithelial ovarian cancer.

The management of ovarian cancer continues to provide major challenges and debates about optimal treatment. For first-line therapy there remain discussions about optimal chemotherapy for early disease, the use of taxanes as standard for advanced newly diagnosed patients, whether there is a definite role for neoadjuvant chemotherapy and the question of maintenance treatment. For relapsed disease, the management hinges around the distinction between platinum-sensitive and -resistant cancer, and the recent AGO-2.5 and ICON-4 studies suggest that treating with carboplatin and paclitaxel or carboplatin and gemcitabine is recommended. Intraperitoneal chemotherapy remains an enigma with at least three studies showing survival advantage; however, there has been no move to incorporate it into standard management of those patients who achieve complete remission after first-line chemotherapy. Finally, neoadjuvant chemotherapy prior to debulking surgery is the subject of several ongoing clinical trials and may turn out to be one of the most important developments since the concept of interval debulking surgery was established and proven in Europe.