Months and Severity Score (MOSES) in a Phase III trial (PARCER): A new comprehensive method for reporting adverse events in oncology clinical trials.

Background: Adverse event reporting in oncology trials lacks temporal description. We propose a toxicity summarizing method that incorporates time. Methods: Patients recruited in a phase III trial (NCT01279135) that compared three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) for late toxicity in cervical cancer were included. Adverse events were reported using Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and quality of life (QOL) with EORTC QLQ-C30 and CX24. A total of six symptoms with a related QOL question (diarrhoea, abdominal pain, anorexia, urinary incontinence, frequency and fatigue) were included. Month and severity score [MOSES= ∑ (CTCAE grade x proportionate time)] was calculated. Cumulative-MOSES (C-MOSES) was calculated by summating these 6 individual MOSES. QoL was categorized as "substantially symptomatic" or "not". Receiver operator curve analysis was performed to determine the MOSES cut off that predicts for substantial QOL symptoms. CTCAE and MOSES were tested for accurately categorizing QOL impact. Findings: In the construction dataset, 201/300 patients had symptoms. MOSES > 0.20 had higher accuracy than CTCAE for predicting impact on QOL related to diarrhoea (85% vs. 69%), anorexia (61% vs 51%), abdominal pain (71% vs. 57%), urinary incontinence (72% vs. 61%) and frequency (62% vs. 59%). C-MOSES > 0·70 correlated with reduction in role functioning and global QOL. While no difference was seen in CTCAE grade ≥1 Gastrointestinal (GI) toxicity between 3DCRT or IMRT arm, 3DCRT had higher C-MOSES than IMRT (HR=0.64;95% CI 0.41-0.99, p = 0.04). Interpretation: MOSES has higher accuracy than CTCAE in categorizing symptom specific and functional QOL. These results require further external validation. Funding: None.

Outcomes of osteosarcoma, chondrosarcoma and chordoma treated with image guided-intensity modulated radiation therapy.

BACKGROUND & PURPOSE: To evaluate the efficacy and toxicity of dose-escalated image guided-intensity modulated radiation therapy (IG-IMRT) in osteosarcoma (OGS), chondrosarcoma (CS) and chordoma (CH) of head and neck (H&N) and pelvis. METHODS AND MATERIALS: In this prospective non-randomized study, 65 patients of H&N or pelvic OGS (24), CS (7) and CH (34) mandating definitive or post-operative radiotherapy from May 2013 to December 2018 were included. Radiotherapy doses in definitive setting were 72.0 Gy for CH and 70.2 Gy for OGS and CS; while in post-operative setting it was 66.6 Gy and 64.8 Gy respectively (at 1.8 Gy per fraction). RESULTS: Planned doses of radiotherapy could be completed in 61 (93.8%) patients; with grade III or higher acute and late toxicities of 3% and 0% respectively. With a median follow-up of 52 (range 6-92) months, the five-year actuarial local control (LC) rates were 66% in OGS, 38.1% in CS and 75.9% in CH; while cause-specific survival (CSS) rates were 54.7%, 64.3% and 92.2% respectively. There was no statistically significant difference in outcomes for patients receiving definitive and post-operative radiotherapy. Locally controlled disease at first follow-up after radiotherapy was associated with improved CSS and OS in CS (p = 0.014) and CH (p < 0.001). Radiotherapy resulted in significant and sustained improvement in Musculoskeletal tumour society (MSTS) score and reduction in pain score. Salvage re-irradiation was feasible in local progression after radiotherapy, with good outcomes and tolerability. CONCLUSION: Dose-escalated IG-IMRT results in good LC & functional improvement with minimal toxicity in OGS, CS and CH.

Indigenous Groin Board Immobilization Reduces Planning Target Volume Margins in Groin Radiotherapy.

PURPOSE: To quantify the relative motion of pelvic and groin lymph nodes (PLN and GLN) and define indicative margins for image-guided radiotherapy based on bony anatomy for the frog-leg position (FLP) and groin immobilization board (GIB). MATERIALS AND METHODS: Twenty patients with planning computed tomography (CT) scan and on treatment cone beam CTs (median = 8) for groin and pelvic radiotherapy were included in the study. Of these nine were treated with FLP and eleven with GIB. The PLN and GLN regions on the left and right were outlined in each scan. Systematic and random uncertainties were determined along with correlations between the motions of these regions. The clinical target volume to planning target volume (PTV) margins required to take motion into account was calculated for each immobilization. RESULTS: The mean shifts for PLN and GLN were lesser but not statistically lower using GIB over FLP. There was significant concordance in the vertical, longitudinal and lateral motion of the pelvis and right groin (P = 0.015, 0.09 and 0.049, respectively), pelvis and left groin (P = 0.001, 0.048, and 0.006, respectively) and between left and right groin (P = 0.013, 0.01 and 0.07, respectively) for FLP and not GIB. The PTV margins required by Van Herk and Stroom's formula were reduced from 11 mm and 9 mm to 6 mm and 5 mm for pelvis; 12 mm and 11 mm to 7 mm and 6 mm for groin, respectively, using FLP over GIB. CONCLUSIONS: GIB brings concordance in shifts between pelvis and groin and between bilateral groins, thereby reducing the required PTV margins.

Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial.

PURPOSE: Postoperative Adjuvant Radiation in Cervical Cancer (PARCER), a phase III randomized trial, compared late toxicity after image-guided intensity-modulated radiotherapy (IG-IMRT) with three-dimensional conformal radiation therapy (3D-CRT) in women with cervical cancer undergoing postoperative radiation. METHODS: Patients were randomly assigned to receive either IG-IMRT or 3D-CRT after stratification for the type of hysterectomy and use of concurrent chemotherapy. The primary end point was 3-year grade ≥ 2 late GI toxicity assessed using Common Toxicity Criteria for Adverse Events v 3.0 and estimated using time-to-event, intention-to-treat analysis, with a study level type I error of 0.05 and a nominal α of .047 after accounting for one interim analysis. Secondary end points included acute toxicity, health-related quality of life, and pelvic relapse-free, disease-free, and overall survival. RESULTS: Between 2011 and 2019, 300 patients were randomly assigned (IG-IMRT 151 and 3D-CRT 149). At a median follow-up of 46 (interquartile range, 20-72) months, the 3-year cumulative incidence of grade ≥ 2 late GI toxicity in the IG-IMRT and 3D-CRT arms were 21.1% versus 42.4% (hazard ratio [HR] 0.46; 95% CI, 0.29 to 0.73; P < .001). The cumulative incidence of grade ≥ 2 any late toxicity was 28.1% versus 48.9% (HR 0.50; 95% CI, 0.33 to 0.76; P < .001), respectively. Patients reported reduced diarrhea (P = .04), improved appetite (P = .008), and lesser bowel symptoms (P = .002) with IG-IMRT. However, no difference was observed in the time by treatment interaction. The 3-year pelvic relapse-free survival and disease-free survival in the IG-IMRT versus the 3D-CRT arm were 81.8% versus 84% (HR 1.17; 95% CI, 0.68 to 1.99; P = .55) and 76.9% versus 81.2% (HR 1.03; 95% CI, 0.62 to 1.71; P = .89), respectively. CONCLUSION: IG-IMRT results in reduced toxicity with no difference in disease outcomes.

Defining the role of high-dose radiation in oligometastatic & oligorecurrent cervical cancer.

Around 5-8 per cent of women diagnosed with cervical cancer present with metastatic disease at presentation and 16-25 per cent of patients fail at either within irradiated fields or at distant sites post-curative therapy in advanced cervical cancers. Conventionally, chemotherapy with palliative intent constituted the mainstay of treatment with modest survival outcomes and radiation therapy was reserved for symptomatic benefit only. While targeted therapies and immunotherapy have been added in therapeutic armamentarium, the impact on the outcomes is modest. In limited metastatic disease, radiation therapy to metastatic sites from different primary cancers has shown survival benefits; however, the data are scarce in cervical cancer. With a better understanding of the molecular biology of the metastases and recurrence pattern, emphasis is laid upon total eradication of the disease rather than offering relief from symptoms. This article summarizes the role of radiation therapy in limited metastatic disease and recurrent cervical cancer.

Management of oligo-metastatic and oligo-recurrent cervical cancer: A pattern of care survey within the EMBRACE research network.

BACKGROUND: In the metastatic or recurrent cervical cancer, systemic chemotherapy constitutes the main treatment. Though there is an increasing use of high dose external radiation and brachytherapy in the metastatic setting, no consensus exists. METHODS: A 17-item survey was designed with additional case-based questions to explore present management of oligo-metastatic and oligo-recurrent cervix cancer within EMBRACE research group participating sites. The questions were designed to elicit prevailing practices in the management of de-novo oligo-metastasis and oligo-recurrent setting after completing the primary treatment of cervix cancer. The survey was sent electronically with two rounds of email reminders to respond over a 2-week survey period. The online survey was designed such that it was mandatory to complete all questions. The responses were recorded and results were summarized as proportions and summary statistics were generated. RESULTS: Twenty-two centers responded to this survey. A majority (90%) of respondents reported a low incidence of de-novo oligo-metastatic cervical cancer in their practice (<5%), with a higher proportion of patients with oligo-recurrence after completing primary treatment (5-10%). All responding sites preferred to treat pelvic disease in the de-novo oligo-metastatic setting albeit with different fractionation regimens. While 68.2% of respondents recommended chemo-radiation and brachytherapy, 31.8% considered additional systemic therapy. Overall 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis. For out-of-field nodal recurrences, 63.7% of respondents considered treating with curative intent, while 59% preferred treating in-field recurrence with palliative intent. A vast majority of the participating centers (90%) have stereotactic radiation therapy capacity and would consider a clinical trial addressing oligo-metastatic and oligo-recurrent cervical cancer. CONCLUSION: Although contemporary practice is variable, a substantial proportion of EMBRACE centers consider high dose radiation in de-novo metastatic and oligo-recurrence settings. However, there is clear need for a joint clinical protocol and prospective studies to address the role of high dose radiation within oligo-recurrent and oligo-metastatic scenarios.