Is MRI-Linac helpful in SABR treatments for liver cancer?

Objective: To determine the MRI-Linac added value over conventional image-guided radiation therapy (IGRT) in liver tumors Stereotactic ablative radiation therapy (SABR). Materials and methods: We retrospectively compared the Planning Target Volumes (PTVs), the spared healthy liver parenchyma volumes, the Treatment Planning System (TPS) and machine performances, and the patients' outcomes when using either a conventional accelerator (Versa HD®, Elekta, Utrecht, NL) with Cone Beam CT as the IGRT tool or an MR-Linac system (MRIdian®, ViewRay, CA). Results: From November 2014 to February 2020, 59 patients received a SABR treatment (45 and 19 patients in the Linac and MR-Linac group, respectively) for 64 primary or secondary liver tumors. The mean tumor size was superior in the MR-Linac group (37,91cc vs. 20.86cc). PTV margins led to a median 74%- and 60% increase in target volume in Linac-based and MRI-Linac-based treatments, respectively. Liver tumor boundaries were visible in 0% and 72% of the cases when using CBCT and MRI as IGRT tools, respectively. The mean prescribed dose was similar in the two patient groups. Local tumor control was 76.6%, whereas 23.4% of patients experienced local progression (24.4% and 21.1% of patients treated on the conventional Linac and the MRIdian system, respectively). SABR was well tolerated in both groups, and margins reduction and the use of gating prevented ulcerous disease occurrence. Conclusion: The use of MRI as IGRT allows for the reduction of the amount of healthy liver parenchyma irradiated without any decrease of the tumor control rate, which would be helpful for dose escalation or subsequent liver tumor irradiation if needed.

Early clinical outcomes of hybrid brachytherapy for locally advanced cervical cancer: making adverse situations in a favorable scenario.

Purpose: To investigate the feasibility and early clinical outcomes of combined intra-cavitary (IC) and interstitial (IS) image-guided adaptive brachytherapy (IGABT) as curative and definitive treatment of patients treated with chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Material and methods: Data from medical records of all consecutive patients with histologically proven cervical cancer (FIGO 2018 stage IB-IV), treated by brachytherapy after CCRT at our institution between 2017 and 2020 were reviewed. Results: One hundred and forty-two patients with LACC FIGO 2018 stages (IB: 20.4%, II: 31.7%, III: 45.8%, IV: 2.1%) underwent brachytherapy at our institution, out of which 53.5% underwent combined brachytherapy technique (IC/IS). Median number of implanted catheters was 3 (range, 1-6 catheters). None of the 142 patients required invasive hemorrhage management. With a median follow-up of 21.6 (95% CI [confidence interval]: 19.1-23.5%) months, local relapse was observed in nine patients (6.3%), with four showing persistent and progressive disease. The estimated 2-year local and pelvic relapse-free survival were 92% (95% CI: 84-96%) and 90% (95% CI: 83-94%), respectively. The estimated 2-year disease-free survival for the entire population was 80% (95% CI: 71-87%). The 2-year overall survival (OS) rate for the entire population was 92% (95% CI: 84-96%). Acute toxicity G3 was reported in two (1.4%) patients. High-grade late toxicity (grade 3) was reported in 9 (6.3%) patients. Conclusions: Combined IC/IS brachytherapy for LACC allows for recommended doses to achieve local control even in large tumors after CCRT improving target volume coverage, with low rates of acute morbidity. Hybrid brachytherapy technique (IC/IS) is essential to have a favorable scenario at the time of brachytherapy to correctly treat locally advanced cervical cancer patients.

[Start of activity with the MRIdian® system: The first 200 patients treated at the Institut Paoli-Calmettes]. / Retour d'expérience clinique à propos des 200 premiers patients traités au MRIdian® à l'Institut Paoli-Calmettes.

INTRODUCTION: Several centers have recently been equipped with MRI-guided radiotherapy systems, including the Paoli-Calmettes Institute which was the first French center to start this activity. We report in this article our early experience. METHODS: Data related to patients treated on the MRIdian® (Viewray®) were prospectively collected. Procedures concerning the implementation of the system and internal organizational issues were summarized. RESULTS: Between February 2019 and March 2020, 201 patients were treated: 40% of treatments were normofractionated (n=70) and 60% used hypofractionation (n=105). The reported monthly occupancy rate at one, six and twelve months was 30%, 62%, and 90%. The distribution of normofractionated treatments was dominated by prostatic (29%) and pancreatic (26%) cancers, followed by abdomino-pelvic irradiations for gynecological cancers (12%) or lymph node diseases (12%) and boosts for rectal or vaginal cancers (11%). Regarding treatments with moderate hypofractionation (dose by fraction between 3 and 5Gy), they corresponded mainly to integrated boost for abdomino-pelvic lymph nodes (38%), while the stereotaxic treatments primarily concerned hepatic lesions (15%), bones (30%). DISCUSSION: The MRIdian® was initially used widely in our service corresponding to a learning curve for MRI guidance. This new tool for image-guided radiotherapy helped us to secure our practice providing solutions for both inter and intra-fraction movements making it possible to reduce the additional margin in order to better protect the organs at risk. The main technical difference with conventional accelerators is the possibility of performing adaptive radiotherapy in real time, the start of which was more gradual.

Reducing dose to rectum by placement of a rectum-emptying tube in cervical cancer patients treated with brachytherapy.

PURPOSE: Only scarce data are available on the possibility to reduce rectal dose by controlling rectum filling before HDR (high dose rate) IGABT (image-guided adaptive brachytherapy) in LACC (locally advanced cervical carcinoma) patients. We compared dosimetric outcomes before and after the evacuation of gasses using a rectum emptying tube. METHODS AND MATERIAL: Sixty CT (computed tomography) scans from 30 consecutive patients with cancer of the cervix undergoing HDR IGABT after EBRT were reviewed. Patients who underwent at least one gas evacuation were included in the analysis. The three-dimensional dosimetric data of the dosimetric plan performed before and after gas evacuation were compared. Primary endpoint was the difference between D2cc of the rectum before and after the procedure. Expected probability of grade 2-4 overall rectum morbidity was assessed using a probit model from the prospective multicenter EMBRACE study. RESULTS: Thirty five (58.3%) CT scans from 23 patients (76.7%) requiring gas evacuation were analysed. The mean rectum volume, before and after gas evacuation, was 123.1 cc (sd, ± 60.4) and 66.4 cc (sd, ± 34.8), respectively. For each patient, the volume of the rectum after gas evacuation was lower than before. No major complication occurred during and after the procedure. After gas evacuation, a significant reduction in rectal dose per fraction was observed, on average -4.3 Gy (-38.4%, p < 0.001) for D0.1cc and -1.9 Gy (-30.6%, p < 0.001) for D2cc. Estimated mean probability to develop a grade 2-4 rectum morbidity was significantly lower after gas evacuation, 6.9% (sd,± 1.94) versus 9.5% (sd,± 3.17), p < 0.001. CONCLUSION: Gas evacuation using a rectal emptying tube in selected LACC patients treated with HDR BT after chemoradiotherapy, allowed a substantial reduction in the dose to the rectum. Such procedure could be of particular interest when a dose escalation strategy is being considered.

Impact of time to radiation therapy in adjuvant settings in endometrial carcinoma: A multicentric retrospective study.

OBJECTIVE: Time to adjuvant treatment could have an impact on cancer prognosis. It is possible that robotic surgery lengthens the healing time of vaginal cuff after minimally invasive hysterectomy. The objective of this study was to state the impact of time to RT (TTR) on prognosis in endometrial carcinoma (EC) patients and to assess variables associated with TTR. STUDY DESIGN: We conducted a multicentric retrospective study in two cancer centers. We included EC patients, between January 1996 and January 2016. We searched variables associated with TTR and impact of TTR on end-points: local recurrence-free survival, metastatic-free survival, event-free survival and overall survival. RESULTS: 329 patients were included and 279 were analyzed for TTR impact. Robotic surgery was associated with shorter TTR (8 weeks, 8.9 w for laparotomy, 9.2 w for laparoscopy). Pelvic lymphadenectomy, para-aortic lymphadenectomy, discussion in multidisciplinary meeting and treatment center was independently associated with TTR. No impact of TTR was shown on metastatic-free survival, event-free survival and overall survival but there was a trend of a decreased local recurrence rate in case of prolonged TTR (HRcontinuous variable = 1.08; CI95 %: 0.97-1.2). CONCLUSION: Our study did not show any impact of treatment delay on survival end-points although prolonged TTR could moderate the benefit of radiotherapy on local control rate. Surgical route was not associated with TTR, particularly robot-associated laparoscopy did not lengthen treatment delay. TTR seems dependent of health-care organization and could represent a quality criterion of EC care for institutions.

Lessons from radiochemotherapy and modern image-guided adaptive brachytherapy followed by hysterectomy.

PURPOSE: To analyze the clinical outcomes and the safety of radiochemotherapy (RCT) and image-guided adaptive brachytherapy (IGABT) and to evaluate the impact of hysterectomy (HT) as completion of treatment for cervical cancer. METHODS AND MATERIALS: 145 patients with locally advanced cervical cancer were treated at our institution. Patients underwent RCT and IGABT, then hysterectomy (HT) as completion of treatment was performed, with the exception of patients with surgical contraindications, para aortic metastatic disease or patients who refused surgery. Clinical outcomes and morbidity were retrospectively reviewed in both groups. Local relapse free survival (LRFS), pelvic relapse free survival (PRFS) and overall survival (OS) were analyzed. RESULTS: Completion HT was performed in 90 (62.1%) patients. Complete histological response and microscopic disease were found in 77 patients (85.6%). Local relapse was observed in 14 patients (9.6%) without differences between completion HT group and the definitive RCT and IGABT group (Odds Ratio OR = 1.73 [0.57-5.23], p = 0.33). The estimated 3-year LRFS and PRFS for the entire population were respectively 90% [84%-94%] and 93% [87%-96%], with no significant differences between them (respectively Hazard Ratio HR = 0.57 [0.20-1.64], p = 0.30 and HR = 0.37 [0.10-1.31], p = 0.12). The estimated 3-year OS rate for the whole population was 84% [75%-91%] with no significant differences between groups (HR = 0.81 [0.32-2.06], p = 0.65). Regarding morbidity, grade ≥ 2 vaginal toxicity was more frequent in the definitive RCT and IGABT group (43.6% vs 26.7%, p = 0.04). All grade 4 toxicity events were reported in the completion HT group. CONCLUSIONS: Due to high severe toxicity, RCT and IGABT with dose escalation followed by completion hysterectomy don't seem compatible. No benefit and increased severe late morbidity were observed. Combined intracavitary/interstitial technique is mandatory in large target volume at brachytherapy.

Multivariate normal tissue complication probability modeling of vaginal late toxicity after brachytherapy for cervical cancer.

PURPOSE: To explore the best variables combination for a predictive model of vaginal toxicity in cervical cancer patients undergoing brachytherapy (BT). METHODS AND MATERIALS: Clinical and 3-dimensional dosimetric parameters were retrospectively extracted from an institutional database of consecutive patients undergoing intracavitary BT after external beam radiation therapy from 2006 to 2013 for a cervical cancer. A least absolute shrinkage and selection operator selection procedure in Cox's proportional hazards regression model was performed to select a set of relevant predictors for a multivariate normal tissue complication probability model of Grade ≥2 vaginal late toxicity. Outcomes reliability was internally assessed by bootstrap resampling method. RESULTS: One hundred sixty-nine women were included in the present study with a median followup time of 3.8 years (interquartile range [IQR], 1.9-5.6 years). The 2 years and 5 years cumulative incidence rates of Grade ≥2 late vaginal toxicity were 19.9% and 27.5%, respectively. Among 31 metrics and six clinical factors extracted, the optimal model included two dosimetric variables: V70Gy and D5% (the percentage volume that received a dose greater or equal to 70 Gy and the minimum dose given to the hottest 5% volume, respectively). Area under the ROC curve at 2 and 5 years of followup were 0.85 and 0.91, respectively. Regarding internal validation, median area under the ROC curve of bootstrap predictions was 0.83 (IQR, 0.78-0.88) and 0.89 (IQR, 0.85-0.93) at 2 and 5 years of followup, respectively. CONCLUSIONS: A multivariate normal tissue complication probability model for severe vaginal toxicity based on two dosimetric variables (V70Gy and D5%) provides reliable discrimination capability in a cohort of cervical cancer treated with external beam radiation therapy and BT.

Safety and benefit of using a virtual bolus during treatment planning for breast cancer treated with arc therapy.

PURPOSE: This study evaluates the benefit of a virtual bolus method for volumetric modulated arc therapy (VMAT) plan optimization to compensate breast modifications that may occur during breast treatment. METHODS: Ten files were replanned with VMAT giving 50 Gy to the breast and 47 Gy to the nodes within 25 fractions. The planning process used a virtual bolus for the first optimization, then the monitors units were reoptimized without bolus, after fixing the segments shapes. Structures and treatment planning were exported on a second scanner (CT) performed during treatment as a consequence to modifications in patient's anatomy. The comparative end-point was clinical target volume's coverage. The first analysis compared the VMAT plans made using the virtual bolus method (VB-VMAT) to the plans without using it (NoVB-VMAT) on the first simulation CT. Then, the same analysis was performed on the second CT. Finally, the level of degradation of target volume coverage between the two CT using VB-VMAT was compared to results using a standard technique of forward-planned multisegment technique (Tan-IMRT). RESULTS: Using a virtual bolus for VMAT does not degrade dosimetric results on the first CT. No significant result in favor of the NoVB-VMAT plans was noted. The VB-VMAT method led to significant better dose distribution on a second CT with modified anatomies compared to NoVB-VMAT. The clinical target volume's coverage by 95% (V95%) of the prescribed dose was 98.9% [96.1-99.6] on the second CT for VB-VMAT compared to 92.6% [85.2-97.7] for NoVB-VMAT (P = 0.0002). The degradation of the target volume coverage for VB-VMAT is not worse than for Tan-IMRT: the median differential of V95% between the two CT was 0.9% for VMAT and 0.7% for Tan-IMRT (P = 1). CONCLUSION: This study confirms the safety and benefit of using a virtual bolus during the VMAT planning process to compensate potential breast shape modifications.

Contribution of intraoperative radiotherapy (IORT) for therapeutic de-escalation in early breast cancer: Report of a single institution's experience.

The spread of systematic screening and the emergence of oncoplastic techniques allow more breast conservative treatment associating lumpectomy and external beam radiation therapy. In order to furthermore facilitate the patient's treatment, intraoperative radiation therapy (IORT) has been developed. The oncological safety of this technique has been studied, and is considered acceptable. Many questions remain unsolved in regard of the toxicity of this procedure as well as the patient's selection criteria. In this study, we present the first results and complications rate of patients treated by IORT in a single French institution. Between 2012 and 2015, all patients with breast cancer treated in a one-step procedure associating lumpectomy and IORT were retrospectively included in a monocentric cohort. Acute and long-term toxicities were evaluated using CTCAE v4.0 classification. 280 breast cancers were treated using IORT procedure. Additional external beam radiation therapy was requested for 45.7% patients. The acute complications rate was 14.6%, with 5 surgical revisions needed (1.78%). With a median follow up of 911 days, the long-term grade-3 toxicity rate was 1.1%. The only risk factor for local fibrosis was external beam radiation therapy (EBRT) (OR = 1.99; IC95 [1.05-3.81], P = 0.036). Three patients (1.07%) were diagnosed with local recurrence. The results from this cohort confirm the low complication and recurrence rate of IORT procedure. A good selection of patients is necessary in order to lower the EBRT rate and allow therapeutic de-escalation. The classification of tumors into IHC subsets seems a good selection gate. Intraoperative radiation therapy appears to have a low toxicity rate with an acceptable local recurrence risk, and should therefore be considered as an option in the treatment of early breast cancer.

Flattening Filter Free vs. Flattened Beams for Lung Stereotactic Body Radiation Therapy.

BACKGROUND/AIM: To assess the clinical impact of high dose rate stereotactic body radiation therapy (SBRT) in patients with lung neoplastic lesions. PATIENTS AND METHODS: From January 2014 to June 2016, a single-center retrospective analysis was performed including all patients treated by either flattening filter free (FFF) beams or flattening filter beams (FF) three-dimensional (3D) SBRT for lung neoplastic lesions. RESULTS: A total of 99 SBRT were performed on 75 patients. Among these, 29 SBRT were performed using a FFF technique while 70 other SBRT were done using a FF technique. Median follow-up time was 12.9 months. Overall, no difference between the two groups was found except for the mean beam on time which was reduced by 3.3 to 0.9 minutes in the FFF group (p<0.001). CONCLUSION: We report a low toxicity rate and a shortened beam on time in patients treated with 3D FFF SBRT for lung neoplastic lesions.

Volumetric-modulated arc therapy for left-sided breast cancer and all regional nodes improves target volumes coverage and reduces treatment time and doses to the heart and left coronary artery, compared with a field-in-field technique.

We compared two intensity-modulated radiotherapy techniques for left-sided breast treatment, involving lymph node irradiation including the internal mammary chain. Inverse planned arc-therapy (VMAT) was compared with a forward-planned multi-segment technique with a mono-isocenter (MONOISO). Ten files were planned per technique, delivering a 50-Gy dose to the breast and 46.95 Gy to nodes, within 25 fractions. Comparative endpoints were planning target volume (PTV) coverage, dose to surrounding structures, and treatment delivery time. PTV coverage, homogeneity and conformality were better for two arc VMAT plans; V95%(PTV-T) was 96% for VMAT vs 89.2% for MONOISO. Homogeneity index (HI)(PTV-T) was 0.1 and HI(PTV-N) was 0.1 for VMAT vs 0.6 and 0.5 for MONOISO. Treatment delivery time was reduced by a factor of two using VMAT relative to MONOISO (84 s vs 180 s). High doses to organs at risk were reduced (V30(left lung) = 14% using VMAT vs 24.4% with MONOISO; dose to 2% of the volume (D2%)(heart) = 26.1 Gy vs 32 Gy), especially to the left coronary artery (LCA) (D2%(LCA) = 34.4 Gy vs 40.3 Gy). However, VMAT delivered low doses to a larger volume, including contralateral organs (mean dose [Dmean](right lung) = 4 Gy and Dmean(right breast) = 3.2 Gy). These were better protected using MONOISO plans (Dmean(right lung) = 0.8 Gy and Dmean(right breast) = 0.4 Gy). VMAT improved PTV coverage and dose homogeneity, but clinical benefits remain unclear. Decreased dose exposure to the LCA may be clinically relevant. VMAT could be used for complex treatments that are difficult with conventional techniques. Patient age should be considered because of uncertainties concerning secondary malignancies.

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients.

PURPOSE: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. EXPERIMENTAL DESIGN: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients. RESULTS: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18). CONCLUSIONS: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.

Open questions in the management of nodular lymphocyte predominant hodgkin lymphoma.

Localized Nodular Lymphocyte Predominant Hodgkin Lymphoma is a rare disease with an overall good prognosis but frequent late relapses. Due to it's rarity there is no standard therapeutic approach and pathological diagnosis may be hard. In this paper we discuss the technical aspects of the radiation therapy and histological issues. The new fields reductions proposed for classical Hodgkin lymphoma cannot be applied to early stages Nodular Lymphocyte Predominant Hodgkin lymphomas which are usually treated with radiation therapy without systemic chemotherapy.

[Feasibility and morbidity of sentinel lymph node detection in patients with vulvar carcinoma]. / Faisabilité et morbidité du prélèvement du ganglion sentinelle pour les carcinomes épidermoïdes vulvaires.

The aim of this study was to investigate the feasibility and the morbidity of sentinel lymph node detection in patients with vulvar carcinoma. In 15 patients with vulvar squamous cell carcinoma, the inguinal sentinel lymph nodes was detected using both peritumoral injection of technetium-99m sulfur colloid and isosuflan blue before the surgical time. The detection of the inguinal sentinel lymph node was never completed by an inguinal lymphadenectomy. In case of metastatic lymph node, patients were treated by complementary inguinal irradiation. A total of 19 inguinal node dissection were performed. The sentinel lymph node was identified in 18/19 (94.7%) groin dissections. A total of 38 sentinel lymph nodes were removed. 4 patients were found to have metastatic lymph node (26.7%) with a total of 6 metastatic lymph nodes. The postoperative morbidity was minimal, with only one patient presenting a permanent edema of the extremity (6.7%) after complementary inguinal irradiation. We confirm the results of previous studies that sentinel node dissection appears to be technically feasible in patients with vulvar carcinoma. This may reduce the morbidity of usual inguinal lymphadenectomy without under-evaluate the nodal status. This procedure could be implemented in future therapy concepts.

Retinoids, cisplatin and interferon-alpha in recurrent or metastatic cervical squamous cell carcinoma: clinical results of 2 phase II trials.

BACKGROUND: There is no standard treatment for inoperable recurrent or metastatic cancer of the uterine cervix. Retinoids and interferon, in combination with cytotoxic compounds, have been shown to be active in squamous cell carcinoma (SCC). This phase II trial sought to estimate the response rate and the tolerance to a 3-month treatment combining cisplatin, interferon-alpha (IFN-alpha) and all-trans-retinoic (tRA) or 13 cis retinoic acid (13Cis), in women with recurrent or metastatic cervical SCC. PATIENTS AND METHODS: Between November 1994 and October 1996, 33 patients, who had previously received aggressive treatment, and with metastatic and/or bulky disease were enrolled: 22 received tRA(40 mg/m(2)/day), 11 received 13Cis (1 mg/kg/day) in combination with IFN-alpha (6.106 UI/day SC) for 84 days plus cisplatin (40 mg/m(2)IV, days 1, 28 and 56). RESULTS: All patients were evaluable for response and/or toxicity. Toxicities were easily manageable and were never life-threatening, with major grade 3/4 vomiting (54%) and asthenia (54%). Seventeen patients (52%) stopped or reduced treatment because of toxicity or progression. Six objective responses (18%) were observed. No complete response was recorded. Median response duration was 4 months. Time to progression was 9 months [range 3.3 to 20.9] for responders and 7 months [range 1.7 to 32] for all patients. CONCLUSIONS: Regarding toxicity, this regimen should no longer be recommended in previously treated, advanced uterine SCC. However, the consistent response rate reported here may warrant further investigations in an early setting. Retinoid-based treatment with cytokines remains a promising field of research.