Updating approach for lexicographic optimization-based planning to improve cervical cancer plan quality.

BACKGROUND: To investigate the capability of a not-yet commercially available fully automated lexicographic optimization (LO) planning algorithm, called mCycle (Elekta AB, Stockholm, Sweden), to further improve the plan quality of an already-validated Wish List (WL) pushing on the organs-at-risk (OAR) sparing without compromising target coverage and plan delivery accuracy. MATERIAL AND METHODS: Twenty-four mono-institutional consecutive cervical cancer Volumetric-Modulated Arc Therapy (VMAT) plans delivered between November 2019 and April 2022 (50 Gy/25 fractions) have been retrospectively selected. In mCycle the LO planning algorithm was combined with the a-priori multi-criterial optimization (MCO). Two versions of WL have been defined to reproduce manual plans (WL01), and to improve the OAR sparing without affecting minimum target coverage and plan delivery accuracy (WL02). Robust WLs have been tuned using a subset of 4 randomly selected patients. The remaining plans have been automatically re-planned by using the designed WLs. Manual plans (MP) and mCycle plans (mCP01 and mCP02) were compared in terms of dose distributions, complexity, delivery accuracy, and clinical acceptability. Two senior physicians independently performed a blind clinical evaluation, ranking the three competing plans. Furthermore, a previous defined global quality index has been used to gather into a single score the plan quality evaluation. RESULTS: The WL tweaking requests 5 and 3 working days for the WL01 and the WL02, respectively. The re-planning took in both cases 3 working days. mCP01 best performed in terms of target coverage (PTV V95% (%): MP 98.0 [95.6-99.3], mCP01 99.2 [89.7-99.9], mCP02 96.9 [89.4-99.5]), while mCP02 showed a large OAR sparing improvement, especially in the rectum parameters (e.g., Rectum D50% (Gy): MP 41.7 [30.2-47.0], mCP01 40.3 [31.4-45.8], mCP02 32.6 [26.9-42.6]). An increase in plan complexity has been registered in mCPs without affecting plan delivery accuracy. In the blind comparisons, all automated plans were considered clinically acceptable, and mCPs were preferred over MP in 90% of cases. Globally, automated plans registered a plan quality score at least comparable to MP. CONCLUSIONS: This study showed the flexibility of the Lexicographic approach in creating more demanding Wish Lists able to potentially minimize toxicities in RT plans.

Vaginal Toxicity Management in Patients with Locally Advanced Cervical Cancer following Exclusive Chemoradiation-A Nationwide Survey on Knowledge and Attitudes by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Gynecology Study Group.

Background and Objective: Exclusive radiotherapy, including external beam radiotherapy (EBRT) and interventional radiotherapy/brachytherapy (IRT/BT), with concurrent cisplatin-based chemotherapy, represents the standard of care in patients with locally advanced cervical cancer (LACC). The emerging topic of vaginal toxicity has become a key endpoint in LACC management, although different approaches and non-standardized procedures were available. Our aim was to analyze a nationwide study of the attitudes of Italian gynecological radiation oncology teams in the management of LACC patients' vaginal toxicities. Methods: A nationwide survey of radiation oncologists specializing in the treatment of gynecological malignancies was performed, using the free SurveyMonkey platform, consisting of 26 items. The questionnaire was proposed by the Italian Association of Radiation Oncologists (AIRO) gynecological working group to all 183 Italian radiation oncology institutions, as per AIRO's website. Results: Fifty-eight questionnaires (31%) were completed and returned. The assessment of acute and late vaginal toxicities was systematic in 32 (55.2%) and 26 (44.8%) centers, respectively. In the case of EBRT, 70.7% of centers, according to the contouring and treatment plan data, did not contour the vagina as an organ at risk (OAR). Vaginal dose constraints were heterogeneous for both EBRT and IRT/BT. Local treatment to prevent vaginal toxicity was prescribed by 60.3% of radiation oncologists, mostly vaginal hyaluronic acid cream, and one center recommended vaginal estrogen preparations. During follow-up visits, vaginal toxicity was considered an issue to be investigated always (n = 31) or in sexually active women only (n = 11). Conclusions: This survey showed that wide variation exists with regard to recording and treating vaginal toxicity after exclusive chemoradiation for cervical cancer, underscoring the need to develop more comprehensive guidelines for contouring e-dose reporting of the vagina, so as to implement clinical approaches for vaginal toxicity.

Peritransplant Radiation Therapy in Patients With Refractory or Relapsed Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant: Long-Term Results of a Retrospective Study of the Fondazione Italiana Linfomi.

PURPOSE: In this multicenter collaboration, we report real-world data in the largest published series of long-term outcomes for patients with relapsed/refractory (r/r) Hodgkin lymphoma (HL) treated with peritransplant radiation therapy (pt-RT) and high-dose chemotherapy with autologous stem cell transplant (ASCT). METHODS AND MATERIALS: We conducted a retrospective analysis including data from 12 institutions. Eligibility required histologic diagnosis of HL, receipt of ASCT plus pt-RT between 2004 and 2014 for r/r HL, and age ≥18 years at the time of ASCT. All patients received salvage chemotherapy for maximum debulking before ASCT. Metabolic responses were scored according to the Lugano Classification. The primary endpoint was overall survival (OS). Univariate and multivariate Cox proportional hazards were calculated to estimate the effect of covariates on patients' outcome. RESULTS: One hundred thirty-one patients were eligible: 68 were male (52%), and median age at ASCT was 32 years (range, 18-70). At the time of diagnosis with r/r HL, 92 patients (70%) had limited (stage I-II) disease, and 10 patients (8%) had bulky disease. Pt-RT was given pre-ASCT in 32 patients (24%) and post-ASCT in 99 (76%); median prescribed dose was 30.6 Gy (range, 20-44 Gy). With median follow-up of 60 months, 3- and 5-year OS were 84% and 77%, while 3- and 5-year progression-free survival were 75% and 72%, respectively. On univariate and multivariate analysis, advanced stage at relapse (hazard ratio [HR], 2.18; P = .04), irradiation of >3 sites (HR, 3.69; P = .01), and incomplete metabolic response after salvage chemotherapy (HR, 2.24; P = .01) had a negative effect on OS. The sequencing of pt-RT (pre- vs post-ASCT) did not affect outcomes. CONCLUSIONS: Overall, the addition of pt-RT to ASCT for patients with r/r HL is associated with very good outcomes. Limited relapsed disease with ≤3 sites involved and achievement of complete metabolic response after salvage chemotherapy were predictive of more favorable prognosis.

Comprehensive dosimetric and clinical evaluation of lexicographic optimization-based planning for cervical cancer.

Aim: In this study, a not yet commercially available fully-automated lexicographic optimization (LO) planning algorithm, called mCycle (Elekta AB, Stockholm, Sweden), was validated for cervical cancer. Material and methods: Twenty-four mono-institutional consecutive treatment plans (50 Gy/25 fx) delivered between November 2019 and April 2022 were retrospectively selected. The automatic re-planning was performed by mCycle, implemented in the Monaco TPS research version (v5.59.13), in which the LO and Multicriterial Optimization (MCO) are coupled with Monte Carlo calculation. mCycle optimization follows an a priori assigned priority list, the so-called Wish List (WL), representing a dialogue between the radiation oncologist and the planner, setting hard constraints and following objectives. The WL was tuned on a patient subset according to the institution's clinical protocol to obtain an optimal plan in a single optimization. This robust WL was then used to automatically re-plan the remaining patients. Manual plans (MP) and mCycle plans (mCP) were compared in terms of dose distributions, complexity (modulation complexity score, MCS), and delivery accuracy (perpendicular diode matrices, gamma analysis-passing ratio, PR). Their clinical acceptability was assessed through the blind choice of two radiation oncologists. Finally, a global quality score index (SI) was defined to gather into a single number the plan evaluation process. Results: The WL tuning requested four patients. The 20 automated re-planning tasks took three working days. The median optimization and calculation time can be estimated at 4 h and just over 1 h per MP and mCP, respectively. The dose comparison showed a comparable organ-at-risk spare. The planning target volume coverage increased (V95%: MP 98.0% [95.6-99.3]; mCP 99.2%[89.7-99.9], p >0.05). A significant increase has been registered in MCS (MP 0.29 [0.24-0.34]; mCP 0.26 [0.23-0.30], p <0.05) without affecting delivery accuracy (PR (3%/3mm): MP 97.0% [92.7-99.2]; mCP 97.1% [95.0-98.6], p >0.05). In the blind choice, all mCP results were clinically acceptable and chosen over MP in more than 75% of cases. The median SI score was 0.69 [0.41-0.84] and 0.73 [0.51-0.82] for MP and mCP, respectively (p >0.05). Conclusions: mCycle plans were comparable to clinical manual plans, more complex but accurately deliverable and registering a similar SI. Automated plans outperformed manual plans in blinded clinical choice.

Postoperative treatment of intermediate-risk early stage cervical cancer: results of a survey from the Gynecology Study Group in the AIRO Gyn and MITO Groups.

This survey investigated prognostic factors, treatment modalities, references followed and radiation oncologists' opinions to prescribe adjuvant therapy in early intermediate-risk cervical cancer. All but one recommended pelvic radiotherapy ± vaginal boost (45%) with or without chemotherapy (20%). 88% believed other prognostic factors could integrate classic risk criteria. 66% considered chemo-radiation indicated in case of lymphovascular invasion and suboptimal node dissection, high grade, size ≥ 4 cm, non squamous histology and risk factors combination. This wide heterogeneity of treatments reflects the different guideline options due to the lack of defined indications. The need of integrating the classic prognostic factors with others factors was unanimously expressed by radiation oncologists. The best local and systemic therapy should be established through new studies. These results highlighted the need of a position paper to standardize adjuvant treatment in Italy and to design collaborative studies to clarify the controversial aspects.

Fondazione Italiana Linfomi (FIL) expert consensus on the use of intensity-modulated and image-guided radiotherapy for Hodgkin's lymphoma involving the mediastinum.

AIM: Advances in therapy have resulted in improved cure rates and an increasing number of long-term Hodgkin's lymphoma (HL) survivors. However, radiotherapy (RT)-related late effects are still a significant issue, particularly for younger patients with mediastinal disease (secondary cancers, heart diseases). In many Centers, technological evolution has substantially changed RT planning and delivery. This consensus document aims to analyze the current knowledge of Intensity-Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy (IGRT) for mediastinal HL and formulate practical recommendations based on scientific evidence and expert opinions. METHODS: A dedicated working group was set up within the Fondazione Italiana Linfomi (FIL) Radiotherapy Committee in May 2018. After a first meeting, the group adopted a dedicated platform to share retrieved articles and other material. Two group coordinators redacted a first document draft, that was further discussed and finalized in two subsequent meetings. Topics of interest were: 1) Published data comparing 3D-conformal radiotherapy (3D-CRT) and IMRT 2) dose objectives for the organs at risk 3) IGRT protocols and motion management. RESULTS: Data review showed that IMRT might allow for an essential reduction in the high-dose regions for all different thoracic OAR. As very few studies included specific dose constraints for lungs and breasts, the low-dose component for these OAR resulted slightly higher with IMRT vs. 3D-CRT, depending on the technique used. We propose a set of dose objectives for the heart, breasts, lungs, and thyroid. The use of IGRT is advised for margin reduction without specific indications, such as the use of breath-holding techniques. An individual approach, including comparative planning and considering different risk factors for late morbidity, is recommended for each patient. CONCLUSIONS: As HL therapy continues to evolve, with an emphasis on treatment reduction, radiation oncologists should use at best all the available tools to minimize the dose to organs at risk and optimize treatment plans. This document provides indications on the use of IMRT/IGRT based on expert consensus, providing a basis for clinical implementation and future development.

A Rare Case Report: Isolated Mediastinal Lymph Node Recurrence in High-Risk Endometrial Cancer at 5 Years after Primary Laparoscopic Surgery.

Endometrial cancer is the most common malignancy in some developed countries, with an estimated 102 423 new cases reported in 2015. Isolated mediastinal lymph node recurrence has not been reported previously in this setting. We report a 78-year-old woman with an isolated lymph node recurrence in the mediastinal aortic region detected 5 years after her initial surgical treatment and postoperative adjuvant chemotherapy. Following curative radiotherapy with volumetric-modulated arc therapy at 60 Gy, the recurrence disappeared. To our knowledge, this is the first reported case of recurrent endometrial cancer with isolated mediastinal recurrence.

Comparative evaluation of CT-based and respiratory-gated PET/CT-based planning target volume (PTV) in the definition of radiation treatment planning in lung cancer: preliminary results.

PURPOSE: The aim of this study was to compare planning target volume (PTV) defined on respiratory-gated positron emission tomography (PET)/CT (RG-PET/CT) to PTV based on ungated free-breathing CT and to evaluate if RG-PET/CT can be useful to personalize PTV by tailoring the target volume to the lesion motion in lung cancer patients. METHODS: Thirteen lung cancer patients (six men, mean age 70.0 years, 1 small cell lung cancer, 12 non-small cell lung cancer) who were candidates for radiation therapy were prospectively enrolled and submitted to RG-PET/CT. Ungated free-breathing CT images obtained during a PET/CT study were visually contoured by the radiation oncologist to define standard clinical target volumes (CTV1). Standard PTV (PTV1) resulted from CTV1 with the addition of 1-cm expansion of margins in all directions. RG-PET/CT images were contoured by the nuclear medicine physician and radiation oncologist according to a standardized institutional protocol for contouring gated images. Each CT and PET image of the patient's respiratory cycle phases was contoured to obtain the RG-CT-based CTV (CTV2) and the RG-PET/CT-based CTV (CTV3), respectively. RG-CT-based and RG-PET/CT-based PTV (PTV2 and PTV3, respectively) were then derived from gated CTVs with a margin expansion of 7-8 mm in head to feet direction and 5 mm in anterior to posterior and left to right direction. The portions of gated PTV2 and PTV3 geometrically not encompassed in PTV1 (PTV2 out PTV1 and PTV3 out PTV1) were also calculated. RESULTS: Mean ± SD CTV1, CTV2 and CTV3 were 30.5 ± 33.2, 43.1 ± 43.2 and 44.8 ± 45.2 ml, respectively. CTV1 was significantly smaller than CTV2 and CTV3 (p = 0.017 and 0.009 with Student's t test, respectively). No significant difference was found between CTV2 and CTV3. Mean ± SD of PTV1, PTV2 and PTV3 were 118.7 ± 94.1, 93.8 ± 80.2 and 97.0 ± 83.9 ml, respectively. PTV1 was significantly larger than PTV2 and PTV3 (p = 0.038 and 0.043 with Student's t test, respectively). No significant difference was found between PTV2 and PTV3. Mean ± SD values of PTV2 out PTV1 and PTV3 out PTV1 were 12.8 ± 25.4 and 14.3 ± 25.9 ml, respectively. The percentage values of PTV2 out PTV1 and PTV3 out PTV1 were not lower than 10 % of PTV1 in 6/13 cases (46.2 %) and than 20 % in 3/13 cases (23.1 %). CONCLUSION: Our preliminary data showed that RG-PET/CT in lung cancer can affect not only the volume of PTV but also its shape, as demonstrated by the assessment of gated PTVs outside standard PTV. The use of a gating technique is thus crucial for better delineating PTV by tailoring the target volume to the lesion motion in lung cancer patients.

Impact of radiotherapy technique on the outcome of early breast cancer treated with conservative surgery: A multicenter observational study on 1,176 patients.

PURPOSE: To quantify the impact of radiotherapy technique on cosmetic outcome and on 5-year local control rate of early breast cancer treated with conservative surgery and adjuvant radiation. METHODS AND MATERIALS: A total of 1,176 patients irradiated to the breast in 1997 were entered by eight centers into a prospective, observational study. Surgical procedure was quadrantectomy in 97% of patients, with axillary dissection performed in 96%; pT-stage was T1 in 81% and T2 in 19% of cases; pN-stage was N0 in 71%, N + (1-3) in 21%, and N + (>3) in 8% of cases. An immobilization device was used in 17% of patients; external contour-based and computed tomography-based treatment planning were performed in 20% and 72% of cases, respectively; 37% of patients were treated with a telecobalt unit and 63% with a linear accelerator; portal verification was used in 55% of patients; a boost dose to the tumor bed was delivered in 60% of cases. RESULTS: With a median follow-up of 6.2 years, local, regional, and distant control rates at 5 years are 98%, 99%, and 92%, respectively. Use of less sophisticated treatment technique was associated with a less favorable cosmetic outcome. Local control was comparable between centers despite substantial technical differences. In a multivariate analysis including clinical and technical factors, only older age and prescription of medical adjuvant treatment significantly predicted for better local control, whereas use of portal verification was of borderline significance. CONCLUSIONS: Radiation technical factors impacted negatively on cosmetic outcome, but had relatively small effects on local control compared with other clinical factors.

Are international guidelines for the prescription of adjuvant treatment for early breast cancer followed in clinical practice? Results of a population-based study on 1547 patients.

AIMS AND BACKGROUND: The results of several randomized trials and meta-analyses have been reported on adjuvant treatment for early breast cancer and treatment guidelines have been defined accordingly, but detailed data are lacking on the appropriateness of treatment prescription in clinical practice. METHODS: We performed a prospective, observational, multicenter study to monitor the prescription, delivery and effectiveness of radiotherapy following conservative surgery for early breast cancer; 1610 patients treated with postoperative radiation to the breast in 1997 were entered by 12 centers in Lombardy, Italy. Here we report the results of a secondary analysis focused on the prescription of medical adjuvant treatment (1547 eligible patients). RESULTS: Chemotherapy only was prescribed to 526 patients (33%), hormonal therapy only to 539 (33%), and both treatments to 85 patients (5%); 460 women (29%) received no medical adjuvant treatment. We compared the collected data with guidelines defined in 1995 by the St Gallen Consensus Conference. Undertreatment was most frequent in node-negative patients at intermediate/high risk, no treatment (instead of tamoxifen or chemotherapy) being prescribed in 21-45% of cases. Node-negative patients at low risk, on the other hand, were overtreated with tamoxifen in 31% of cases. In node-positive, premenopausal women compliance with guidelines was far better, with a 91-96% rate of chemotherapy prescription. In node-positive, postmenopausal, estrogen receptor-positive patients chemotherapy was unduly prescribed in as many as 56% of cases. Comparison of clinical practice with the next version of the guidelines (1998) showed a somewhat better compliance. CONCLUSIONS: Despite the availability of official and authoritative guidelines, adjuvant treatment prescription for early breast cancer in Lombardy in 1997 was suboptimal, especially in well-defined subgroups of patients.