The 2022 Assisi Think Tank Meeting: White paper on optimising radiation therapy for breast cancer.

The present white paper, referring to the 4th Assisi Think Tank Meeting on breast cancer, reviews state-of-the-art data, on-going studies and research proposals. <70% agreement in an online questionnaire identified the following clinical challenges: 1: Nodal RT in patients who have a) 1-2 positive sentinel nodes without ALND (axillary lymph node dissection); b) cN1 disease transformed into ypN0 by primary systemic therapy and c) 1-3 positive nodes after mastectomy and ALND. 2. The optimal combination of RT and immunotherapy (IT), patient selection, IT-RT timing, and RT optimal dose, fractionation and target volume. Most experts agreed that RT- IT combination does not enhance toxicity. 3: Re-irradiation for local relapse converged on the use of partial breast irradiation after second breast conserving surgery. Hyperthermia aroused support but is not widely available. Further studies are required to finetune best practice, especially given the increasing use of re-irradiation.

Adaptive radiation therapy: When, how and what are the benefits that literature provides?

PURPOSE: To identify from the current literature when is the right time to replan and to assign thresholds for the optimum process of replanning. Nowadays, adaptive radiotherapy (ART) for head and neck cancer plays an exceptional role consisting of an evaluation procedure of the prominent anatomical and dosimetric variations. By performing complex radiotherapy methods, the credibility of the therapeutic result is crucial. Image guided radiotherapy (IGRT) was developed to ensure locoregional control and thus changes that might occur during radiotherapy be dealt with. MATERIALS AND METHODS: An electronic research of articles published in PubMed/MEDLINE and Science Direct databases from January 2004 to October 2020 was performed. Among a total of 127 studies assessed for eligibility, 85 articles were ultimately retained for the review. RESULTS: The most noticeable changes have been reported in the middle fraction of the treatment. Therefore, the suggested optimal time to replan is between the third and the fourth week. Anatomical deviations>1cm in the external contour, average weight loss>10%, violation in the dose coverage of the targets>5%, and violation in the dose of the peripherals were some of the thresholds that are currently used, and which lead to replanning. CONCLUSION: ART may decrease toxicity and improve local-control. Whether it is beneficial or not, depends ultimately on each patient. However, more investigation of the changes should be performed in future prospective studies to obtain more accurate results.

Novel treatment planning approaches to enhance the therapeutic ratio: targeting the molecular mechanisms of radiation therapy.

Radiation acts not only through cell death but has also angiogenic, immunomodulatory and bystander effects. The realization of its systemic implications has led to extensive research on the combination of radiotherapy with systemic treatments, including immunotherapy and antiangiogenic agents. Parameters such as dose, fractionation and sequencing of treatments are key determinants of the outcome. However, recent high-quality research indicates that these are not the only radiation therapy parameters that influence its systemic effect. To effectively integrate systemic agents with radiation therapy, these new aspects of radiation therapy planning will have to be taken into consideration in future clinical trials. Our aim is to review these new treatment planning parameters that can influence the balance between contradicting effects of radiation therapy so as to enhance the therapeutic ratio.

Three dimensional printed electron beam modifier for total skin electron treatments.

Total Skin Electron Beam (TSEB) treatment, despite its proven effectiveness in skin malignancies, is a rather exhausting irradiation method, especially for feeble patients. In an effort to reduce treatment time by creating a clinically acceptable single TSEB field, various beam modifiers of different materials and shapes were tested. Using the TSEB immobilization device of our department and 3D printing technology, aluminum and thermoplastic modifiers were designed and constructed, according to the resulting profiles at treatment distance. Electron beam characteristics were measured and calculated both at SSD = 100 cm and at treatment level. Aluminum scatterers of the same thickness caused different modification according to the area of blocking. Aluminum modifiers reduced significantly central dose deposition for the same amount of MUs and therefore they expanded treatment time in undesirable levels. Plastic modifiers offer a good combination of field dimensions and treatment time. The final 3D printed modifier shaped the electron beam as desired resulting to a clinically acceptable 6 MeV field of 176 × 70 cm field with 10% inhomogeneity in vertical and 3% in the lateral dimension with adequate skin coverage at SSD = 400 cm. This modification offered approximately a two-minute treatment time reduction compared to the current technique. Underdosed areas appear near the edge of the field, but in regions that are far from the torso of the patient. Bremsstrahlung radiation was kept at clinically accepted levels (< 5%). This modification of the original six dual-field technique of our hospital could probably benefit fragile patients who could not easily tolerate a twenty-minute standing position without compromising the quality of their treatment.

From imaging to biology of glioblastoma: new clinical oncology perspectives to the problem of local recurrence

GBM is one of the most common and aggressive brain tumors. Surgery and adjuvant chemoradiation have succeeded in providing a survival benefit. Although most patients will eventually experience local recurrence, the means to fight recurrence are limited and prognosis remains poor. In a disease where local control remains the major challenge, few trials have addressed the efficacy of local treatments, either surgery or radiation therapy. The present article reviews recent advances in the biology, imaging and biomarker science of GBM as well as the current treatment status of GBM, providing new perspectives to the problem of local recurrence

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From imaging to biology of glioblastoma: new clinical oncology perspectives to the problem of local recurrence.

GBM is one of the most common and aggressive brain tumors. Surgery and adjuvant chemoradiation have succeeded in providing a survival benefit. Although most patients will eventually experience local recurrence, the means to fight recurrence are limited and prognosis remains poor. In a disease where local control remains the major challenge, few trials have addressed the efficacy of local treatments, either surgery or radiation therapy. The present article reviews recent advances in the biology, imaging and biomarker science of GBM as well as the current treatment status of GBM, providing new perspectives to the problem of local recurrence.

The potential role of brachytherapy in the irradiation of patients with lung cancer: a systematic review

To review the use of brachytherapy as an adjuvant therapy to reduce recurrences after sublobar resections and as a palliation to patients with inoperable disease. Α review of all published studies was performed to identify the recurrence rate after brachytherapy adjuvant to sublobar resection and assess the palliation of symptoms and the complications of brachytherapy as a palliative treatment. Most of the studies that we found about brachytherapy as an adjuvant therapy to sublobar resection due to patient’s poor cardiopulmonary reserve showed that brachytherapy offered low recurrence rate with low toxicity. Ten studies concerning palliative brachytherapy showed improvement of symptoms with good tolerance and good endoscopic response rates. Literature suggests that brachytherapy for inoperable symptomatic disease can be delivered for symptom improvement with acceptable toxicity. Brachytherapy as an alternative treatment option for lung cancer needs more investigation with more prospective trials (AU)

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The role of radiotherapy in bone metastases: A critical review of current literature.

Radiotherapy is considered the treatment of choice for painful bone metastases. However, novel modalities of radiotherapy have emerged in the concept of oligometastasic disease. In addition, the increase of overall survival of patients with bone metastatic disease in the last decades due to systemic treatments has issued the silent topic of re-irradiation. The aim of this manuscript was to present a current thorough search of relevant literature. Originally, 6,087 articles revealed from PubMed database related to radiotherapy and bone metastases. The first objective was to identify prospective randomised phase III studies dealing with bone metastases and which treated primary with radiotherapy. Abstracts and non-English citations were excluded. Twenty-three phase III clinical trials, 17 prospective studies and eight meta-analysis/systemic reviews matching with these criteria, were identified. Eleven randomised studies were comparing single dose fraction to multi-fraction schedules of radiotherapy. The overall response rates and complete response rates were not significant between the two arms. Re-irradiations rates were significantly higher for the single dose fraction arms. Stereotactic radiotherapy showed excellent tumour control rates more than 80%. All trials showed the equivalence of either single or multi-fractionated radiotherapy for metastatic bone lesions. Stereotactic irradiation is feasible and safe for oligometastatic disease. However, it seems that the single fraction of 8 Gy is superior to 4 Gy, in terms of efficacy.

Computed tomography-guided radiofrequency ablation of intra-articular osteoid osteoma: a single centre's experience.

OBJECTIVE: To evaluate safety and efficacy of radiofrequency ablation (RFA) in the treatment of painful intra-articular osteoid osteoma. MATERIALS AND METHODS: During the last 3 years, 15 patients underwent computed tomography (CT)-guided biopsy and RFA of symptomatic intra-articular osteoid osteoma. In order to assess and sample the nidus, a coaxial bone biopsy system was used. Biopsy was performed and followed by ablation session with osteoid osteoma protocol in all cases. Procedure time (i.e. drilling including local anaesthesia and ablation), amount of scans, the results of biopsy and pain reduction during follow-up period are reported. RESULTS: Access to the nidus through normal bone, biopsy and electrode insertion was technically feasible in all cases. Median procedure time was 54 min. Histologic verification of osteoid osteoma was performed in all cases. Median amount CT scans, performed to control correct positioning of the drill and precise electrode placement within the nidus was 9. There were no complications or material failure reported in our study. There was no need for protective techniques of the articular cartilage. Pain reduction was significant from the first morning post ablation and complete at the one week and during the follow-up period. No recurrences were noted. CONCLUSIONS: RFA under CT guidance is a safe and efficient technique for the treatment of painful intra-articular osteoid osteoma. Imaging guidance, extra-articular access through normal bone and exact positioning of the needle-electrode inside the nidus facilitate safety of the technique and prevention of damage to the articular cartilage.

The potential role of brachytherapy in the irradiation of patients with lung cancer: a systematic review.

To review the use of brachytherapy as an adjuvant therapy to reduce recurrences after sublobar resections and as a palliation to patients with inoperable disease. Α review of all published studies was performed to identify the recurrence rate after brachytherapy adjuvant to sublobar resection and assess the palliation of symptoms and the complications of brachytherapy as a palliative treatment. Most of the studies that we found about brachytherapy as an adjuvant therapy to sublobar resection due to patient's poor cardiopulmonary reserve showed that brachytherapy offered low recurrence rate with low toxicity. Ten studies concerning palliative brachytherapy showed improvement of symptoms with good tolerance and good endoscopic response rates. Literature suggests that brachytherapy for inoperable symptomatic disease can be delivered for symptom improvement with acceptable toxicity. Brachytherapy as an alternative treatment option for lung cancer needs more investigation with more prospective trials.

Hypofractionated irradiation for gliomas with 45.5Gy in 13 fractions: a retrospective study.

AIM: The aim of the present retrospective study was to evaluate the efficacy and toxicity of a hypofractionated radiotherapy (HFRT) schedule for grade IV glioblastoma multiforme (GBM). METHODS: Fourteen elderly patients with KPS less than 70, received 13 fractions of 350cGy with 3D-conformal technique (3DCRT) and non-coplanar fields. Acute and late skin and CNS toxicity was graded according to EORTC/RTOG criteria. RESULTS: The median follow-up was 9 months. All patients completed the irradiation without interruptions due to toxicity and received temozolomide (TMZ) after the completion of 3DCRT. The KPS during RT and at follow-up was not significantly changed (P=0.108). The median overall survival was 7 months. No severe skin acute or late toxicity was noted. In terms of CNS toxicity, only one patient presented grade III toxicity requiring hospitalization for two days. The irradiation schedule of 45.5Gy in 13 fractions seems effective and without moderate or severe toxicity. CONCLUSION: The suggested HFRT schedule might be an alternative one, for elderly patients with dismal prognosis, unfit for six weeks of daily irradiation. Prospective studies are needed for further validation of our results, especially with the use of TMZ.

Current clinical practice guidelines on chemotherapy and radiotherapy for the treatment of non-metastatic muscle-invasive urothelial cancer: a systematic review and critical evaluation by the Hellenic Genito-Urinary Cancer Group (HGUCG).

Radical cystectomy is the treatment of choice in localized muscle-invasive urothelial cancer. Nevertheless, relapses are frequent and systemic chemotherapy has been employed in order to reduce this risk. In addition, bladder preservation strategies are appealing. During the last decade, there has been a difficulty in conducting and completing large-scale trials in urothelial cancer. This has resulted in relatively few changes in the existing guidelines. Recent studies have created renewed interest in certain fields, such as the role of chemo-radiotherapy and management of unfit patients. In addition, application of certain guidelines has been limited in everyday practice. We conducted a systematic review of the existing guidelines and recent randomized trials not included in these guidelines, and developed a treatment algorithm, regarding non-surgical therapies for non-metastatic, muscle-invasive urothelial cancer based predominantly on patients' fitness for the available therapeutic modalities.

Locus of control and distressing symptoms in young cancer patients when assessing depression.

PURPOSE: The aim of the current study was to evaluate the correlation between depression, sense of control (internal and external) and cancer-related distressing symptoms in younger patients (<65 years) with locally advanced or metastatic cancer, and to investigate their potential predictive role when screening for depression. METHODS: 70 patients completed the Beck Depression Inventory (BDI), the Cancer Locus of Control Scale, the Linear Analogue System Assessment (LASA) (for Quality of Life/ QoL) and the M.D. Anderson Symptom Inventory (MDASI). Distressing symptoms, QoL, and locus of control (LOC) were correlated with the presence of depression. RESULTS: The total BDI score was suggestive of depression. In univariate analysis significant correlations were found between the presence of depression and poor QoL, low Eastern Cooperative Oncology Group performance status and 'sense of control over the course of cancer' (p<0.0005). Depression was significantly correlated with pain, distress and poor general activity, overall enjoyment of life and relationships (p=0.004), as well as anxiety, fatigue, anorexia, dyspnoea and sleep disturbances (p=0.001). Multivariate analysis demonstrated that poor QoL and 'sense of control over the course of cancer', as well as anxiety, fatigue, anorexia, dyspnoea and sleep disturbances were significantly correlated with depression (p<0.0005). CONCLUSIONS: We suggest that younger cancer patients' poor QoL, 'sense of control over the course of cancer', as well as anxiety, fatigue, anorexia, dyspnoea and sleep disturbances are significantly correlated with the presence of depression and can eventually represent potential screening predictors.

Combined chemoradiotherapy with local microwave hyperthermia for treatment of T3N0 laryngeal carcinoma: a retrospective study with long-term follow-up.

The purpose of our study was to test the efficacy and toxicity of hyperthermia in conjunction with chemoradiotherapy for T3N0 laryngeal cancer. From 1997-2006, 25 patients diagnosed with T3N0 laryngeal carcinoma who denied laryngectomy were selected for this retrospective study. Patients received a total dose of 70 Gy (2 Gy per fraction, 5 days per week) in combination with 6 weekly sessions of hyperthermia, in addition to weekly cisplatin chemotherapy. The hyperthermia device was operated as a 433 MHz microwave heating with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. The median follow-up was 60 months, while 23 of 25 patients (92%) presented complete response to treatment. The two patients that did not respond to thermoradiotherapy underwent total laryngectomy, and during follow-up were alive and free of disease. According to EORTC/RTOG criteria, toxicity was mild: three patients (12%) presented grade III, eight (32%) presented grade II and 14 (56%) presented grade I acute skin toxicity. Grade III laryngeal late toxicity (vocal cord malfunction due to severe oedema) was noted in two patients (8%) at 6-8 months post-thermo-chemoradiotherapy. Tmin was correlated (Spearman rho, p < 0.05) with response to treatment as well as with acute skin toxicity and laryngeal function. When a patient with T3N0 laryngeal carcinoma denies laryngectomy, an alternative treatment is combined thermo-chemoradiotherapy which seems to be effective and generally tolerable with radiation-induced skin toxicity and/or late side effects. A larger patient cohort is needed to confirm these results.

Measurement of blood phosphorus: a quick and inexpensive method for detection of the existence of cancer in the body. Too good to be true, or forgotten knowledge of the past?

The possible elevation of phosphorous (P) in cancer patients blood serum has been reported in the past. This however seems to have passed unnoticed. One hundred individuals, divided into two groups of fifty each, i.e. cancer patients (group A) and healthy individuals (group B), were included in this retrospective study. The incidence of cancer by site in group A was 24% head and neck, 50% non-small cell lung cancer (SCLC) and 26% cervical cancer. In all cancer patients in group A the serum P was over the normal values, in contrast with the normal values of P measured in group B. The mean value of serum P in group A and B were 7.80 (± 2.24) and 3.38 (± 0.58), respectively (P<0.001, Mann Whitney test). Increased amount of phosphorus in the blood, when other causes justifying the increase were excluded, should be considered as indicative for the existence of unidentified cancerous lesions.

Sucralfate gel as a radioprotector against radiation induced dermatitis in a hypo-fractionated schedule: a non-randomized study.

External beam radiotherapy with high doses provokes many acute skin reactions, such as erythema and moist desquamation. Many topical preparations are used in radiation oncology departments in the skin care. Sucralfate humid gel, a colloidal physical form of the anti-ulcer drug sucralfate, promotes epithelial regeneration and activates cell proliferation. Based on this knowledge, we performed a non-randomized clinical trial to evaluate the efficacy of topical sucralfate gel in 30 breast cancer patients receiving postoperative accelerated hypofractionated photon beam therapy. The comparison was performed with 30 patients as historical controls. The acute reaction of the skin was significantly lower in the group receiving the sucralfate gel (p<0.05, Mann Whitney test), while 90% of the patients had no evidence of radiation induced skin toxicity. There was no sucralfate gel related toxicity reported by any patient in this study. More patients in a randomized way are needed for more definite results.

Evaluation of efficacy and toxicity in two different hypofractionated 3D-conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer.

PURPOSE: To evaluate the efficacy as well as acute and late toxicity of two different accelerated hypofractionated 3D-conformal radiotherapy (Hypo-3DCRT) schedules in patients with bladder cancer. METHODS: Between February 2006 and June 2011, 50 elderly patients with cT1-2N0 bladder carcinoma were treated with Hypo-3DCRT. Mean age was 75 years. All patients were medically inoperable, with poor performance status, who couldn't tolerate either cystectomy or radical external beam irradiation on a daily basis. A dose of 36 Gy in 6 weekly fractions (arm A, N=39) or 39.96 Gy of 3.33 Gy twice daily, once a week, for 6 weeks (arm B, N=11) were prescribed. The primary study endpoints were the evaluation of acute/late gastrointestinal (GI) toxicity according to the EORTC/RTOG scale together with the visual analogue bladder-related pain score (VAS). RESULTS: The GI acute toxicities were: grade 1: arm A 24/39 (61.5%), arm B 9/11 (81.8%); grade 2: arm A 14/39 (35.9%), arm B 1/11 (9.1%); grade 3: arm A 1/39 (9.1%) (x(2), p=0.29). Only grade 1 late GI toxicity was seen and was significantly higher in arm A: arm A 17/39 (43.6%) and arm B 1/11 (9.1%) (x(2), p=0.037). The reduction of VAS score was similar in both arms (p=0.065). The median relapse free survival (RFS) was 15 and 16 months for arm A and B, respectively (log rank, p=0.71). CONCLUSIONS: Beyond the non-randomized design of the trial, the Hypo-3DCRT schedules used appear to be an acceptable alternative to the traditional longer radiotherapy (RT) schedules for elderly patients unfit for daily irradiation.

Microwave hyperthermia in conjunction with radiotherapy in superficial tumours: correlation of thermal parameters with tumour regression / Hipertermia de microonda de conjunto con radioterapia en los tumores superficiales: correlación de los parámetros térmicos con la regresión del tumor

OBJECTIVE: The aim of the present study is to evaluate the correlation between the thermal parameters of hyperthermia and the clinical outcome in patients with superficial tumours. METHODS: In this study, 20 patients were included with either submandibular lymph nodes from head and neck cancer, or breast cancer relapses post-mastectomy. They were treated with radiation in combination with one session of433 MHz microwave hyperthermia (1 hour, 42.5 ºC-46 ºC). The dose of irradiation ranged from 54 to 60 Gy. The thermal parameters calculated were the minimum volume temperature, the maximum volume temperature and the time interval where the volume temperature was greater than 44 ºC. RESULTS: All patients responded positively to the combined treatment and 60% of the patients showed a complete response. Of the three parameters tested, the only parameter that was found to correlate with the reduction of the tumour diameter was the time with volume temperatures greater than 44 ºC (p < 0.001, Spearman rho). No moderate toxicity was observed. CONCLUSION: Microwave heating should be over 44 ºC for favourable treatment response, when combined with radiotherapy. More patients are needed to confirm the above results.

OJETIVO: El objetivo del presente estudio es evaluar la correlación entre los parámetros térmicos de la hipertermia y el resultado clínico en pacientes con tumores superficiales. MÉTODO: En este estudio, se incluyeron 20 pacientes con ganglios linfáticos submandibulares de cáncer de cabeza y cuello, o post-mastectomía por recidivas de cáncer de mama. Los pacientes fueron tratados con radiación en combinación con una sesión de hipertermia de microondas de 433 MHz (1 hora, 42.5 ºC-46 ºC). La dosis de irradiación osciló entre 54 y 60 Gy. Los parámetros térmicos calculados fueron la temperatura de volumen mínimo, la temperatura de volumen máximo y el intervalo de tiempo donde el volumen de la temperatura fue superior a 44 ºC. RESULTADOS: Todos los pacientes respondieron positivamente al tratamiento combinado y el 60% de los pacientes demostrados una respuesta completa. De los tres parámetros probados, el único parámetro que se comprobó que se correlaciona con la reducción del diámetro del tumor fue el tiempo con temperaturas de volumen superiores a 44 ºC (p < 0.001, rho de Spearman). No se observó ninguna toxicidad moderada. CONCLUSIÓN: Calentamiento por microondas debe estar por encima de 44 ºC para que la respuesta sea favorable al tratamiento en combinación con radioterapia. Se requieren más pacientes para confirmar los resultados anteriores.

A weekly hypofractionated radiotherapeutic schedule for bladder carcinoma in elderly patients: local response, acute and late toxicity, dosimetric parameters and pain relief.

PURPOSE: To investigate the early and late toxicity of a hypofractionated radiotherapy (RT) schedule to treat muscle- invasive bladder cancer in relation to radiation parameters according to the organs at risk. METHODS: Forty-three patients with T2-T3 bladder carcinoma were irradiated with a weekly hypofractionated schedule with a total dose of 36 Gy in 6 fractions. Included in this study were elderly patients with poor performance status or unfit for surgery, while they complained of daily pain on urination. Pain evaluation was assessed with the use of the visual analogue scale (VAS) of pain, acute and late toxicities were assessed using the combined RTOG/EORTC criteria by using a dose of 50 Gy (D50), and the relapse free survival (RFS) was estimated from the date of recurrence. RESULTS: No acute side effects were observed in the majority of the patients. Grade I rectal toxicity was registered in 67.4% of the patients, while grade II and III were noted in 30.25% and 2.37percnt; of the patients, respectively. The worst late rectal toxicity was grade I in 30.2% of the patients. The VAS score of pain showed a significant improvement after the hypofractionated schedule. There was a significant correlation between acute and late toxicity on the one hand and the D50 dosimetric parameter on the other. The Kaplan-Meier plot showed a median RFS of 15 months, while age did not have any impact on RFS in patients above or under 75 years of age. CONCLUSION: The performed hypofractionated schedule permitted delivery of an increased radiation dose without increased toxicity, and with a high probability of local control for elderly patients with low survival perspective.