Randomized phase II selection trial of FLASH and conventional radiotherapy for patients with localized cutaneous squamous cell carcinoma or basal cell carcinoma: A study protocol.

Background: Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most prevalent skin cancers in western countries. Surgery is the standard of care for these cancers and conventional external radiotherapy (CONV-RT) with conventional dose rate (0.03-0.06 Gy/sec) represents a good alternative when the patients or tumors are not amenable to surgery but routinely generates skin side effects. Low energy electron FLASH radiotherapy (FLASH-RT) is a new form of radiotherapy exploiting the biological advantage of the FLASH effect, which consists in delivering radiation dose in milliseconds instead of minutes in CONV-RT. In pre-clinical studies, when compared to CONV-RT, FLASH-RT induced a robust, reproducible and remarkable sparing of the normal healthy tissues, while the efficacy on tumors was preserved. In this context, we aim to prospectively evaluate FLASH-RT versus CONV-RT with regards to toxicity and oncological outcome in localized cutaneous BCC and SCC. Methods: This is a randomized selection, non-comparative, phase II study of curative FLASH-RT versus CONV-RT in patients with T1-T2 N0 M0 cutaneous BCC and SCC. Patients will be randomly allocated to low energy electron FLASH-RT (dose rate: 220-270 Gy/s) or to CONV-RT arm. Small lesions (T1) will receive a single dose of 22 Gy and large lesions (T2) will receive 30 Gy in 5 fractions of 6 Gy over two weeks.The primary endpoint evaluates safety at 6 weeks after RT through grade ≥ 3 toxicity and efficacy through local control rate at 12 months. Approximately 60 patients in total will be randomized, considering on average 1-2 lesions and a maximum of 3 lesions per patients corresponding to the total of 96 lesions required. FLASH-RT will be performed using the Mobetron® (IntraOp, USA) with high dose rate functionality.LANCE (NCT05724875) is the first randomized trial evaluating FLASH-RT and CONV-RT in a curative setting.

Clinical implementation of deep learning-based automated left breast simultaneous integrated boost radiotherapy treatment planning.

Background and purpose: Automation in radiotherapy treatment planning aims to improve both the quality and the efficiency of the process. The aim of this study was to report on a clinical implementation of a Deep Learning (DL) auto-planning model for left-sided breast cancer. Materials and methods: The DL model was developed for left-sided breast simultaneous integrated boost treatments under deep-inspiration breath-hold. Eighty manual dose distributions were revised and used for training. Ten patients were used for model validation. The model was then used to design 17 clinical auto-plans. Manual and auto-plans were scored on a list of clinical goals for both targets and organs-at-risk (OARs). For validation, predicted and mimicked dose (PD and MD, respectively) percent error (PE) was calculated with respect to manual dose. Clinical and validation cohorts were compared in terms of MD only. Results: Median values of both PD and MD validation plans fulfilled the evaluation criteria. PE was < 1% for targets for both PD and MD. PD was well aligned to manual dose while MD left lung mean dose was significantly less (median:5.1 Gy vs 6.1 Gy). The left-anterior-descending artery maximum dose was found out of requirements (median values:+5.9 Gy and + 2.9 Gy, for PD and MD respectively) in three validation cases, while it was reduced for clinical cases (median:-1.9 Gy). No other clinically significant differences were observed between clinical and validation cohorts. Conclusion: Small OAR differences observed during the model validation were not found clinically relevant. The clinical implementation outcomes confirmed the robustness of the model.

Comparison of ultra-high versus conventional dose rate radiotherapy in a patient with cutaneous lymphoma.

A patient with a cutaneous lymphoma was treated on the same day for 2 distinct tumors using a 15 Gy single electron dose given in a dose rate of 0.08 Gy/second versus 166 Gy/second. Comparing the two treatments, there was no difference for acute reactions, late effects at 2 years and tumor control.

Dose indicator for CyberKnife image-guided radiation therapy.

PURPOSE: The purpose of this study was to calculate dose distributions from CyberKnife image-guided radiation therapy (IGRT) for brain, H&N, lung, and pelvis treatment regions and use them to extract the corresponding effective dose and estimate-related risk. METHODS: We developed a CyberKnife IGRT kV beam model in a standard treatment planning system and validated it against measurements in heterogeneous phantoms. Five brain, five head and neck, five thorax, and 10 (five male and five female) pelvis patient computed tomographies (CTs) were contoured. The dose distribution resulting from different CyberKnife IGRT protocols was calculated. From them, the effective dose was calculated according to ICRP publication Nr 103, using the average dose to contoured organs. The corresponding risk factors were calculated. Entrance surface dose (ESD) was also calculated and compared with existing data. RESULTS: The maximum effective dose produced by CyberKnife IGRT protocols was 0.8 mSv (brain), 1.9 mSv (H&N), 20.2 (pelvis), and 42.4 mSv (thorax) per fraction for a risk estimate of 0.004% (brain), 0.01% (H&N), 0.1% (pelvis), and 0.2% (thorax). Calculated ESD were compatible with existing data. CONCLUSIONS: Dose calculation models for CyberKnife IGRT kV beams were implemented in a clinical treatment planning system and validated in water and heterogeneous phantoms. We determined the effective dose and the related risk estimate resulting from CyberKnife IGRT protocols for brain, head and neck, thorax, and pelvis cases. The effective doses calculated for CyberKnife IGRT protocols were similar to those obtained for cone beam CT protocols on conventional C-arm linear accelerators, except for extreme irradiation conditions for thorax cases (140 kV X-ray tube tension).

Clinical translation of FLASH radiotherapy: Why and how?

Over the past decades, technological advances have transformed radiation therapy (RT) into a precise and powerful treatment for cancer patients. Nevertheless, the treatment of radiation-resistant tumors is still restricted by the dose-limiting normal tissue complications. In this context, FLASH-RT is emerging in the field. Consisting of delivering doses within an extremely short irradiation time, FLASH-RT has been identified as a promising new tool to enhance the differential effect between tumors and normal tissues. Indeed, preclinical studies on various animal models and a veterinarian clinical trial have recently shown that compared to conventional dose-rate RT, FLASH-RT could control tumors while minimizing normal tissue toxicity. In the present review, we summarize the main data supporting the clinical translation of FLASH-RT and explore its feasibility, the key irradiation parameters and the potential technologies needed for a successful clinical translation.

Determination of the effective dose delivered by image guided radiotherapy in head & neck and breast treatments.

PURPOSE: Image guided radiotherapy (IGRT) improves patient positioning for treatment delivery at the cost of an additional dose. This work aimed to calculate the effective dose (as an indicator of dose) for head & neck (H&N) and breast IGRT treatments by implementing dose calculation models to determine the dose distributions. METHODS: The kV dose-models were created for the IGRT systems of Elekta Synergy (XVI) and Varian Clinac (OBI) linear accelerators within Philips Pinnacle TPS. Profiles and depth dose curves were measured in water. The models were validated in a CIRS thorax phantom. The IGRT dose distributions for five H&N and five breast patients were calculated. The effective dose was determined from the dose distributions following ICRP 103 recommendations. Moreover, time-saving approximations were studied in order to propose an alternative way of segmenting the tissues for a clinical implementation of the method. RESULTS AND CONCLUSION: The effective dose specifically associated with IGRT varied from 1 to 10mSv depending on the protocol. The kV dose-model allowed us to calculate the dose distributions from IGRT for different configurations and patients, and to determine effective dose for IGRT protocols. The clinical implementation of the method was found to reduce time and to introduce a small enough increase of uncertainty in the results to be clinically usable.

A treatment planning comparison of contemporary photon-based radiation techniques for breast cancer.

BACKGROUND AND PURPOSE: Adjuvant radiation therapy (RT) of the whole breast (WB) is still the standard treatment for early breast cancer. A variety of radiation techniques is currently available according to different delivery strategies. This study aims to provide a comparison of six treatment planning strategies commonly adopted for breast-conserving adjuvant RT and to use the Pareto concept in an attempt to assess the degree of plan optimization. MATERIALS AND METHODS: Two groups of six left- and five right-sided cases with different dose prescriptions were involved (22 patients in total). Field-in-Field (FiF), two and four Fields static-IMRT (sIMRT-2f and sIMRT-4f), Volumetric-Modulated-Arc-Therapy (VMAT), Helical Tomotherapy (HT) and Static-Angles Tomotherapy (TomoDirect™ - TD) were planned. Dose volume constraints were taken from the RTOG protocol 1005. Pareto fronts were built for a selected case to evaluate the reliability of the plan optimization process. RESULTS: The best target dose coverage was observed for TD able to improve significantly (p < 0.01) the V95% in a range varying from 1.2% to 7.5% compared to other techniques. The V105% was significantly reduced up to 2% for HT (p < 0.05) although FiF and VMAT produced similar values. For the ipsilateral lung, V5Gy, V10Gy and Dmean were significantly lower than all other techniques (p < 0.02) for TD while the lowest value of V20Gy was observed for HT. The maximum dose to contralateral breast was significantly lowest for TD (p < 0.02) and for FiF (p < 0.05). Minor differences were observed for the heart in left-sided patients. Plans for all tested techniques were found to lie on their respective Pareto fronts. CONCLUSIONS: Overall, TD provided significantly better results in terms of target coverage and dose sparing of ipsilateral lung with respect to all other evaluated techniques. It also significantly minimized dose to contralateral breast together with FiF. Pareto front analysis confirmed the reliability of the optimization for a selected case.

[Selective therapeutic de-escalation in early stage breast cancer]. / Cancer du sein de stade précoce : la désescalade thérapeutique sélective.

The survival of patients with breast cancer has improved considerably thanks to adjuvant radiotherapy and systemic treatments. Due to the potential adverse events associated with these treatments, a de-escalation effort was undertaken concerning surgery and more recently the adjuvant treatments. Conservative breast surgery and the avoidance of axillary dissection were possible for the majority of the patients without detrimental effect on survival. New radiotherapy techniques and the consideration of cancer biology allowed to better protect the peripheral organs and even to avoid treatment in certain low-risk patients. The refinement of prognostic and predictive criteria helped reducing the use of chemotherapy and adapting the duration of endocrine therapy to the risk.

La survie des patientes ayant présenté un cancer du sein s'est considérablement améliorée grâce à la radiothérapie et aux traitements systémiques adjuvants. Au vu des effets adverses liés à ces traitements, un effort de désescalade thérapeutique a été entrepris en ce qui concerne la chirurgie et plus récemment les traitements adjuvants. La chirurgie conservatrice du sein et l'abandon du curage axillaire sont possibles pour la majorité des patientes sans altérer leur survie. Les nouvelles techniques de radiothérapie et la prise en compte de la biologie tumorale ont permis de mieux protéger les organes périphériques, voire éviter le traitement chez certaines patientes à bas risque. L'affinement des critères pronostiques et prédictifs a aidé à diminuer le recours à la chimiothérapie et adapter la durée de l'hormonothérapie au risque.

Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: implications for secondary cancer risk assessment.

BACKGROUND AND PURPOSE: To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). MATERIALS AND METHODS: Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. RESULTS: Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. CONCLUSIONS: In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart).

Management of adenoid cystic carcinoma of the breast: a Rare Cancer Network study.

BACKGROUND: Mammary adenoid cystic carcinoma (ACC) is a rare breast cancer. The aim of this retrospective study was to assess prognostic factors and patterns of failure, as well as the role of radiation therapy (RT), in ACC. METHODS: Between January 1980 and December 2007, 61 women with breast ACC were treated at participating centers of the Rare Cancer Network. Surgery consisted of lumpectomy in 41 patients and mastectomy in 20 patients. There were 51(84%) stage pN0 and 10 stage cN0 (16%) patients. Postoperative RT was administered to 40 patients (35 after lumpectomy, 5 after mastectomy). RESULTS: With a median follow-up of 79 months (range, 6-285), 5-year overall and disease-free survival rates were 94% (95% confidence interval [CI], 88%-100%) and 82% (95% CI, 71%-93%), respectively. The 5-year locoregional control (LRC) rate was 95% (95% CI, 89%-100%). Axillary lymph node dissection or sentinel node biopsy was performed in 84% of cases. All patients had stage pN0 disease. In univariate analysis, survival was not influenced by the type of surgery or the use of postoperative RT. The 5-year LRC rate was 100% in the mastectomy group versus 93% (95% CI, 83%-100%) in the breast-conserving surgery group, respectively (p = 0.16). For the breast-conserving surgery group, the use of RT significantly correlated with LRC (p = 0.03); the 5-year LRC rates were 95% (95% CI, 86%-100%) for the RT group versus 83% (95% CI, 54%-100%) for the group receiving no RT. No local failures occurred in patients with positive margins, all of whom received postoperative RT. CONCLUSION: Breast-conserving surgery is the treatment of choice for patients with ACC breast cancer. Axillary lymph node dissection or sentinel node biopsy might not be recommended. Postoperative RT should be proposed in the case of breast-conserving surgery.

Primary breast lymphoma: patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study.

BACKGROUND: To asses the clinical profile, treatment outcome and prognostic factors in primary breast lymphoma (PBL). METHODS: Between 1970 and 2000, 84 consecutive patients with PBL were treated in 20 institutions of the Rare Cancer Network. Forty-six patients had Ann Arbor stage IE, 33 stage IIE, 1 stage IIIE, 2 stage IVE and 2 an unknown stage. Twenty-one underwent a mastectomy, 39 conservative surgery and 23 biopsy; 51 received radiotherapy (RT) with (n = 37) or without (n = 14) chemotherapy. Median RT dose was 40 Gy (range 12-55 Gy). RESULTS: Ten (12%) patients progressed locally and 43 (55%) had a systemic relapse. Central nervous system (CNS) was the site of relapse in 12 (14%) cases. The 5-yr overall survival, lymphoma-specific survival, disease-free survival and local control rates were 53%, 59%, 41% and 87% respectively. In the univariate analyses, favorable prognostic factors were early stage, conservative surgery, RT administration and combined modality treatment. Multivariate analysis showed that early stage and the use of RT were favorable prognostic factors. CONCLUSION: The outcome of PBL is fair. Local control is excellent with RT or combined modality treatment but systemic relapses, including that in the CNS, occurs frequently.

[Breast cancer: pathology, the cornerstone of therapeutic decision]. / Cancer du sein : la pathologie, pierre angulaire de la décision therapeutique.

Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.

The reasons for discrepancies in target volume delineation : a SASRO study on head-and-neck and prostate cancers.

PURPOSE: To understand the reasons for differences in the delineation of target volumes between physicians. MATERIAL AND METHODS: 18 Swiss radiooncology centers were invited to delineate volumes for one prostate and one head-and-neck case. In addition, a questionnaire was sent to evaluate the differences in the volume definition (GTV [gross tumor volume], CTV [clinical target volume], PTV [planning target volume]), the various estimated margins, and the nodes at risk. Coherence between drawn and stated margins by centers was calculated. The questionnaire also included a nonspecific series of questions regarding planning methods in each institution. RESULTS: Fairly large differences in the drawn volumes were seen between the centers in both cases and also in the definition of volumes. Correlation between drawn and stated margins was fair in the prostate case and poor in the head-and-neck case. The questionnaire revealed important differences in the planning methods between centers. CONCLUSION: These large differences could be explained by (1) a variable knowledge/interpretation of ICRU definitions, (2) variable interpretations of the potential microscopic extent, (3) difficulties in GTV identification, (4) differences in the concept, and (5) incoherence between theory (i.e., stated margins) and practice (i.e., drawn margins).