Fractional Delivery Research Articles

49921 Safety of Ablative Fractional Laser-Assisted Drug Delivery

49921 Safety of Ablative Fractional Laser-Assisted Drug Delivery

Efficacy of fractional carbon dioxide laser-assisted drug delivery in the management of post-burn scars - A prospective study.

The objective of our study is to assess the efficacy of fractional carbon dioxide (CO2) laser-assisted drug delivery (LADD) in the management of post-burn scars. It is a prospective study conducted from March 2021 to February 2022, with 32 patients ranging in age from 9 to 52 years. The scars lasted anywhere from 6 months to 18 years. The ethical clearance of the Institutional Ethics Committee was obtained. The patient's median age was 22 (range, 09-52). Patients were assessed using a modified Vancouver scar scale (mVSS) score before and after receiving fractional CO2 laser at monthly intervals. After one treatment, statistically significant improvements in pigment, thickness, and pliability were seen according to the mVSS scores, and these improvements persisted through the final laser session. Our study has demonstrated that fractional CO2 LADD seems to be an encouraging approach in the management of post-burn scars with good patient satisfaction.

Fractional Ablative Carbon Dioxide Laser-Assisted Photodynamic Therapy for keloids: Clinical, Histopathological and Immunohistochemical Evaluation

Abstract Background Keloids present a therapeutic challenge due to lack of satisfactory treatment and high rate of recurrence. Various treatment modalities exist, including intralesional steroids, photodynamic therapy (PDT), lasers and different combinations have been used to reach better results. Aim To study whether fractional ablative CO2-assisted delivery of Methylene blue-PDT is an effective method of treatment of keloids. Methods twenty patients with untreated keloids have been treated with 3 monthly sessions of fractional CO2 laser and methylene blue PDT. In the first session debulking of the keloid’s height by at least 50% with ablative CO2 was performed. Patients were photographed and assessed before treatment and 2 months after last session, clinically using modified Vancouver Scar Scale (mVSS) & patient and observer scar assessment scale (POSAS), histopathologically by H&E, Masson trichrome and immunohistochemically by TGF-b. Results total score for mVSS dropped from 8.25 ± 2.489 to 6.45 ± 2.8 (p = 0.013) after treatment, with a percentage change of -18.6 ± 39.6. Also, POSAS (observer) decreasaed from 26.90 ± 6.545 to 18.75 ± 8.045 (p = 0.001). POSAS (patient) decreased from 27.40 ± 6.644 to 19.05 ± 7.722 (p = 0.0001) Histopathologically, collagen improved from 3.45 ± 1.05to 2.65 ± 0.875. The TGFb staining increased post treatment but not significantly. Conclusions clinical and histopathological improvement was seen after MB-PDT but further controlled studies are needed to compare its effectiveness with other established modalities. Also compare results of different parameters of fractional CO2-PDT, more treatment sessions and study the long term follow up results.

Delta radiomics to track radiation response in lung tumors receiving stereotactic magnetic resonance-guided radiotherapy

Background and purposeLung cancer is a leading cause of cancer-related mortality, and stereotactic body radiotherapy (SBRT) has become a standard treatment for early-stage lung cancer. However, the heterogeneous response to radiation at the tumor level poses challenges. Currently, standardized dosage regimens lack adaptation based on individual patient or tumor characteristics. Thus, we explore the potential of delta radiomics from on-treatment magnetic resonance (MR) imaging to track radiation dose response, inform personalized radiotherapy dosing, and predict outcomes. Materials and methodsA retrospective study of 47 MR-guided lung SBRT treatments for 39 patients was conducted. Radiomic features were extracted using Pyradiomics, and stability was evaluated temporally and spatially. Delta radiomics were correlated with radiation dose delivery and assessed for associations with tumor control and survival with Cox regressions. ResultsAmong 107 features, 49 demonstrated temporal stability, and 57 showed spatial stability. Fifteen stable and non-collinear features were analyzed. Median Skewness and surface to volume ratio decreased with radiation dose fraction delivery, while coarseness and 90th percentile values increased. Skewness had the largest relative median absolute changes (22 %–45 %) per fraction from baseline and was associated with locoregional failure (p = 0.012) by analysis of covariance. Skewness, Elongation, and Flatness were significantly associated with local recurrence-free survival, while tumor diameter and volume were not. ConclusionsOur study establishes the feasibility and stability of delta radiomics analysis for MR-guided lung SBRT. Findings suggest that MR delta radiomics can capture short-term radiographic manifestations of the intra-tumoral radiation effect.

Magnetic resonance image-guided adaptive radiotherapy enables safe CTV-to-PTV margin reduction in prostate cancer: a cine MRI motion study.

We aimed to establish if stereotactic body radiotherapy to the prostate can be delivered safely using reduced clinical target volume (CTV) to planning target volume (PTV) margins on the 1.5T MR-Linac (MRL) (Elekta, Stockholm, Sweden), in the absence of gating. Cine images taken in 3 orthogonal planes during the delivery of prostate SBRT with 36.25 Gray (Gy) in 5 fractions on the MRL were analysed. Using the data from 20 patients, the percentage of radiotherapy (RT) delivery time where the prostate position moved beyond 1, 2, 3, 4 and 5 mm in the left-right (LR), superior-inferior (SI), anterior-posterior (AP) and any direction was calculated. The prostate moved less than 3 mm in any direction for 90% of the monitoring period in 95% of patients. On a per-fraction basis, 93% of fractions displayed motion in all directions within 3 mm for 90% of the fraction delivery time. Recurring motion patterns were observed showing that the prostate moved with shallow drift (most common), transient excursions and persistent excursions during treatment. A 3 mm CTV-PTV margin is safe to use for the treatment of 5 fraction prostate SBRT on the MRL, without gating. In the context of gating this work suggests that treatment time will not be extensively lengthened when an appropriate gating window is applied.

Effective keloid management using a combinatorial continuous-wave and repeat fractionated ablative CO2 laser regimen.

Keloids are benign proliferative scars that form as a result of dysregulated growth and collagen deposition in response to cutaneous injury. Laser therapies have emerged as promising options for the treatment of keloids, with performance varying by laser type and lesion characteristics. To assess the combined continuous wave and repetitive fractionated CO2 laser treatment of keloids. A retrospective chart review of 22 cases of keloid scars treated with combined CO2 laser modes. A single session of continuous wave followed by five sessions of fractional delivery. Efficacy was assessed using the Patient and Observer Scar Assessment Scale (POSAS) and the Vancouver Scar Scale. The Numeric Rating Scale was used to assess patient satisfaction and pain. Most patients were female (77.3%) with skin type IV (72.7%), age was 24.3 ± 9.3 years, most keloids were located on the earlobe (56.5%) or arm or hand (17.4%), size ranged from 5 to 10 cm, and time since injury ranged from 3 months to 35 years. No serious adverse events were reported. At 6 months, significant improvements from baseline occurred in all characteristics, scar color (4.8 ± 2.8 to 1.9 ± 1.1), rigidity (5.0 ± 2.8 vs. 5.4 ± 2.8), thickness (5.4 ± 2.8 vs. 2.0 ± 1.1), and irregularity (5.9 ± 2.4 vs. 1.9 ± 0.9). The Vancouver scores followed a similar trend. Patient-rated overall improvement from 37 ± 17.6 at baseline to 16.1 ± 8.5 at 6 months, and improvement in associated pain and pruritus. Combination of two ablative laser delivery modes within a single laser platform provided for effective and safe keloid management and left patients highly satisfied.

213 Radiotherapy fraction delivery time does not affect survival outcomes in patients with oropharynx cancer, unselected for chronotype

213 Radiotherapy fraction delivery time does not affect survival outcomes in patients with oropharynx cancer, unselected for chronotype

Dust and Ice in the Interstellar Medium

In this paper, we present an introduction to bare dust particles and grains covered by ice sheets in diffuse and dense interstellar clouds. It follows the life cycle of dust from its formation in stellar environments to its incorporation into the body of the Solar system. Dust particles play an important role in the physics and chemistry of many space environments. Regarding dust composition, two different populations are generally observed: silicate and carbonaceous dust. Energetic processing of ice layers with UV rays, X – rays or cosmic rays, after which the heat leads to the formation of complex organic molecules; some of them have prebiotic properties. Delivery of this organic fraction to the early Earth by meteorites and asteroids may have contributed to the origin of life.

Advances in laser therapies for the scar.

Scars are classified into 5 types: Superficial scars, hypertrophic scars, atrophic scars, depressed scars, and keloid. These types are primarily characterized by abnormal production of fibroblasts and collagen, as well as the disorderly arrangement of connective tissue. Laser treatment for scars involves the coordinated activation of various signaling pathways and cytokines. However, the exact pathological mechanism for scar formation remains unclear, leading to a lack of radical treatment. Recently, laser treatment has gained popularity as a new minimally invasive approach for scar treatment. The emergence of new theories such as fractional, picosecond laser, and laser-assisted drug delivery has led to continuous advance in laser treatment. Up to now, it has been developed numerous novel treatments, including combined with drug, physical, and other treatments, which have shown superior therapeutic effects. In order to optimize laser treatment in the future, it is crucial to combine new materials with postoperative care. This will help clinicians develop more comprehensive treatment strategies. Therefore, it is important to explore treatment options that have broader applicability.

Nonsurgical Treatment of Postburn Hypopigmentation: A Literature Review.

The treatment of postburn hypopigmentation was primarily surgical before the advent of new technologies. Medical devices and therapies are emerging to manage scar sequelae that can be disfiguring and associated with severe psychosocial impact. These innovations have been poorly investigated for hypopigmentation, but they represent a real hope. We reviewed all articles published on Pubmed up to June 2022. Included studies had to specifically focus on treating postburn hypopigmented scars. All articles evaluating transient solutions such as make-up, and articles describing inflammation-linked hypopigmentation with no etiological details or no burn injury history were excluded. Through this review, we have highlighted 6 different types of nonsurgical treatments reported in postburn leukoderma potentially allowing definitive results. Electrophoto-biomodulation or E light (combining intensive pulsed light, radiofrequency, and cooling), topical daylight psoralen UVA therapy, and lasers (fractional lasers using pulse energies or CO2FL devices, lasers-assisted drug delivery as local bimatoprost and tretinoin or pimecrolimus) have been explored with encouraging results in hypopigmented burns. Finally, other promising medical strategies include using FK506, a nonsteroidal anti-inflammatory drug, to induce melanogenesis or using melanocyte-stimulating hormones with fractional laser-assisted drug deliveries, which are expected to emerge soon.

The role of fractional laser-assisted drug delivery in enhancing the efficacy of topical bimatoprost solution in the treatment of alopecia areata: An intra-patient comparative randomized clinical trial.

Transepidermal drug delivery is a novel therapeutic technique to boost efficacy of topical drugs. In this clinical trial we evaluate the efficacy of the combination of fractional carbon dioxide (FCO2) laser and bimatoprost solution compared to bimatoprost alone in the treatment of alopecia areata. This is a prospective intra-patient comparative randomized clinical trial on 20 patients with alopecia areata. In each participant two patches were chosen to randomly receive either topical 0.03% bimatoprost solution (twice a day for 12 weeks) alone or in combination with FCO2 laser (every 2 weeks for 12 weeks). Then response to treatment was evaluated by the measurement of the severity of alopecia tool score system (SALT) score, percentage of hair regrowth, physician assessment and patients' satisfaction. SALT score was reduced significantly during treatment sessions and after a 3-month follow-up in both treatment groups (p = 0.000). The mean percentage of improvement in SALT score in the combination therapy and monotherapy groups were 46.43 ± 4.35% and 21.16 ± 4.06% at the end of the study and 46.42 ± 5.75% and16.11 ± 3.10% at the end of the follow-up period, respectively (p = 0.000). A general linear model of two-way analysis demonstrated a significantly superior outcome in the combination therapy group compared to the monotherapy group during time (F1.6, 13.2 = 43.8. p = 0.000). Fractional ablative laser can be considered as an assistant method for enhancing of efficacy of topical drugs especially in refractory cases of patchy alopecia areata.

Safety and Effectiveness of Fractional Ablative CO 2 Laser-Assisted Delivery of Topical Poly- l -Lactic Acid for Rhytides and Scars.

Safety and Effectiveness of Fractional Ablative CO 2 Laser-Assisted Delivery of Topical Poly- l -Lactic Acid for Rhytides and Scars.

4D dosimetric-blood flow model: impact of prolonged fraction delivery times of IMRT on the dose to the circulating lymphocytes

To investigate the impact of prolonged fraction delivery of modern intensity-modulated radiotherapy (IMRT) on the accumulated dose to the circulating blood during the course of fractionated radiation therapy. We have developed a 4D dosimetric blood flow model (d-BFM) capable of continuously simulating the blood flow through the entire body of the cancer patient and scoring the accumulated dose to blood particles (BPs). We developed a semi-automatic approach that enables us to map the tortuous blood vessels of the surficial brain of individual patients directly from standard magnetic resonance imaging data of the patient. For the rest of the body, we developed a fully-fledged dynamic blood flow transfer model according to the International Commission on Radiological Protection human reference. We proposed a methodology enabling us to design a personalized d-BFM, such it can be tailored for individual patients by adopting intra- and inter-subject variations. The entire circulatory model tracks over 43 million BPs and has a time resolution of = 10−3 s. A dynamic dose delivery model was implemented to emulate the spatial and temporal time-varying pattern of the dose rate during the step-and-shoot mode of IMRT. We evaluated how different configurations of the dose rate delivery, and a time prolongation of fraction delivery may impact the dose received by the circulating blood (CB).Our calculations indicate that prolonging the fraction treatment time from 7 to 18 min will augment the blood volume receiving any dose from 36.1% to 81.5% during one single fraction. The results indicate that increasing the segment number has only a negligible effect on the irradiated blood volume, when the fraction time is kept identical. We developed a novel concept of customized 4D d-BFM that can be tailored to the hemodynamics of individual patients to quantify dose to the CB during fractionated radiotherapy. The prolonged fraction delivery and the variability of the instantaneous dose rate have a significant impact on the accumulated dose distribution during IMRT treatments. This impact should be considered during IMRT treatments design to reduce RT-induced immunosuppressive effects.

Fractional CO2 Laser-induced Delivery of Topical Corticosteroids Hastens Resolution of Localized Plaque Sarcoidosis.

Fractional CO2 Laser-induced Delivery of Topical Corticosteroids Hastens Resolution of Localized Plaque Sarcoidosis.

Nebulizers effectiveness on pulmonary delivery of alpha-1 antitrypsin

The nebulization of alpha-1 antitrypsin (AAT) for its administration to the lung could be an interesting alternative to parenteral infusion for patients suffering from AAT genetic deficiency (AATD). In the case of protein therapeutics, the effect of the nebulization mode and rate on protein conformation and activity must be carefully considered. In this paper two types of nebulizers, i.e., a jet and a mesh vibrating system, were used to nebulize a commercial preparation of AAT for infusion and compared. The aerosolization performance, in terms of mass distribution, respirable fraction, and drug delivery efficiency, as well as the activity and aggregation state of AAT upon in vitro nebulization were investigated. The two nebulizers demonstrated equivalent aerosolization performances, but the mesh nebulizer provided a higher efficiency in the delivery of the dose. The activity of the protein was acceptably preserved by both nebulizers and no aggregation or changes in its conformation were identified. This suggests that nebulization of AAT represents a suitable administration strategy ready to be translated to the clinical practice for delivering the protein directly to the lungs in AATD patients, either as a support therapy to parenteral administration or for subjects with a precocious diagnosis, to prevent the onset of pulmonary symptoms.Graphical

The Role of Fractional CO2 and Pulsed Dye Laser in Scar Management

Introduction: An estimated 100 million patients acquire scars of any type every year, a few of which will lead to hypertrophic, contracting scars or keloids. Management remains challenging and encompasses surgical and non-surgical treatment options. The introduction of fractional photothermolysis (FP) in 2004,marked a major advancement in treatment. Unlike classic non-fractional ablative lasers, FP uses well focused laser beams to create small columns of ablation called microscopic treatment zones (MTZ).FP has since been discovered to be particularly useful in relieving scar contractures with efficacy on improving functionality and cosmetic outcomes. We aim to present a case of a contracting scald burn over the buttocks improving exceptionally following pulsed dye (595 nm) laser and fractional resurfacing using an ablative CO2 (10600 nm) laser associated with transepidermal triamcinolone delivery. Materials and Methods: Case presentation of the management of a hypertrophic scar following a scald burn. Results: A 12 year old boy suffered a third degree scald burn on the right buttock requiring a split thickness skin graft. The follow-up was complicated by a contracting, hypertrophic scar with a negative impact on his soccer playing due to diminished running ability. we started treatment with pulsed dye laser (595 nm, handpiece of 12 mm, pulse duration of 6 ms, fluence of 5 à 6 J/cm2),fractional resurfacing treatments using an ablative fractional CO2 laser(10600 nm, Deep-Fx, 30 to 50 mJ/MTZ, 5% coverage)followed by topical triamcinolone application by the principle of fractional laser-assisted drug delivery. We applied a hydrocolloid dressing 24/7,wearing compression shorts and to massage the scar regularly. After a total of 19 treatments, we observed a smooth scar without any signs of contraction and a normal range of motion of the hip joint. The patient was highly satisfied with the functional and aesthetic result. Conclusion: Lasers are a safe and effective treatment option for traumatic scars. Choosing the appropriate laser with the appropriate dosimetry is one of the cornerstones to a good scar-management.

Assessing the impact of intrafraction motion correction on PTV margins and target and OAR dosimetry for single-fraction free-breathing lung stereotactic body radiation therapy.

The objective of this research is to investigate intrafraction motion correction on planning target volume (PTV) margin requirements and target and organ-at-risk (OAR) dosimetry in single-fraction lung stereotactic body radiation therapy (SBRT). Sixteen patients (15 with upper lobe lesions, 1 with a middle lobe lesion) were treated with single-fraction lung SBRT. Cone-beam computed tomography (CBCT) images were acquired before the treatment, between the arcs, and after the delivery of the treatment fraction. Shifts from the reference images were recorded in anterior-posterior (AP), superior-inferior (SI), and lateral (LAT) dimensions. The deviations from the reference image were calculated for 3 clinical scenarios: not applying intratreatment couch shifts and not correcting for pretreatment deviations < 3 mm ( scenario 1), not applying intratreatment couch shifts and correcting for pretreatment deviations < 3 mm ( scenario 2), and applying all pre- and intratreatment couch shifts (scenario 3). PTV margins were determined using the van Herk formalism for each scenario and maximum and average deviations were assessed. The clinical scenarios were modelled in the treatment planning system based on each patient dataset to assess target and OAR dosimetry. Calculated lower-bound PTV margins in the AP, SI, and LAT dimensions were [4.6, 3.5, 2.3] mm in scenario 1, [4.6, 2.4, 2.2] mm in scenario 2, and [1.7, 1.2, 1.0] mm in scenario 3. The margins are lower bounds because they do not include contributions from nonmotion related errors. Average and maximum intrafraction deviations were larger in the AP dimension compared to the SI and LAT dimensions for all scenarios. A unidimensional movement (several mm) in the negative AP dimension was observed in clinical scenarios 1 and 2 but not scenario 3. Average intrafraction deviation vectors were 1.2, 1.1, and 0.3 mm for scenarios 1, 2, and 3, respectively. Modelled clinical scenarios revealed that using scenario 3 yields significantly fewer treatment plan objective failures compared to scenarios 1 and 2 using a Wilcoxon signed-rank test. Intratreatment motion correction between each arc may enable reductions PTV margin requirements. It may also compensate for unidimensional negative AP movement, and improve target and OAR dosimetry.

Clinical Practice Evolvement for Post-Operative Prostate Cancer Radiotherapy—Part 2: Feasibility of Margin Reduction for Fractionated Radiation Treatment with Advanced Image Guidance

Purpose: Planning target volume (PTV) expansion for post-prostatectomy radiotherapy is typically ≥5 mm. Recent clinical trials have proved the feasibility of a reduced margin of 2−3 mm for treatments on MRI-linac. We aim to study the minimum PTV margin needed using iterative cone-beam CT (iCBCT) as image guidance on conventional linacs. Materials/Methods: Fourteen patients who received post-prostatectomy irradiation (8 with an endorectal balloon and 6 without a balloon) were included in this study. Treatment was delivered with volumetric modulated radiation therapy (VMAT). Fractional dose delivery was evaluated in 165 treatment fractions. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. PTV margins (0 mm, 2 mm, and 4 mm) were evaluated on daily iCBCT. CTV coverage and OAR dose parameters were assessed with each PTV margin. Results: CTV D100% was underdosed with a 0 mm margin in 32% of fractions in comparison with 2 mm (6%) and 4 mm (6%) PTV margin (p ≤ 0.001). CTV D95% > 95% was met in 93−94% fractions for all PTV expansions. CTV D95% > 95% was achieved in more patients with an endorectal balloon than those without: 0 mm—90/91 (99%) vs. 63/74 (85%); 2 mm—90/91 (99%) vs. 65/75 (87%); 4 mm—90/90 (100%) vs. 63/73 (86%). There was no difference in absolute median change in CTV D95% (0.32%) for 0-, 2-, and 4 mm margins. The maximum dose remained under 108% for 100% (0 mm), 97% (2 mm), and 98% (4 mm) of images. Rectal wall maximum dose remained under 108% for 100% (0 mm), 100% (2 mm), and 98% (4 mm) of images. Conclusions: With high-quality iCBCT image guidance, PTV margin accounting for inter-fractional uncertainties can be safely reduced for post-prostatectomy radiotherapy. For fractionated radiotherapy, an isotropic expansion of 2 mm and 4 mm may be considered for margin expansion with and without the endorectal balloon. Future application for margin reduction needs to be further evaluated and considered with the advent of shorter post-prostatectomy radiation courses.

Clinical Practice Evolvement for Post-Operative Prostate Cancer Radiotherapy-Part 1: Consistent Organs at Risk Management with Advanced Image Guidance.

Purpose: Post-operative prostate cancer patients are treated with full bladder instruction and the use of an endorectal balloon (ERB). We reassessed the efficacy of this practice based on daily image guidance and dose delivery using high-quality iterative reconstructed cone-beam CT (iCBCT). Methods: Fractional dose delivery was calculated on daily iCBCT for 314 fractions from 14 post-operative prostate patients (8 with and 6 without ERB) treated with volumetric modulated radiotherapy (VMAT). All patients were positioned using novel iCBCT during image guidance. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. The dose-volume parameters of the contoured organs at risk (OAR) and CTV coverage were assessed for the clinical impact of daily bladder volume variations and the use of ERB. Minimum bladder volume was studied, and a straightforward bladder instruction was explored for easy clinical adoption. Results: A “minimum bladder” contour, the overlap between the original bladder contour and a 15 mm anterior and superior expansion from prostate bed PTV, was confirmed to be effective in identifying cases that might fail a bladder constraint of V65% <60%. The average difference between the maximum and minimum bladder volumes for each patient was 277.1 mL. The daily bladder volumes varied from 62.4 to 590.7 mL and ranged from 29 to 286% of the corresponding planning bladder volume. The bladder constraint of V65% <60% was met in almost all fractions (98%). CTVs (D90%, D95%, and D98%) remained well-covered regardless of the absolute bladder volume daily variation or the presence of the endorectal balloon. Patients with an endorectal balloon showed smaller variation but a higher average maximum rectal wall dose (D0.03mL: 104.3% of the prescription) compared to patients without (103.3%). Conclusions: A “minimum bladder” contour was determined that can be easily generated and followed to ensure sufficient bladder sparing. Further analysis and validation are needed to confirm the utility of the minimal bladder contour. Accurate dose delivery can be achieved for prostate bed target coverage and OAR sparing with or without the use of ERB.

Accumulation of sublethal radiation damage and its effect on cell survival

Objective. Determine the extent of sublethal radiation damage (SRD) in a cell population that received a given dose of radiation and the impact of this damage on cell survival. Approach. We developed a novel formalism to account for accumulation of SRD with increasing dose. It is based on a very general formula for cell survival that correctly predicts the basic properties of cell survival curves, such as the transition from the linear-quadratic to a linear dependence at high doses. Using this formalism we analyzed extensive experimental data for photons, protons and heavy ions to evaluate model parameters, quantify the extent of SRD and its impact on cell survival. Main results. Significant accumulation of SRD begins at doses below 1 Gy. As dose increases, so does the number of damaged cells and the amount of SRD in individual cells. SRD buildup in a cell increases the likelihood of complex irrepairable damage. For this reason, during a dose fraction delivery, each dose increment makes cells more radiosensitive. This gradual radosensitization is evidenced by the increasing slope of survival curves observed experimentally. It continues until the fraction is delivered, unless radiosensitivity reaches its maximum first. The maximum radiosensitivity is achieved when SRD accumulated in most cells is the maximum damage they can repair. After this maximum is reached, the slope of a survival curve, logarithm of survival versus dose, becomes constant, dose independent. The survival curve becomes a straight line, as experimental data at high doses show. These processes are random. They cause large cell-to-cell variability in the extent of damage and radiosensitivity of individual cells. Significance. SRD is in effect a radiosensitizer and its accumulation is a significant factor affecting cell survival, especially at high doses. We developed a novel formalism to study this phenomena and reported pertinent data for several particle types.