Clinical Impact of Computed Tomography-based Image-guided Brachytherapy for Cervix Cancer using the Tandem-ring Applicator — the Addenbrooke's Experience

AimsWe report our initial 3-year experience of chemoradiotherapy for cervical cancer with computed tomography-based image-guided high dose rate (HDR) brachytherapy using the tandem-ring applicator.Materials and methodsTwenty-eight patients were treated between February 2005 and December 2007. All patients received initial external beam radiotherapy (EBRT) followed by HDR brachytherapy (planned dose 21 Gy to point A in three fractions over 8 days). For each insertion, a computed tomography scan was obtained with the brachytherapy applicator in situ. The cervix, uterus and organs at risk (OAR) were contoured on the computed tomography images to create an individualised dosimetry plan. The D₉₀ (the dose delivered to 90% of the tumour target), V₁₀₀ (the percentage of tumour target volume receiving 100% of the prescribed dose) and the minimum dose in the most exposed 2 cm³ volume (D_2cc) of rectum, bladder and bowel were recorded. The equivalent dose in 2 Gy fractions delivered by EBRT and brachytherapy was calculated.ResultsThe 3-year cancer-specific survival was 81%, with a pelvic control rate of 96%. In 24 patients, a D₉₀ ≥74 Gy_α/β10 was achieved. The only patient with local recurrence had a D₉₀ of 63.8 Gy_α/β10. The overall actuarial risk of serious late morbidity was 14%. Seventeen patients had satisfactory OAR doses using the standard loading pattern. Seven patients had modifications to reduce the risk of toxicity, whereas two had modifications to improve the tumour dose. Comparison with a previous cohort of patients treated with chemoradiotherapy and a conventionally planned low dose rate triple source brachytherapy technique showed an improvement in local pelvic control of 20% (P = 0.04).ConclusionsThe implementation of a computed tomography-based tandem-ring HDR brachytherapy technique in conjunction with individual dose adaptation has resulted in a significant improvement in local control at Addenbrooke's without increasing the risk of serious toxicity, and with little effect on radiotherapy resources.     

Correlation of dose-volume parameters, endoscopic and clinical rectal side effects in cervix cancer patients treated with definitive radiotherapy including MRI-based brachytherapy

Purpose

Correlation of dosimetric parameters for MRI-based 3D treatment planning with rectoscopic findings and clinical rectal side effects.

Methods and materials

Rectosigmoidoscopy and rectal morbidity assessment were performed on 35 cervical cancer patients treated with external beam radiotherapy (EBRT) and HDR-intracavitary brachytherapy (ICB). The total doses, normalised to 2 Gy fractions (EQD2, α/β = 3 Gy), in 0.1, 1.0 and 2.0 cm³ (D_0.1cc, D_1cc, D_2cc) of rectum were determined by summation of EBRT and ICB plans. Correlation analysis between clinical symptoms (LENT/SOMA) and rectoscopic changes (Vienna Rectoscopy Score, VRS) was performed. For dose-response analyses, the logit model was applied.

Results

Mean follow-up was 18 months. LENT/SOMA score was 1 in 4 patients, 2 in 8 patients, 4 in 1 patient. Telangiectasia was found in 26 patients (74%), five of them had ulceration corresponding to the 0.1 cm³ volume (anterior wall). Mean values D_0.1cc, D_1cc, and D_2cc were 81 ± 13, 70 ± 9 and 66 ± 8 Gy, respectively. The ED50 values for VRS ? 3 and for LENT/SOMA ? 2 significantly increased with decreasing volumes. D_2cc was higher in patients with VRS ? 3 compared to VRS < 3 (72 ± 6 vs 62 ± 7 Gy; p < 0.001) and in symptomatic vs asymptomatic patients (72 ± 6 vs 63±8 Gy; p < 0.001). VRS correlated with the LENT/SOMA score.

Conclusions

Rectosigmoidoscopy is sensitive in detecting mucosal changes, independent of clinical symptoms. The localization of these changes corresponds to the high dose volumes as defined by imaging. The development of mucosal and clinical changes in the rectum follows a clear dose-effect and volume-effect. DVH parameters could be established.     

The effect of alternative biological modelling parameters (α/β and half time of repair T1/2) on reported EQD2 values in the treatment of advanced cervical cancer

Purpose

To evaluate the effect of different α/β and half-time of repair T_½ on the assessment of clinical treatment plans for patients with cervical cancer.

Materials and methods

We used EBRT and BT treatment plans of five patients, planned with MRI guided BT. We computed 3D EQD2 dose distributions of combined EBRT and BT treatments and calculated D90 of high-risk clinical target volume (HR-CTV) and D_2cc for bladder and rectum, and the ratio D_2cc(bladder)/D90(HR-CTV). BT was modelled as PDR (two applications of 32 × 60 cGy) and HDR (two applications of 2 × 7 Gy). We assumed a low, standard and high value for the biological parameters: HR-CTV α/β = 5/10/15 Gy and T_½ = 0.5/1.5/2.5 h; OAR α/β = 2/3/4 Gy; T_½ = 0.5/1.5/4.5 h.

Results

The chosen variation in modelling parameters had a much larger effect on PDR treatments than on HDR treatments, especially for OAR, thus creating larger uncertainties. The relative mean range of the ratio D_2cc(bladder)/D90(HR-CTV) is 72% for PDR and 25% for HDR. Out of the 125 modelled combinations 48 PDR plans and 23 HDR plans comply with clinical objectives.

Conclusion

For HDR brachytherapy, only α/β has a significant impact on reported EQD2 values, whereas for PDR both α/β and T_1/2 are important.Generally, the ratio D_2cc(bladder)/D90(HR-CTV) is more favourable for PDR, even considering the larger uncertainties in EQD2.     

Proposed Hydrogel-Implant Quality Score and a Matched-Pair Study for Prostate Radiation Therapy

PurposeSpaceOAR hydrogel has been Food and Drug Administration approved to reduce rectal toxicity in prostate radiation therapy. Training and certification for this procedure is performed by the manufacturer, without independent quality measures. We propose a Hydrogel-Implant Quality Score (HIQS) as a surrogate to quantify hydrogel placement accuracy, to assist clinicians in tracking their implant proficiency, and to support quality improvement. A matched-pair study was designed to investigate the benefit of SpaceOAR in rectal dose reduction for low-dose-rate brachytherapy and to validate the principle of the proposed HIQS.MethodsEighty-one prostate patients were retrospectively selected for this study. Each patient had SpaceOAR implantation under manufacturer supervision. Postprocedure computed tomography and T2-weighted magnetic resonance imaging were acquired for radiation planning. A HIQS system was proposed to evaluate the hydrogel placement quality. Hydrogel implantation was performed immediately after LDR seed placement. For each LDR patient, a non-SpaceOAR patient was matched based upon intraoperative rectal dose and prostate coverage. Intraoperative and postoperative rectal dose reduction was compared between SpaceOAR and non-SpaceOAR groups.ResultsThe average HIQS was 77 ± 10.8 (range, 49-97). Rectal anatomic distortions were seen in 17 cases. Significant rectal dose reductions between intraoperative and postoperative plans were found for SpaceOAR patients compared with non-SpaceOAR patients (25.1 Gy vs −5.0 Gy for ΔD_2cc and 65.7 Gy vs 13.0 for ΔD_0.1cc). Additional rectal dose reductions (8.4 Gy for ΔD_2cc and 12.7 Gy for ΔD_0.1cc) were found for patients without rectal distortion when SpaceOAR was used.ConclusionsThe proposed HIQS system measured the hydrogel placement quality and provided insights into clinician learning and DVH outcome. SpaceOAR was shown to be effective in reducing rectal dose for LDR patients.     

Consolidating duodenal and small bowel toxicity data via isoeffective dose calculations based on compiled clinical data

PurposeTo consolidate duodenum and small bowel toxicity data from clinical studies with different dose fractionation schedules using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose–volume (D,v) parameters to different levels of normal tissue complication probability (NTCP) was presented.Methods and MaterialsA set of NTCP model parameters for duodenum toxicity were estimated by the χ² fitting method using literature-based tolerance dose and generalized equivalent uniform dose (gEUD) data. These model parameters were then used to convert (D,v) data into the isoeffective dose in 2 Gy per fraction, (D_MLQED2,v) and convert these parameters to an isoeffective dose at another NTCP (D_MLQED2’,v).ResultsThe literature search yielded 5 reports useful in making estimates of duodenum and small bowel toxicity. The NTCP model parameters were found to be TD₅₀(1)^model = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and δ = 0.09 ± 0.03 Gy^- 1. Isoeffective dose calculations and toxicity rates associated with hypofractionated radiation therapy reports were found to be consistent with clinical data having different fractionation schedules. Values of (D_MLQED2’,v) between different NTCP levels remain consistent over a range of 5%-20%.ConclusionsMLQ-based isoeffective calculations of dose–response data corresponding to grade ≥ 2 duodenum toxicity were found to be consistent with one another within the calculation uncertainty. The (D_MLQED2,v) data could be used to determine duodenum and small bowel dose–volume constraints for new dose escalation strategies.     

Les contraintes du chirurgien dentiste sont compatibles avec les résultats d’une irradiation optimale avec modulation d’intensité dans les cancers de l’oropharynx de stade N0

PurposeWe compared intensity-modulated radiotherapy and 3D-conformal irradiation in oropharyngeal cancers according to the requirement of dentists.Material and methodsFrom the files of seven patients with cancer of the oropharynx, two dosimetry plannings for 3D-conformal radiotherapy and intensity-modulated radiotherapy with tomotherapy were performed. The dose distributions in the target volumes and organs at risk in relation to the dental sphere were compared.ResultsFor the planning target volume of the primitive tumour sites, average values of V_95%, D_2%, D_98% and of the conformal index were statistically in favour of tomotherapy. For the planning target volume of node areas, averages values of V_95%, D_2%, D_98% were statistically in favour of tomotherapy. For ipsi- and controlateral parotide glands, average values of V_15Gy, V_26Gy, V_30Gy, V_40Gy were significantly lower for tomotherapy. For the submaxillary glands, average values of mean doses and V_40Gy were statistically in favour of tomotherapy. For the buccal cavity, the average values of V_45Gy were statistically in favour of tomotherapy. For ipsi- and controlateral masseter muscles, the average values of mean doses were statistically in favour of tomotherapy. For the ipsi- and controlateral temporomandibular joints, average values of mean doses and V_60Gy were statistically in favour of tomotherapy. For mandibular bone, average values of mean doses and V_40Gy, V_50Gy, V_60Gy and V_70Gy were statistically in favour of tomotherapy. For maxillary bone, average values of V_40Gy, V_50Gy and V_60Gy were statistically in favour of tomotherapy.ConclusionThe radiation oncologist can constrain the intensity-modulated radiotherapy dosimetry to the needs of dentists to prevent or improve dental care and quality of life.     

MRI-based low dose-rate brachytherapy experience in locally advanced cervical cancer patients initially treated by concomitant chemoradiotherapy

Purpose

To retrospectively assess the physics contributions and the clinical outcome with preliminary 3D MRI-guided low dose-rate (LDR) intracavitary brachytherapy (BT) experience in locally advanced cervical cancer patients.

Patients and methods

Eighty-four patients with primary locally advanced cervical carcinoma were analyzed. The median tumoral cervical volume was 48.0 cc (range 1-468 cc). Twenty-four patients (53%) had histological and/or radiological pelvic involvement. After pelvic ± paraaortic concomitant chemoradiation, a LDR BT boost was delivered to a 3D MRI-based clinical target volume taking into account dose volume constraints for critical organs and optimization of target volume coverage.

Results

With a median follow-up of 53 months (range 31-79 months), the 4-year overall survival and disease-free survival rates were 57 (95%CI, 43-69) and 52% (95%CI, 40-64), respectively. Adding EBRT and LDR using EQD2 model, the median D₁₀₀ and D₉₀ for the IR-CTV were 56.5 Gy_α/β10 (range 37-83 Gy_α/β10) and 69 Gy_α/β10 (range 52-113 Gy_α/β10), respectively. For HR-CTV, the median D₁₀₀ and D₉₀ were 67 Gy_α/β10 (range 47-119 Gy_α/β10) and 79 Gy_α/β10 (range 53-122 Gy_α/β10), respectively. Thirty-nine late complications were observed in 28 patients (33.3%): 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others. Four grade 3 delayed complications were observed and no grade 4 complication occurred.

Conclusions

Applying an individual treatment planning with 3D MRI-guided LDR brachytherapy appears to be feasible and efficient for patients with locally advanced cervical cancer in routine clinical practice.     

DVH parameters and outcome for patients with early-stage cervical cancer treated with preoperative MRI-based low dose rate brachytherapy followed by surgery

Background

To our knowledge no DVH data have so far been reported for MRI-guided BT in the preoperative setting of early-stage cervical cancer. We assessed DVH parameters and clinical outcome using 3D MRI-guided preoperative intracavitary LDR BT.

Patients and methods

Thirty-nine patients with primary early cervical carcinoma (IB1 37, IIA 1 and IIB 1) were treated with preoperative MRI-based LDR BT, consisting of uterovaginal BT to a total dose of 60 Gy to the intermediate-risk CTV, followed 6 weeks later by bilateral salpingo-oophorectomy and extrafascial hysterectomy plus pelvic node dissection. Adjuvant chemoradiation was delivered to patients with pelvic lymph node involvement.

Results

With a median follow-up of 4.4 years (range 2.6-6.6 years), local recurrence occurred in 1 patient (a lateropelvic relapse) (2.6%). The 4-year actuarial overall survival and disease-free survival were 94% (95% CI, 82-98), and 86% (95% CI, 67-95), respectively. The 2- and 4-year actuarial local relapse-free survival were 94 (95% CI, 86-100) and 91% (95% CI, 81-100), respectively. For intermediate-risk CTV, median D₁₀₀ and D₉₀ were 43 Gy_α/β10 (range 2-74 Gy_α/β10) and 75 Gy_α/β10, respectively (range 29-129 Gy_α/β10). For high-risk CTV, the median D₁₀₀ and D₉₀ were 69 Gy_α/β10 (range 24-137 Gy_α/β10) and 109 Gy_α/β10 (range 37-198 Gy_α/β10), respectively. Twenty grade 1-2 late complications were observed in 13 patients (33.3%): 10 bladder, 3 ureteral, 1 rectal, 1 small bowel, 1 vaginal, 1 pelvic fibrosis, 1 peripheral nerve, and 2 others. No grade 3 or 4 complication occurred.

Conclusion

MRI-guided brachytherapy with adaptation of the time duration and/or the length of each radioactive source allows both high local control and low toxicity in the preoperative settings of early-stage cervical cancers.     

Reirradiation and stereotactic radiotherapy for tumors in the lung: Dose summation and toxicity

Purpose

To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration.

Material and methods

Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2–52).

Results

The median D_max of the lung in the summed plans was 363 Gy₃ (range 123–590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose ?70 Gy₃, with a median D_max of the heart of 115 Gy₃ and 89 Gy₃ for the trachea. Eight patients had in the esophagus an accumulated dose ?70 Gy₃, with a median accumulated dose of 85 Gy₃. No grade 3–5 toxicity was observed.

Conclusion

Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median D_max of 363 Gy₃ to the lung, as low toxicity was observed.     

Correlation of Conventional and Conformal Plan Parameters for Predicting Radiation Pneumonitis in Patients Treated with Breast Cancer

Purpose

The purpose of this study is to evaluate the correlation between the conventional plan parameters and dosimetric parameters obtained from conformal radiotherapy (RT) planning, and between these parameters and radiation pneumontitis (RP) incidence.

Methods

Clinical and dosimetric data of 122 patients that were treated with mastectomy and adjuvant 3D conformal RT (39% received 2-field RT [2-FRT], and in addition, 61% received 4-field RT [4-FRT]) were retrospectively analyzed. Central lung depth (CLD), maximum lung depth (MLD), and lung length were measured by the conventional plan. Lung dose-volume histograms (DVH) were created with conformal planning, and the lung volumes receiving 5 to 50 Gy (V_5Gy to V_50Gy) were calculated. Minimum (D_min), maximum (D_max), and mean doses (D_mean) for the ipsilateral lung and bilateral lungs were measured by DVH. Correlations between 3D dosimetric data and 2D radiographic parameters were analyzed.

Results

The conventional plan parameters did not significantly differ between 2-FRT and 4-FRT. The conformal plan D_min, D_max, and D_mean values were higher in 4-FRT versus 2-FRT. CLD and MLD were correlated with DVH parameter V_5Gy to V_45Gy values for ipsilateral, as well as bilateral lungs for 2-FRT. MLD and ipsilateral D_mean via 2-FRT planning had the strongest positive correlation (r=0.76, p<0.01). Moderate correlations existed between CLD and ipsilateral and bilateral lung V_5Gy-45Gy, and between MLD and bilateral lung V_5Gy-45Gy values in 2-FRT. Only four patients developed symptomatic RP, 4 with 4-FRT and one with 2-FRT.

Conclusion

The conformal plan parameters were strongly correlated with dose-volume parameters for breast 2-FRT. With only 4 cases of Grade 3 RP observed, our study is limited in its ability to provide definitive guidance, however assuming that CLD is an indicator for RP, V_20Gy could be used as a predictor for RP and for 2-FRT. A well-defined parameters are still required to predict RP in 4-FRT.     

Selective modification of the X ray survival response of two mouse mammary adenocarcinoma sublines by N,N-dimethylformamide

The modification of the X ray survival response of two mammary adenocarcinoma tumor cell sublines by the polar solvent N,N-dimethylformamide (DMF) has been studied. The sublines (termed lines 66 and 67) differ significantly in their single dose survival responses to x-irradiation. Survival responses were fitted to the single-hit, multi-target, and linear-quadratic equations. For non-DMF treated cells, line 67 radiation parameters were: D₀ (Gy) = 1.41, D_q (Gy) = 1.41, n (extrapolation number) = 2.73, α (10^?1Gy^?1) = 2.83, and β (10^?2Gy^?2) = 4.17. For line 66, these values were D₀ = 1.63, D_g = 3.01, n = 6.4, α = 0.45, and β = 4.28. For investigation of DMF effects, cells were seeded at 1 x 10⁴ per 25 cm₂ tissue culture flask in a DMF concentration of 0.8 % (0.10 M) and allowed to multiply for 4 days. For line 67, this increased the cell culture doubling time by about 27 %, and for line 66, by about 22 %. Cells were still in exponential growth at the time of irradiation. Immediately prior to irradiation, the media was removed, fresh media added and flasks were exposed to 100 kVp X rays. After exposure, cells were removed by trypsinization, counted and replated at appropriate dilution in fresh media. The survival parameters for line 67 (the radiosensitive line) then became D_{0) = 1.56, Dq = 0.89, n = 1.77}, α = 3.39, and β = 3.49. For line 66 (the radioresistant line), the survival parameters were D₀ = 1.56, D_q, = 0.94, n = 1.83, α = 4.14, and β = 2.41. These results indicate that DMF may have the potential for modifying the low dose “shoulder” region of survival, particularly for cell lines that possess large shoulders.     

VMAT techniques for lymph node-positive left sided breast cancer

PurposeTo investigate the plan quality of two different volumetric modulated arc therapy (VMAT) techniques for lymph node-positive left-sided breast cancer.MethodsTwo VMAT plans were generated for 10 lymph node-positive left-sided breast cancer patients: one plan using one single segment of a full rotation, typically an arc segment of 230° (1s-VMAT); and a second plan consisting of 2 small tangential arc segments of about 50° (2s-VMAT).For plan comparison, various dose and dose volume metrics (D_mean, D_98%, D_2% for target volumes, D_2%, D_mean and V_x% for organs at risk (OAR)) were evaluated.ResultsBoth techniques fulfilled both clinical target dose and OAR goals. 1s-VMAT achieved a slightly better homogeneity and better target coverage (D_2%= 54.2 ± 0.7 Gy, D_98%= 30.3 ± 1.8 Gy) compared to 2s-VMAT (D_2%= 55.0 ± 1.1 Gy, D_98%= 29.9 ± 1.7 Gy). For geometrical reasons, OAR sparing was noticeable but not significant better using 2s-VMAT, particularly heart and contralateral breast. The heart received a mean dose of 4.4 ± 0.8 Gy using 1s-VMAT and 3.3 ± 1.0 Gy using 2s-VMAT; the contralateral breast received 1.5 ± 0.3 Gy and 0.9 ± 0.3 Gy, respectively.ConclusionsA VMAT technique based on two small tangential arc segments enables improved OAR sparing; the differences between the two techniques in target coverage and homogeneity are minor. Patient age and –anatomy must be considered for each individual case when deciding which technique to be used.     

Inter-application displacement of brachytherapy dose received by the bladder and rectum of the patients with inoperable cervical cancer

Background

The aim of the study was to examine on the CT basis the inter-application displacement of the positions D_0.1cc, D_1cc and D_2cc of the brachytherapy dose applied to the bladder and rectum of the patients with inoperable cervical cancer.

Patients and methods

This prospective study included 30 patients with cervical cancer who were treated by concomitant chemo-radiotherapy. HDR intracavitary brachytherapy was made by the applicators type Fletcher tandem and ovoids. For each brachytherapy application the position D_0.1cc was determined of the bladder and rectum that receive a brachytherapty dose. Then, based on the X, Y, and Z axis displacement, inter-application mean X, Y, and Z axis displacements were calculated as well as their displacement vectors (R). It has been analyzed whether there is statistically significant difference in inter-application displacement of the position of the brachytherapy dose D_0.1cc, D_1cc and D_2cc of the bladder and rectum. The ANOVA test and post-hoc analysis by Tukey method were used for testing statistical importance of differences among the groups analyzed. The difference among the groups analyzed was considered significant if p < 0.05.

Results

There are significant inter-application displacements of the position of the brachytherapy dose D_0,1cc, D_1cc and D_2cc of the bladder and rectum.

Conclusions

When we calculate the cumulative brachytherapy dose by summing up D_0,1cc, D_1cc and D_2cc of the organs at risk for all the applications, we must bear in mind their inter-application displacement, and the fact that it is less likely that the worst scenario would indeed happen.     

Comparaison entre arcthérapie volumétrique modulée et tomothérapie pour le cancer du col utérin,avec irradiation lomboaortique

PurposeIntensity-modulated radiotherapy (IMRT) has proven its dosimetric superiority over conformational radiotherapy for cervix cancers in terms of digestive toxicity. Volumetric modulated arctherapy (VMAT) has shown its dosimetric interest when compared to IMRT with static beams. The purpose of our study was to compare conformational radiotherapy, VMAT and tomotherapy for cervical cancers with para-aortic lymph nodes irradiation.Patients and methodsThe dosimetric data from ten patients were compared between the three techniques, with collection of the dose received by the planning target volume, kidneys, bowel, rectum, bladder, bone marrow and spinal cord, as well as the complete dose.ResultsThere was a significant difference in favour of VMAT and tomotherapy when compared with conformational radiotherapy for the organs at risk: intestines (V_20 Gy, V_30 Gy and V_45 Gy), rectum (V_30 Gy and V_45 Gy), bladder (V_30 Gy and V_45 Gy) and kidneys (V_12 Gy, D_average, V_20 Gy). Volumes receiving 20, 30 and 45 Gy were significantly higher in conformational radiotherapy than in VMAT and tomotherapy. There was a significant difference in favour of tomotherapy when compared with VMAT for V_12 Gy in kidneys and V_45 Gy in the bladder.ConclusionThis study confirms the interest of VMAT and tomotherapy for pelvic and para-aortic lymph nodes irradiation of cervix cancer when compared with conformational radiotherapy. There was little difference between VMAT and tomotherapy, except for kidney sparing, which was better with tomotherapy and thus may be interesting for patients receiving nephrotoxic chemotherapy.     

DNA double-strand break repair,DNA-PK,and DNA ligases in two human squamous carcinoma cell lines with different radiosensitivity

Purpose: Variation in sensitivity to radiotherapy among tumors has been related to the capacity of cells to repair radiation-induced DNA double-strand breaks (DSBs). DNA-dependent protein kinase (DNA-PK) and DNA ligases may affect DNA dsb rejoining. This study was performed to compare rate of rejoining of radiation-induced DSBs, DNA-PK, and DNA ligase activities in two human squamous carcinoma cell lines with different sensitivity to ionizing radiation.Methods and Materials: Cell survival of two human squamous carcinoma cell lines, UM-SCC-1 and UM-SCC-14A, was determined by an in vitro clonogenic assay. DSB rejoining was studied using pulsed field gel electrophoresis (PFGE). DNA-PK activity was determined using BIOTRAK DNA-PK enzyme assay system (Amersham). DNA ligase activity in crude cell extracts was measured using [5′-³³P] Poly (dA)·(oligo (dT) as a substrate. Proteolytic degradation of proteins was analyzed by means of Western blotting.Results: Applying the commonly used linear-quadratic equation to describe cell survival, S = e^-αD-βD2, the two cell lines roughly have the same α value (∼0.40 Gy^-1) whereas the β value was considerably higher in UM-SCC-14A (0.067 Gy^-2 ± 0.007 Gy^-2 [SEM]) as compared to UM-SCC-1 (0.013 Gy^-2 ± 0.004 Gy^-2 [SEM]). Furthermore, UM-SCC-1 was more proficient in rejoining of X-ray-induced DSBs as compared to UM-SCC-14A as quantified by PFGE. The constitutive level of DNA-PK activity was 1.6 times higher in UM-SCC-1 as compared to UM-SCC-14A (p < 0.05). The constitutive level of DNA ligase activity was similar in the two cell lines.Conclusions: The results suggest that the proficiency in rejoining of DSBs is associated with DNA-PK activity but not with total DNA ligase activity.     

Sacral Insufficiency Fracture Following Pelvic Radiotherapy in Gynaecological Malignancies: Development of a Predictive Model

AimsTo investigate the time-to-event and the evolution of sacral insufficiency fractures in gynaecological patients receiving pelvic external beam radiotherapy (EBRT) in relation to dosimetric and imaging parameters across a spectrum of radiotherapy delivery techniques, and to develop a predictive model with a clinical nomogram to identify those at risk of sacral insufficiency fracture.Materials and methodsPatients who received radical or adjuvant pelvic EBRT for gynaecological malignancy between 2014 and 2019 were identified. The data collected were: demographics and clinical details; radiotherapy planning data: dose, fractionation, technique (fixed-field intensity-modulated radiotherapy, adaptive arc, and non-adaptive arc), 60 Gy simultaneous integrated boost. Each plan was examined to determine the sacral dose in 5%/Gy₃ increments. Follow-up magnetic resonance scans were reviewed for insufficiency fractures, defined as linear low T1-weighted signal intensity with a high short-T1 inversion recovery (STIR) signal. The site of insufficiency fracture was recreated on the planning computed tomography, the dose to insufficiency fracture contours was recorded and insufficiency fractures were determined as healed with resolution of high STIR signal. Univariable analysis was conducted of the clinical variables. The area under the receiver operator characteristic curve and odds ratio of the risk prediction model with 95% confidence interval are reported with a nomogram for use in clinical practice.Results115 patients were identified; the median imaging follow-up was 12 months (2–47). 37.4% developed sacral insufficiency fractures; 93.0% were detected within 12 months of EBRT. At the final radiological follow-up, 83.7% of insufficiency fractures remained active. The radiotherapy delivery technique was not associated with insufficiency fracture after adjusting for patient age (P = 0.115). The location of the 60 Gy simultaneous integrated boost planning target volume did not impact upon the site of insufficiency fracture or the dose received by the insufficiency fracture sites. Age and V40Gy₃ are predictors for insufficiency fracture and form the clinical risk model (receiver operator characteristic 0.72).ConclusionsAge and V40Gy₃ predict sacral insufficiency fractures; future work should focus on optimising radiotherapy planning with adoption of a bone-sparing planning approach for those patients at high risk of insufficiency fracture.     

Is There a Role for Adjuvant Hysterectomy after Suboptimal Concurrent Chemoradiation in Cervical Carcinoma?

AimsFailure to carry out intracavitary brachytherapy (ICBT) in cervical carcinoma results in suboptimal chemoradiation and increases the risk of recurrence. The aim of this study was to investigate the role of adjuvant hysterectomy after unsuccessful ICBT.Materials and methodsA retrospective analysis was carried out of all women referred with cervical carcinoma between January 1999 and July 2007 where ICBT insertion was unsuccessful after the initial chemoradiation. The data collected and analysed included histology, stage of disease, causes for unsuccessful ICBT insertion, the response to the initial chemoradiation, subsequent treatment, morbidity, recurrence rates and survival rates. Kaplan–Meier and Log-rank methods were used to analyse recurrence-free and overall survival rates.ResultsICBT insertion was unsuccessful in 19 of 208 (9%) patients. The causes of failure were: inability to dilate the cervix; uterine perforation; vesicovaginal fistula; patient refusal; other problems, including the presence of pyometrium, patient not fit for general anaesthetic, and narrow vagina; and consultant choice with no obvious reason. Fourteen of 19 patients (74%) received further pelvic external beam radiotherapy (EBRT) alone; five (26%) patients underwent adjuvant hysterectomy. The median follow-up for all patients was 63 months; 60 months for patients treated with adjuvant hysterectomy (range 31–68 months) and 85 months for patients treated with further EBRT. None of the patients treated with adjuvant hysterectomy developed any significant late toxicity. Seven patients (50%) treated with EBRT have relapsed compared with none in the adjuvant hysterectomy arm (P = 0.068). Six patients (43%) in the EBRT arm have subsequently died of recurrent disease compared with none in the adjuvant hysterectomy arm (P = 0.152).ConclusionsAdjuvant hysterectomy after unsuccessful ICBT does not seem to increase late toxicity and reduces the risk of pelvic recurrence and may improve survival. The role of adjuvant hysterectomy after suboptimal chemoradiation merits further investigation in clinical trials.