Dental extraction, intensity-modulated radiotherapy of head and neck cancer, and osteoradionecrosis : A systematic review and meta-analysis.

OBJECTIVE: To seek evidence for osteoradionecrosis (ORN) after dental extractions before or after intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). METHODS: Medline/PubMed, Embase, and Cochrane Library were searched from 2000 until 2020. Articles on HNC patients treated with IMRT and dental extractions were analyzed by two independent reviewers. The risk ratios (RR) and odds ratios (OR) for ORN related to extractions were calculated using Fisher's exact test. A one-sample proportion test was used to assess the proportion of pre- versus post-IMRT extractions. Forest plots were used for the pooled RR and OR using a random-effects model. RESULTS: Seven of 630 publications with 875 patients were eligible. A total of 437 (49.9%) patients were treated with extractions before and 92 (10.5%) after IMRT. 28 (3.2%) suffered from ORN after IMRT. ORN was associated with extractions in 15 (53.6%) patients, eight related to extractions prior to and seven cases related to extractions after IMRT. The risk and odds for ORN favored pre-IMRT extractions (RR = 0.18, 95% CI: 0.04-0.74, p = 0.031, I2 = 0%, OR = 0.16, 95% CI: 0.03-0.99, p = 0.049, I2 = 0%). However, the prediction interval of the expected range of 95% of true effects included 1 for RR and OR. CONCLUSION: Tooth extraction before IMRT is more common than after IMRT, but dental extractions before compared to extractions after IMRT have not been proven to reduce the incidence of ORN. Extractions of teeth before IMRT have to be balanced with any potential delay in initiating cancer therapy.

Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.

Treatment of radiation-induced maculopathy with fluocinolone acetonide.

PURPOSE: Chronic macular oedema is a well-known presentation of radiation-induced maculopathy (RM) following external beam photon therapy, plaque radiotherapy and proton beam radiotherapy for choroidal tumours. Current therapies vary in respect of efficacy and clinical benefit. The potential of fluocinolone acetonide (FAc) slow-release implants is unknown. We hypothesised that local continuous delivery of low-dose corticosteroids might improve symptoms of RM. METHODS: Five-two male and three female-patients from 37 to 68 years presented with RM following 106Ru-plaque brachytherapy or stereotactic radiation therapy (STx) with photons using a hypofractionated schedule of 5 × 10 Gy. All were treated with triamcinolone injections in first line and proofed to be refractory to steroids. In addition, two patients had received Ozurdex® implants as a second-line treatment, though without any clinical benefit. FAc slow-release implants were injected, and patients were followed up to monitor clinical improvement. RESULTS: All patients responded to therapy by means of a decrease in macular oedema. In four of five (80%) patients, visual acuity improved, and one patient showed stable visual acuity. No toxic effects or complications were observed. CONCLUSION: Slow-release implants of FAc are a promising therapeutic potent steroid treatment option to benefit anatomical structures of the fovea and visual function. Slow-release implants with FAc reduce the frequency of intravitreal injections and the therapeutic burden.

Visualization of the tumor cavity after lumpectomy of breast cancer for postoperative radiotherapy.

To visualize the tumor cavity after lumpectomy, the tumor cavity was coated with the liquid tissue marker sucrose acetate isobutyrate (SAIB) with its radiopaque electron dense SAIB analogue (x-SAIB) and assessed for radiotherapy planning. SAIB/x-SAIB enhanced the confidence for target structure definition. Tissue displacement after oncoplasty may be revealed by SAIB/x-SAIB.

Stereotactic radiotherapy for choroidal melanomas by means of HybridArc™ : Physics and technique of linac-based photon beam therapy.

PURPOSE: Stereotactic radiotherapy (SRT) is suitable to treat ocular tumours. The optimal beam geometry for SRT, however, has not been defined. Here we evaluate a combination technique with dynamic conformal arcs (DCAs) and intensity-modulated static fields (IMRT), known as HybridArc™ (HA). METHODS: For the first consecutive 25 cases with choroidal melanomas with volumes of 0.02 to 1.18 cm3 treated with 50 Gy in five fractions, the results with respect to dose conformity, homogeneity, and dose distributions were summarised. To describe the dose distribution at the planning target volume (PTV) boundary, we defined a spatially averaged dose gradient (SADG) and compared it with Paddick's gradient index (GI). We made dosimetric comparisons between HA and other irradiation techniques. RESULTS: The PTVs ranged from 0.42 to 3.37 cm3. The conformity index (CI) was 1.25 ± 0.15, and the homogeneity index (HI) 0.08 ± 0.02. The SADG was (-3.5 ± 0.5) Gy/mm or (-7.0 ± 1.0) %/mm between the isodose levels 95 and 20%; local minima reached -11.5 Gy/mm or -22.9%/mm. The coefficient of determination for a nonlinear regression of GI on SADG was 0.072. After a median follow-up time of 19.6 months, local tumour control was 100% without any case of post-therapeutic enucleation. Two patients (8%) developed liver metastases. CONCLUSION: SRT of ocular tumours by HA is highly appropriate, and HA is superior to intensity-modulated arc therapy (IMAT) concerning dose reduction in organs at risk (OARs). The novel gradient measure SADG is more informative than Paddick's GI.

Intensity-modulated radiotherapy and volumetric-modulated arc therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy.

Radiotherapy reduces the local relapse rate after pleuropneumonectomy of malignant pleural mesothelioma (MPM). The optimal treatment technique with photons remains undefined. Comparative planning for intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) was performed. Six MPM patients with significant postoperative intrathoracic air cavities were planned with IMRT and VMAT. A dose comparison for the targets and organ at risks (OAR) was performed. Robustness was assessed in respect to the variation of target dose with change in volume of air cavities. VMAT reduced the dose to the contralateral lung by reducing the volume covered by 13 Gy and 20 Gy by a factor 1.8 and 2.8, in respect to IMRT (p = 0.02). Dose distribution with VMAT was the most stable technique in regard to postsurgical air cavity variation. For IMRT, V90, V95, and the minimal target dose decreased by 40%, 64%, and 12% compared to 29%, 47%, and 7% with VMAT when air cavity decreased. Two arcs compared to one arc decreased the dose to all the organs at risk (OAR) while leaving PTV dose coverage unchanged. Increasing the number of arcs from two to three did not reduce the dose to the OAR further, but increased the beam-on time by 50%. Using partial arcs decreased the beam-on time by 43%. VMAT allows a lower lung dose and is less affected by the air cavity variation than IMRT. The best VMAT plans were obtained with two partial arcs. VMAT seems currently the most suitable technique for the treatment of MPM patients when air cavities are remaining and no adaptive radiotherapy is performed.

CD4+ CD25+ Treg regulate the contribution of CD8+ T-cell subsets in repopulation of the lymphopenic environment.

Peripheral T-cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T-cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8(+) central-memory T cells (T(CM) ) and effector-memory T cells (T(EM)) pools after adoptive transfer of sorted CD8(+) T cells from naïve, T(CM) and T(EM) subsets into T-cell-deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8(+) T-cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4(+) CD25(+) Treg play a major role in the repopulation of the CD8(+) T-cell pool and that CD8(+) T-cell subsets impact on each other. In the absence of CD4(+) CD25(+) Treg, a small fraction of naïve CD8(+) T cells strongly proliferates, correlating with further expansion and differentiation of co-expanding CD8(+) T cells. CD4(+) CD25(+) Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered T(CM) and T(EM) fractions, and leading to repopulation of each pool with progeny of its own kind.

Age as a predictive factor in glioblastomas: population-based study.

We evaluated 715 glioblastoma patients diagnosed during 1980-1994 in the Canton of Zurich, Switzerland, to provide information on how patients were treated at the population level. Despite a general policy during the study period of treatment by surgical intervention aimed at maximum tumor removal followed by radiotherapy, there was a marked tendency toward limited treatment with advancing patient age. Of those younger than 65 years, 82% were treated either with surgery followed by radiotherapy, surgery alone or radiotherapy alone, versus 47% of patients 65 years or older. Only 25% of patients older than 75 years underwent surgery and/or radiotherapy, while the remaining patients were given best supportive care (BSC). The mean ages of patients were 54.5 years for those treated with surgery and radiotherapy, 58.3 years for surgery alone, 62.2 years for radiotherapy alone and 69.2 years for BSC. Among patients who were treated with surgery plus radiotherapy and those treated with radiotherapy alone, younger patients (<60 years) had a significantly higher survival rate than older patients (>or=60 years). In contrast, no significant difference in survival was observed between younger and older patients treated with surgery alone or receiving BSC, suggesting that lower survival rates in elderly patients with glioblastoma may be at least in part due to a lesser response to radiotherapy.

Consolidative involved field radiotherapy after high dose chemotherapy and autologous stem cell transplantation for non-Hodgkin's lymphoma: a case-control study.

The role of involved field radiation therapy (IF-RT) after high dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma (NHL) has not been conclusively defined. It has been hypothesized that HDC might obviate the need of consolidative IF-RT. A retrospective matched-pair analysis of patients undergoing HDC and ASCT with or without consolidative IF-RT has been performed. Fifteen patients treated with IF-RT after ASCT were compared with 15 patients without IF-RT, identical for histology, stage and treatment response to HDC/ASCT as well as comparable for international prognostic index (IPI) score, age and gender. After a mean follow-up time of 65 +/- 45 months, none of the patients with consolidative IF-RT following HDC and ASCT relapsed within the involved field compared to six patients without consolidative IF-RT (IF-failure risk at 5 years: 0% vs. 40%; p < 0.005). In most of the cases, local relapse was seen in patients with bulky disease. The 5-year risk for loco-regional failure was 7% after consolidative IF-RT and 38% in patients without IF-RT (p = 0.02) while the 5-year risk for developing distant recurrences was similar in both groups (30% with IF-RT vs. 35% non-IF-RT; p = 0.7). Overall survival at 5 years was similar with 79% (IF-RT) and 65% (non-IF-RT), respectively (p = 0.2). Acute toxicity due to consolidative IF-RT was mild in most cases and severe acute toxicity was noticed in only one patient (7%). Long-term toxicities observed after IF-RT were coronary artery disease, secondary malignancy unrelated to the RT-field, angina abdominalis, hypothyroidism and teeth decay. Recurrence of NHL at sites of macroscopic disease remains common despite HDC. IF-RT achieves excellent local regional control and consolidative IF-RT after ASCT seems indicated, particularly in patients with bulky disease. In the absence of a prospective randomized trial and proven impact on survival rates, IF-RT can be recommended as an option post-ASCT to enhance local disease control.

In-line (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) in patients with carcinoma of the sinus/nasal area and orbit.

BACKGROUND: Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are the standard imaging techniques to evaluate patients with carcinoma in the sinus/nasal area and orbit. The use of positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) in such patients is as yet less well established. PURPOSE: The aim of this study was to assess the clinical impact of PET co-registered with CT (PET/CT). PATIENTS: Evaluation of 21 consecutive patients. METHODS: A retrospective analysis of the whole body PET/CT studies was done. Images were assessed visually without knowing the results of the other imaging technique. Histology and clinical follow-up served to verify lesions. The clinical impact on therapy was assessed together with the physician in charge. RESULTS: All patients underwent PET/CT and CT or MRI for staging (n=9 scans) and restaging (n=17 scans) without treatment between the examinations. PET/CT changed the treatment protocol in 2 patients at staging and in 7 at re-staging. Distant metastases were found in 5 and a secondary tumour in 1 patient. CONCLUSIONS: Whole body PET/CT adds clinically important information to CT or MRI, thus, influencing treatment.

G2/M cell cycle checkpoint is functional in cervical cancer patients after initiation of external beam radiotherapy.

PURPOSE: To investigate changes in cancer of the uterine cervix during radiotherapy (RT) with respect to G2/M transition in relation to tumor cell apoptosis and changes in the tumor vasculature in cervical carcinoma. METHODS AND MATERIALS: A total of 40 consecutive patients with Stage IIA-IIIB cervical cancer underwent RT without any chemotherapy. Tumor biopsy was obtained before RT and after five fractions of 1.8 Gy. The tumor samples were stained for cyclin B1, cdc2, and Ki-67, the apoptotic index, using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. The tumor vasculature density was assessed. In 38 cases, the tissue samples were informative. RESULTS: Cyclin B1 was positive in all biopsies before and after initiation of RT, and staining for cdc2 was positive in 35 (92%) of 38 biopsies before and 33 (87%) of 38 after 1 week of RT. Nuclear staining for cyclin B1 was observed in 92% of patients, staining an average of 15% of cells before RT. After initiating RT, 73% of patients showed positive staining on about 5% of tumor cells (p < 0.01). Nuclear staining for cdc2 was detected in 89% of patients, staining an average of 21% of cells before RT. After initiating RT, 79% of patients showed positive staining on 9% of cells (p < 0.01). The apoptotic index of the tumor cells increased after initiating RT, and a slight decrease in the vascular density after 1 week of RT was noted (p = 0.08). Changes in G2/M were associated with the clinical response, but changes in apoptosis or tumor vasculature were not. CONCLUSION: RT leads to significant changes in the cell cycle in cervical cancer indicating intact G2/M checkpoint function. Targeting G2/M with compounds interfering with G2/M transition may further enhance the effect of RT in cervical cancer patients.

Patupilone acts as radiosensitizing agent in multidrug-resistant cancer cells in vitro and in vivo.

Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 x 2 mg/kg plus 4 x 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis- and G(2)-M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment.Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoprotein-overexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.

On-line correction of beam portals in the treatment of prostate cancer using an endorectal balloon device.

BACKGROUND: Reproducible target volume assessment is required in order to optimize portal field margins in the treatment of prostate cancer. The benefits of an endorectal balloon on target volume assessment remain unclear. MATERIAL AND METHODS: Nine patients were treated with a daily placed air filled rectal balloon. Portal films and computer-associated tomography during the treatment were used to determine the position of the structures of interest. Comparative planning with or without a balloon was performed in order to determine rectal wall exposure to radiation. RESULTS: The range of movements during treatment predicting the position of the prostate in relation to the symphysis was 0.05-0.59 cm in the lateral direction, 0.27-2.2 cm in the antero-posterior direction, and 0.33-1.8 cm in the crano-caudal direction, as compared to the position of the prostate predicted by the balloon ranging from 0.18 to 0.76 cm in the lateral direction, 0.22-1.68 cm in the antero-posterior direction, and 0.58-2.99 cm in the crano-caudal direction. Planning target volumes (PTV) margins as defined by the position of the balloon were 10 mm in the antero-posterior direction, 6 mm in the lateral direction, and 16 mm in the crano-caudal direction. The volume of rectal wall exposed to radiation was reduced from 40 (+/- 12%) to 25% (+/- 19%) with an endorectal balloon (P < 0.05). CONCLUSIONS: Daily online correction with portal vision for external beam set-up is improved by an endorectal balloon device, leading to improved PTV margins and reduced radiation exposure of the rectal wall.

The use of a leg holder immobilisation device in 3D-conformal radiation therapy of prostate cancer.

BACKGROUND AND PURPOSE: To evaluate the impact of a leg holder immobilisation device on patient positioning accuracy in the treatment of prostate cancer. MATERIAL AND METHODS: Twenty patients of similar age and stage of disease treated with curative external beam radiotherapy for prostate cancer were included prospectively. Ten patients were sequentially allocated to one of the two groups, and treated either with or without a leg holder. Treatment set-up alignment accuracy was assessed with an electronic portal imaging device (EPID). RESULTS: Set-up accuracy was 0.3, 0.3 and 0.2 cm for patients with a leg holder, and 0.3, 0.4 and 0.2 cm for patients without a leg holder in the cranio-caudal, anterior-posterior and in the lateral positions, respectively. The difference is not significant. The repositioning accuracy of combined (sagittal and lateral) in-plane rotations on the other hand, was significantly improved with a leg holder device (P = 0.04). CONCLUSIONS: Set-up accuracy can be improved using a leg holder immobilisation device in terms of rotational movement accuracy, thus making on-line corrections more accurate using EPID in the treatment of prostate cancer.