Three cases of retroperitoneal sarcoma in which bioabsorbable spacers (bioabsorbable polyglycolic acid spacers) were inserted prior to carbon ion radiotherapy

From August 2019 to August 2020, we inserted polyglycolic acid (PGA) spacers and administered carbon ion radiotherapy (CIRT) to three cases of retroperitoneal sarcoma at our hospital. We aimed to investigate its utility and safety for retroperitoneal sarcoma. We analyzed changes in PGA spacer volume and corresponding computed tomography (CT) values in addition to the dose distribution using in-room CT images that were obtained during treatment. We assessed adverse events and investigated the suitability, safety and effectivity of PGA spacer insertion. During treatment, changes in PGA spacer volumes and CT values were confirmed. Volumes increased in patients with a folded PGA spacer, and it increased 1.6-fold by the end of irradiation compared with planning CT. The CT values decreased by 20–50 Hounsfield units at the end of irradiation compared to the planning CT. Dose distribution evaluation showed that the dose to the gastrointestinal tract adjacent to the tumor was maintained below the tolerable dose, and a sufficient dose was delivered to the target by PGA spacer insertion. One case of subileus caused during abdominal surgery for PGA spacer insertion occurred. No other adverse events, such as digestive disorders, were observed. CIRT with PGA spacer insertion for retroperitoneal sarcomas is safe and effective. For cases in which there is no option but to perform irradiation using a PGA spacer, precautionary measures such as verification of dose distributions using CT images are necessary.     

Clinical trial of carbon ion radiotherapy for gynecological melanoma

Carbon ion radiotherapy (C-ion RT) is an advanced modality for treating malignant melanoma. After we treated our first case of gynecological melanoma using C-ion RT in November 2004, we decided to conduct a clinical trial to evaluate its usefulness for the treatment of gynecological melanoma. The eligibility criteria for enrollment in this study were histologically proven malignant melanoma of the gynecological regions with lymph node metastasis remaining in the inguinal and pelvic regions. The small pelvic space, including the GTV and the metastatic lymph node, was irradiated with up to a total dose of 36 GyE followed by a GTV boost of up to a total dose of 57.6 GyE or 64 GyE in 16 fractions. A series of 23 patients were treated between November 2004 and October 2012. Patient age ranged from 51–80 with a median of 71. Of the tumor sites, 14 were located in the vagina, 6 in the vulva, and 3 in the cervix uteri. Of the 23 patients, 22 were irradiated with up to a total dose of 57.6 GyE, and 1 patient was irradiated with up to a total dose of 64 GyE. Chemotherapy and interferon-β were also used to treat 11 of the patients. Acute and late toxicities of Grade 3 or higher were observed in 1 patient treated with concurrent interferon-β. The median follow-up time was 17 months (range, 6–53 months). There was recurrence in 14 patients, and the 3-year local control and overall survival rates were 49.9% and 53.0%, respectively. C-ion RT may become a non-invasive treatment option for gynecological melanoma.     

Prediction of the minimum spacer thickness required for definitive radiotherapy with carbon ions and photons for pelvic tumors: an in silico planning study using virtual spacers

We aimed to predict the minimum distance between a tumor and the gastrointestinal (GI) tract that can satisfy the dose constraint by creating simulation plans with carbon-ion (C-ion) radiotherapy (RT) and photon RT for each case assuming insertion of virtual spacers of various thicknesses. We enrolled 55 patients with a pelvic tumor adjacent to the GI tract. Virtual spacers were defined as the overlap volume between the GI tract and the volume expanded 7–17 mm from the gross tumor volume (GTV). Simulation plans (70 Gy in 35 fractions for at least 95% of the planning target volume [PTV]) were created with the lowest possible dose to the GI tract under conditions that meet the dose constraints of the PTV. We defined the minimum thickness of virtual spacers meeting D2 cc of the GI tract <50 Gy as ‘MTS’. Multiple regression was used with explanatory variables to develop a model to predict MTS. We discovered that MTSs were at most 9 mm and 13 mm for C-ion RT and photon RT plans, respectively. The volume of overlap between the GI tract and a virtual spacer of 14 mm in thickness (OV14)-PTV was found to be the most important explanatory variable in the MTS prediction equation for both C-ion and photon RT plans. Multiple R² values for the regression model were 0.571 and 0.347 for C-ion RT and photon RT plans, respectively. In conclusion, regression equations were developed to predict MTS in C-ion RT and photon RT.     

Relative clinical effectiveness of carbon ion radiotherapy: theoretical modelling for H&N tumours

Comparison of the efficiency of photon and carbon ion radiotherapy (RT) administered with the same number of fractions might be of limited clinical interest, since a wide range of fractionation patterns are used clinically today. Due to advanced photon treatment techniques, hypofractionation is becoming increasingly accepted for prostate and lung tumours, whereas patients with head and neck tumours still benefit from hyperfractionated treatments. In general, the number of fractions is considerably lower in carbon ion RT. A clinically relevant comparison would be between fractionation schedules that are optimal within each treatment modality category. In this in silico study, the relative clinical effectiveness (RCE) of carbon ions was investigated for human salivary gland tumours, assuming various radiation sensitivities related to their oxygenation. The results indicate that, for hypoxic tumours in the absence of reoxygenation, the RCE (defined as the ratio of D₅₀ for photons to carbon ions) ranges from 3.5 to 5.7, corresponding to carbon ion treatments given in 36 and 3 fractions, respectively, and 30 fractions for photons. Assuming that interfraction local oxygenation changes take place, results for RCE are lower than that for an oxic tumour if only a few fractions of carbon ions are used. If the carbon ion treatment is given in more than 12 fractions, the RCE is larger for the hypoxic than for the well-oxygenated tumour. In conclusion, this study showed that in silico modelling enables the study of a wide range of factors in the clinical considerations and could be an important step towards individualisation of RT treatments.     

Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes

The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.     

Technical Note: validation of a material assignment method for a retrospective study of carbon-ion radiotherapy using Monte Carlo simulation

We propose a two-step method to converse human tissue materials from patient computed tomography (CT) images, which is required in dose reconstructions for a retrospective study of carbon-ion radiotherapy (CIRT) using Monte Carlo (MC) simulation. The first step was to assign the standard tissues of the International Commission on Radiological Protection reference phantoms according to the CT-number. The second step was to determine the mass density of each material based on the relationship between CT-number and stopping power ratio (Hounsfield unit [HU]-SPR) registered in treatment planning system (TPS). Direct implementation of the well-calibrated HU-SPR curve allows the reproduction of previous clinical treatments recorded in TPS without uncertainty due to a mismatch of the CT scanner or scanning conditions, whereas MC simulation with realistic human tissue materials can fulfill the out-of-field dose, which was missing in the record. To validate our proposed method, depth-dose distributions in the homogenous and heterogeneous phantoms irradiated by a 400 MeV/u carbon beam with an 8 cm spread-out Bragg peak (SOBP) were computed by the MC simulation in combination with the proposed methods and compared with those of TPS. Good agreement of the depth-dose distributions between the TPS and MC simulation (within a 1% discrepancy in range) was obtained for different materials. In contrast, fluence distributions of secondary particles revealed the necessity of MC simulation using realistic human tissue. The proposed material assignment method will be used for a retrospective study using previous clinical data of CIRT at the National Institute of Radiological Sciences (NIRS).     

Simulation approach for the evaluation of tracking accuracy in radiotherapy: a preliminary study

Real-time tumor tracking in external radiotherapy can be achieved by diagnostic (kV) X-ray imaging with a dynamic flat-panel detector (FPD). It is important to keep the patient dose as low as possible while maintaining tracking accuracy. A simulation approach would be helpful to optimize the imaging conditions. This study was performed to develop a computer simulation platform based on a noise property of the imaging system for the evaluation of tracking accuracy at any noise level. Flat-field images were obtained using a direct-type dynamic FPD, and noise power spectrum (NPS) analysis was performed. The relationship between incident quantum number and pixel value was addressed, and a conversion function was created. The pixel values were converted into a map of quantum number using the conversion function, and the map was then input into the random number generator to simulate image noise. Simulation images were provided at different noise levels by changing the incident quantum numbers. Subsequently, an implanted marker was tracked automatically and the maximum tracking errors were calculated at different noise levels. The results indicated that the maximum tracking error increased with decreasing incident quantum number in flat-field images with an implanted marker. In addition, the range of errors increased with decreasing incident quantum number. The present method could be used to determine the relationship between image noise and tracking accuracy. The results indicated that the simulation approach would aid in determining exposure dose conditions according to the necessary tracking accuracy.     

RapidArc radiotherapy for whole pelvic lymph node in cervical cancer with 6 and 15 MV: a treatment planning comparison with fixed field IMRT

Dosimetric differences were investigated among single and dual arc RapidArc and fixed-field intensity-modulated radiotherapy (f-IMRT) treatment plans for whole pelvic irradiation of lymph nodes. A total of 12 patients who had undergone radical surgery for cervical cancer and who had demonstrated multiple pelvic lymph node metastases were treated with radiotherapy. For all 12 cases, 7-field IMRT, single-arc RapidArc and dual-arc RapidArc were applied with 6 MV and 15 MV X-ray energies. The radiation dosimetric parameters for the different plans were compared with one another. All the plans met the clinical requirements. The homogeneity, conformity and external volume indices of f-IMRT and dual-arc RapidArc were better than for single-arc RapidArc (P < 0.05), while the differences between f-IMRT and dual-arc RapidArc were not significant. There were no significant differences in the radiation dose to organs at risk, except for the small bowel receiving >40 Gy (f-IMRT and dual-arc < single-arc, P < 0.05). The differences in dose distributions between the two applied X-ray energies for each of the modality plans were not significant. RapidArc plans resulted in fewer monitor units than the corresponding f-IMRT plans. Also, there were no differences between the two photon energies, except for a reduction in the number of MUs for 15 MV (P > 0.05). Compared to f-IMRT, no significant dosimetric benefits were found using RapidArc for whole pelvic lymph node irradiation. However, RapidArc has been associated with shorter treatment time and fewer monitor units, supporting the case for its safety and efficacy for pelvic irradiation.     

Adjuvant radiotherapy after prostatectomy for prostate cancer in Japan: a multi-institutional survey study of the JROSG

In Japan, the use of adjuvant radiotherapy after prostatectomy for prostate cancer has not increased compared with the use of salvage radiotherapy. We retrospectively evaluated the outcome of adjuvant radiotherapy together with prognostic factors of outcome in Japan. Between 2005 and 2007, a total of 87 patients were referred for adjuvant radiotherapy in 23 institutions [median age: 64 years (54–77 years), median initial prostate-specific antigen: 11.0 ng/ml (2.9–284 ng/ml), Gleason score (GS): 6, 7, 8, 9, 10 = 13.8, 35.6, 23.0, 27.6, 0%, respectively]. Rates of positive marginal status, seminal vesicle invasion (SVI) and extra-prostatic extension (EPE) were 74%, 26% and 64%, respectively. Median post-operative PSA nadir: 0.167 ng/ml (0–2.51 ng/ml). Median time from surgery to radiotherapy was 3 months (1–6 months). A total dose of ≥60 Gy and <65 Gy was administered to 69% of patients. The median follow-up time was 62 months. The 3- and 5-year biochemical relapse-free survival (bRFS) rates for all patients were 66.5% and 57.1%, respectively. The GS and marginal status (P = 0.019), GS and SVI (P = 0.001), marginal status and EPE (P = 0.017), type of hormonal therapy and total dose (P = 0.026) were significantly related. The 5-year bRFS rate was significantly higher in SVI-negative patients than SVI-positive patients (P = 0.001), and significantly higher in patients with post-operative PSA nadir ≤0.2 than in patients with post-operative PSA nadir >0.2 (P = 0.02), and tended to be more favorable after radiotherapy ≤3 months from surgery than >3 months from surgery (P = 0.069). Multivariate analysis identified SVI and post-operative PSA nadir as independent prognostic factors for bRFS (P = 0.001 and 0.018, respectively).     

Usefulness of double dose contrast-enhanced magnetic resonance imaging for clear delineation of gross tumor volume in stereotactic radiotherapy treatment planning of metastatic brain tumors: a dose comparison study

The purpose of this study was to compare the size and clearness of gross tumor volumes (GTVs) of metastatic brain tumors on T1-weighted magnetic resonance images between a single dose contrast administration protocol and a double dose contrast administration protocol to determine the optimum dose of contrast-enhancement for clear delineation of GTV in stereotactic radiotherapy (SRT). A total of 28 small metastatic brain tumors were evaluated in 13 patients by intra-individual comparison of GTV measurements using single dose and double dose contrast-enhanced thin-slice (1-mm) magnetic resonance imaging (MRI). All patients had confirmed histological types of primary tumors and had undergone hypo-fractionated SRT for metastatic brain tumors. The mean tumor diameter with single dose and double dose contrast-enhancement was 12.0 ± 1.1 mm and 13.2 ± 1.1 mm respectively (P < 0.001). The mean incremental ratio (MIR) obtained by comparing mean tumor diameters was 11.2 ± 0.02 %. The mean volume of GTV-1 (single dose contrast-enhancement) and GTV-2 (double dose contrast-enhancement) was 1.38 ± 0.41 ml and 1.59 ± 0.45 ml respectively (P < 0.01). The MIR by comparing mean tumor volumes was 32.3 ± 0.4 %. The MIR of GTV-1 with < 1ml volume and GTV-1 with > 1ml volume was 41.8 ± 0.05 % and 12.4 ± 0.03 % respectively (P < 0.001). We conclude that double dose contrast-enhanced thin-slice MRI is a more useful technique than single dose contrast-enhanced thin-slice MRI, especially for clear delineation of GTVs of small metastatic brain tumors in treatment planning of highly precise SRT.     

A multi-institutional survey of the quality of life after treatment for uterine cervical cancer: a comparison between radical radiotherapy and surgery in Japan

This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important.     

Real-world outcomes of postmastectomy radiotherapy in breast cancer patients with 1–3 positive lymph nodes: a retrospective study

Objective: To assess the treatment outcomes and to explore the determinants of clinical outcome in breast cancer patients with 1–3 positive nodes who did or did not receive postmastectomy radiotherapy (PMRT) in a tertiary care referral cancer center in Northern Thailand. Methods: We investigated a retrospective cohort of registered breast cancer patients at the Faculty of Medicine, Chiang Mai University, Thailand from 2001–2007. Analysis was performed using Cox regression models to identify factors affecting the overall survival (OS) and relapse-free survival (RFS) rates. Comparisons were made between two cohorts: women who received adjuvant PMRT (74 patients) and women who did not receive adjuvant PMRT (81 patients). Results: A total of 155 patients were included with a median follow-up period of 4.45 years. There was a statistically significant 4-year OS difference between the two groups of patients: 100% for the PMRT group and 93.1% for the non-PMRT group (P = 0.044). The 4-year RFS was 85.9% for patients receiving PMRT and 78.3% for patients who did not receive PMRT (P = 0.291). On multivariate analysis of OS, using hormonal treatment was the only significant independent factor associated with improved OS. On multivariate analysis of RFS, none of the variables were significantly associated with improved RFS. PMRT was notfound to be a prognostic variable related to the outcome of patients using a logistic regression model. Conclusion: Our retrospective, hospital-based analysis demonstrated that PMRT improved the treatment outcome in terms of OS for women with 1–3 node positive early-stage breast cancer.     

A comparison of missing data methods for hypothesis tests of the treatment effect in substance abuse clinical trials: a Monte-Carlo simulation study

Background  

Missing data due to attrition are rampant in substance abuse clinical trials. However, missing data are often ignored in the presentation of substance abuse clinical trials. This paper demonstrates missing data methods which may be used for hypothesis testing.     

Quality of private personal care for elderly people in Italy living at home with disabilities: risk of nursing home placement at a 1-year follow-up

The aim of this prospective study was to evaluate the correlation between the self-perceived quality of private personal care for elderly people living at home and the 1-year risk of hospital admission, nursing home placement and death. We enrolled 100 community-dwelling elderly outpatients (mean age 85 years), who had been receiving private personal care for any kind of disability for at least 1 month. Quality of care was described by both the elderly person without overt cognitive impairment and their informal caregivers, and this was categorised for analysis as 'poor or fair' or 'optimal or intermediate'. Rates of hospital admission, long-term care placement and death were assessed at a 1-year follow-up, between May 2006 and January 2008. One year after enrolment, 67 elderly people were still living at home, 10 had been institutionalised and 23 had died. Forty-six had experienced at least one hospital admission. The elderly people belonging to the 'poor or fair care' group ( n  = 16) showed a higher risk of nursing home placement when compared to the people belonging to the 'optimal or intermediate care' group ( n  = 84) (relative risk = 5.25, 95% confidence interval 1.72–16.06), without there being any significant difference between the two groups in terms of baseline assessment and basic functional status at follow-up. The quality of personal care was not a predictor of either hospital admission or death. Therefore, a poor or fair quality of personal care turned out to be a 1-year predictor of placement in a long-term care facility for community-dwelling older adults with a disability.     

Three-fraction CyberKnife radiotherapy for brain metastases in critical areas: referring to the risk evaluating radiation necrosis and the surrounding brain volumes circumscribed with a single dose equivalence of 14 Gy (V14)

The efficacy and toxicity of three-fraction CyberKnife radiotherapy were evaluated in patients with brain metastases in critical areas. One hundred and fifty-nine metastases in 145 patients including tumors >10 cm³ were treated with three-fraction CyberKnife radiotherapy with a median marginal dose of 27 Gy at a median prescribed isodose of 60%. Changes in the neurological manifestations, local tumor control and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 23.1 Gy (single dose equivalence of 14 Gy: V14) were measured to evaluate the risk of adverse effects. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 26 of 97 patients (26.8%). Local tumor control was obtained in 137 of 143 metastases (95.8%) during a median follow-up of 7 months. Nine patients had symptomatic edema and three of them (2.1%) required surgical resection because of radiation necrosis. The V14 of these patients was 4.6–31.5 cm³. There were 35 lesions with a V14 of 7 cm³ or more and three of them developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7 cm³ exhibited edema requiring an operation. We therefore conclude that a high rate of local tumor control and low rates of complications are obtained after three-fraction CyberKnife radiotherapy for metastases in critical areas. The V14 of the surrounding brain therefore seems to be a useful indicator for the risk evaluation of radiation necrosis in patients with larger metastases.     

Five-fraction CyberKnife radiotherapy for large brain metastases in critical areas: impact on the surrounding brain volumes circumscribed with a single dose equivalent of 14 Gy (V14) to avoid radiation necrosis

The efficacy and toxicity of five-fraction CyberKnife radiotherapy were evaluated in patients with large brain metastases in critical areas. A total of 85 metastases in 78 patients, including tumors >30 cm³ (4 cm in diameter) were treated with five-fraction CyberKnife radiotherapy with a median marginal dose of 31 Gy at a median prescribed isodose of 58%. Changes in the neurological manifestations, local tumor control, and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 28.8 Gy (single dose equivalent to 14 Gy: V14) were measured to evaluate the risk of radiation necrosis. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 28 of 55 patients (50.9%). Local tumor control was obtained in 79 of 85 metastases (92.9%) during a median follow-up of eight months. Symptomatic edema occurred in 10 patients, and two of them (2.6%) required surgical resection because of radiation necrosis. The V14 of these patients was 3.0–19.7 cm³. There were 16 lesions with a V14 of ≥7.0 cm³, and two of these lesions developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7.0 cm³ exhibited edema requiring surgical intervention. We therefore conclude that a high rate of local tumor control and low rates of complications can be obtained after five-fraction CyberKnife radiotherapy for large metastases in critical areas. The V14 of the surrounding brain is therefore a useful indicator for the risk of radiation necrosis in patients with large metastases.     

Modelling the hierarchical structure in datasets with very small clusters: a simulation study to explore the effect of the proportion of clusters when the outcome is continuous

In cluster‐randomised trials, the problem of non‐independence within clusters is well known, and appropriate statistical analysis documented. Clusters typically seen in cluster trials are large in size and few in number, whereas datasets of preterm infants incorporate clusters of size two (twins), size three (triplets) and so on, with the majority of infants being in ‘clusters’ of size one. In such situations, it is unclear whether adjustment for clustering is needed or even possible. In this paper, we compared analyses allowing for clustering (linear mixed model) with analyses ignoring clustering (linear regression). Through simulations based on two real datasets, we explored estimation bias in predictors of a continuous outcome in different size datasets typical of preterm samples, with varying percentages of twins. Overall, the biases for estimated coefficients were similar for linear regression and mixed models, but the standard errors were consistently much less well estimated when using a linear model. Non‐convergence was rare but was observed in approximately 5% of mixed models for samples below 200 and percentage of twins 2% or less. We conclude that in datasets with small clusters, mixed models should be the method of choice irrespective of the percentage of twins. If the mixed model does not converge, a linear regression can be fitted, but standard error will be underestimated, and so type I error may be inflated. Copyright © 2012 John Wiley & Sons, Ltd.