Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: Part I--correlating internal lung motion with skin fiducial motion

PURPOSE: To measure the internal lung motion due to respiration using magnetic resonance images (MRIs); to evaluate the correlation between lung motion and skin surface motion and the reliability of tracking lung motion with external fiducials. METHODS AND MATERIALS: An MRI protocol using fast gradient-echo sequences was developed to acquire dynamic cine images of the thoracoabdominal region along the axial, sagittal, and coronal planes. The subjects (3 healthy volunteers and 4 lung cancer patients) were instructed to perform normal or altered breathing during MRI. Lung vessels identified on MRI were used as anatomic landmarks for internal lung structures. From sagittal cine MRI scans, the positions of the lung vessels and skin surface were tracked and their movements measured. Correlation between the movements of the external markers and internal structures was then calculated and analyzed. RESULTS: Lung vessel motion in the superior-inferior (SI) direction correlated best with mid-upper abdominal skin surface movement (correlation coefficient, 0.89 +/- 0.09 and 0.87 +/- 0.23 for volunteers and patients, respectively). The anterior-posterior (AP) vessel motion generally correlated poorly with the skin surface movement, with marker placement on the upper chest yielding the strongest results (correlation coefficient, 0.72 +/- 0.23 and 0.44 +/- 0.27 for volunteers and patients, respectively). The strength of the correlation depended on the locations of the tracked vessels, locations of the skin surface, and subjects' breathing patterns. The best correlation was seen between the motion of an abdominal fiducial and SI lung motion. Significant intersubject variability was also observed. CONCLUSION: Movement of an external fiducial may not correlate fully with, or predict, internal lung motion. Effective monitoring of respiration may have to rely on a combination of multiple fiducials and other physiologic parameters, such as lung volume and/or air flow.     

Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: Part II-margin reduction of internal target volume

PURPOSE: To analyze the relationship between lung motion and skin surface motion during respiration, determine the uncertainties and variability of such a relationship, and assess the potential of reducing internal target margin for gated radiotherapy. METHODS AND MATERIALS: Three healthy volunteers and four lung cancer patients were recruited in a prospective imaging study using MRI to track the internal lung and external skin motion during breathing. The relationship between the lung and skin motion was modeled using linear regression analysis. The slope of the linear fit and its confidence interval were analyzed for different lung locations, skin surface locations, and breathing patterns from separate imaging sessions. The margins of the internal target volume were calculated based on the residual lung motion during gating and its uncertainties from multiple treatment fractions for the gated treatment. RESULTS: The slope and confidence interval of the linear regression from the motion analysis were uniquely defined by the locations of the lung, skin surface, and breathing patterns. Statistically significant differences were observed among individuals and between different times of measurement. The normal free-breathing motion averaged from all volunteer and patient data was 13.4 +/- 7.4 mm along the superior-inferior (SI) direction and 6.9 +/- 2.6 mm along the anterior-posterior (AP) direction. With simulated respiratory gating, the average margin reduction was 5.5 +/- 4.8 mm and 1.6 +/- 1.0 mm, respectively, along the SI and AP directions (or 36% +/- 15% and 25% +/- 14%, respectively, relative to free-breathing motion). CONCLUSION: Because respiratory movement is rather complex, the relationship between the lung and skin surface motion is affected by many anatomic and physiologic factors. The reduction of internal target margin and efficacy of the free-breathing gating technique should be assessed for individual cases.     

四维CT前瞻式呼吸门控技术在肺部肿瘤放疗中的应用研究

目的 研究使用基于四维CT呼吸门控技术时的肿瘤靶区脱靶情况,探索放疗过程中门控准确性。方法 收集2018—2019年在南京医科大学附属肿瘤医院放疗科行四维CT呼吸门控放疗的18例肺部肿瘤患者资料,获取患者治疗时的呼吸波形数据,对比分析各治疗工作周期中体表波形与采集四维CT时的体表波形,研究肺癌患者放疗过程中是否存在脱靶的可能。结果 18例患者共154个治疗分次、20 790个治疗呼吸周期,其中7例患者共95个治疗呼吸周期门控开束脱靶振幅阈值Δm-en>0,占所有周期的0.46%,有13例患者共1419个治疗呼吸周期的门控关束脱靶振幅阈值Δm-dis>0,占所有周期的6.83%。13例Δm-dis>0的患者,实际肿瘤运动范围值（R_G）均大于靶区外放范围值（M）与计划靶区运动范围值（R_T）之和,R_G大于M+R_T值1.5倍以上者为7例,出束时相中含有处于呼吸曲线急速上升和下降时相者也为7例。R_G-M-R_T值与开束脱靶周期百分比（T_en%）、关束脱靶周期百分比（T_dis%）的相关系数分别为0.41、0.57。结论 呼吸门控放射治疗时,R_G大于M+R_T值1.5倍以上且门控出束时相中含有处于呼吸曲线急速上升和下降中的时相,将导致放射治疗脱靶的可能性大幅增加。     

四维CT前瞻式呼吸门控技术在肺部肿瘤放疗中的应用研究北大核心CSCD

目的研究使用基于四维CT呼吸门控技术时的肿瘤靶区脱靶情况,探索放疗过程中门控准确性。方法收集2018—2019年在南京医科大学附属肿瘤医院放疗科行四维CT呼吸门控放疗的18例肺部肿瘤患者资料,获取患者治疗时的呼吸波形数据,对比分析各治疗工作周期中体表波形与采集四维CT时的体表波形,研究肺癌患者放疗过程中是否存在脱靶的可能。结果18例患者共154个治疗分次、20790个治疗呼吸周期,其中7例患者共95个治疗呼吸周期门控开束脱靶振幅阈值Δm-en>0,占所有周期的0.46%,有13例患者共1419个治疗呼吸周期的门控关束脱靶振幅阈值Δm-dis>0,占所有周期的6.83%。13例Δm-dis>0的患者,实际肿瘤运动范围值(R_(G))均大于靶区外放范围值(M)与计划靶区运动范围值(R_(T))之和,R_(G)大于M+R_(T)值1.5倍以上者为7例,出束时相中含有处于呼吸曲线急速上升和下降时相者也为7例。R_(G)-M-R_(T)值与开束脱靶周期百分比(T_(en)%)、关束脱靶周期百分比(T_(dis)%)的相关系数分别为0.41、0.57。结论呼吸门控放射治疗时,R_(G)大于M+R_(T)值1.5倍以上且门控出束时相中含有处于呼吸曲线急速上升和下降中的时相,将导致放射治疗脱靶的可能性大幅增加。     

Changes in the respiratory pattern during radiotherapy for cancer in the lung.

BACKGROUND AND PURPOSE: To quantify changes in patients' diaphragm motion pattern over the course of radiotherapy and to evaluate the implications of these changes for 4D radiotherapy. PATIENTS AND METHODS: From January 2004 to October 2004, 10 patients with lung malignancies treated at our department underwent weekly respiratory motion verification during the course of external beam radiation. An onboard kilovoltage imaging system was used to acquire fluoroscopy weekly for patients with lung neoplasms. The diaphragm position as a function of time was extracted automatically from the fluoroscopy and used to calculate the daily mean and daily SD of motion. The diaphragm position was related to both a bony reference point and machine isocenter. Changes in the daily mean and daily SD in relation to the reference (first day) daily mean and reference daily SD were measured. RESULTS: The mean change in the daily mean was 0.32 mm+/-6.11 mm in relation to the bony reference point and 0.38 mm+/-6.28 mm in relation to isocenter. The mean change in the daily SD was 0.91 mm+/-1.81 mm. The mean systematic change in the daily mean was 4.97 mm, and the mean random change in the daily mean was 3.61 mm. CONCLUSIONS: Daily verification of 4D radiotherapy techniques to assess the necessity of online set-up correction may be required due to the large change in the mean diaphragm position observed for these patients. However, the variation of the daily SD was small for most patients. Adaptive adjustment of the margin may be necessary for those patients with larger variation of the daily SD.     

Patient's perception of care quality during radiotherapy sessions using respiratory gating techniques: validation of a specific questionnaire

This prospective study was designed to validate a questionnaire on patients' perception of care quality during respiratory-gated radiotherapy for breast or lung cancer. Psychometric tests were performed on selected patients. Confirmatory factorial analyses and capacity to discriminate the responses were achieved to validate the best model on 297 patients. Factorial analyses identified the following three scales: (a) perception of quality, (b) global satisfaction, and (c) physical or emotional experience. The scales were able to differentiate patients' responses according to radiotherapy modalities. The questionnaire presented adequate psychometric properties. This tool could be used for the assessment from the patient's point of view.     

Bulb of penis as a marker for prostatic apex in external beam radiotherapy of prostate cancer

PURPOSE: To investigate the relationship between the bulb of the penis and the peak of the urethrogram, and to compare this measurement with the ischial tuberosities (ITs) to peak distance. METHODS AND MATERIALS: Pelvic CT scans from 50 consecutive patients with localized prostate cancer were analyzed to identify the penile bulb. Each patient was required to undergo retrograde urethrography during CT-based treatment planning with 3-mm slices. The peak of the urethrogram was defined as the last CT slice in which the contrast dye in the urethra could be visualized. Measurements were taken from the slice containing the most superior aspect of the penile bulb to the last slice of the urethrogram peak. The superior aspect of the penile bulb was defined as the CT slice nearest the peak that contained a bulbous structure at the base of the penis. This distance was defined as the bulb-peak distance. Similarly, the IT-peak distance was recorded for comparison. RESULTS: The mean bulb-peak and IT-peak distances were calculated for 47 of 50 patients. The peak of the urethrogram was unable to be evaluated in 3 patients. The mean, median, and range bulb-peak distance was 2.4 mm (SD 1.8), 3 mm, and 0-6 mm, respectively. The mean, median, and range IT-peak distance was 20.1 mm (SD 6.6), 21 mm, and 6-33 mm, respectively. No patient had the bulb located above the apex of the urethrogram. CONCLUSION: The bulb of the penis is a relatively consistent soft-tissue landmark compared with the ITs and is located an average of 3 mm below the peak of the urethrogram. Therefore, the bulb of the penis is another landmark for the identification of the prostatic apex and is less invasive than retrograde urethrography.     

N-acetylcysteine in combination with radiotherapy in the treatment of non-small cell lung cancer: a feasibility study.

N-Acetylcysteine (NAC) is a free radical scavenger and could therefore act as a radioprotector. To test the feasibility of administering NAC in combination with radiotherapy, we studied 10 patients with inoperable non-small cell lung cancer who were receiving hyperfractionated radiotherapy (RT) of 1.25 Gy B.I.D. (6-h interval) up to a total dose of 60 Gy/48 fractions/32 days. They were given NAC concomitantly with RT: 100 mg/kg i.v. 30 min before the first RT session followed by 30 mg/kg as an i.v. infusion over 7 h; and 600 mg inhaled 30 min before and after each RT session. The patients were assessed by serial CT scans and lung function studies during a 1-year follow-up period. The treatment regime was feasible, but expensive in time and resources. Normal tissue reactions and tumour responses were similar to those in a control group.     

Investigating the temporal effects of respiratory-gated and intensity-modulated radiotherapy treatment delivery on in vitro survival: an experimental and theoretical study

PURPOSE: To experimentally and theoretically investigate the temporal effects of respiratory-gated and intensity-modulated radiotherapy (IMRT) treatment delivery on in vitro survival. METHODS AND MATERIALS: Experiments were designed to isolate the effects of periodic irradiation (gating), partial tumor irradiation (IMRT), and extended treatment time (gating and IMRT). V79 Chinese hamster lung fibroblast cells were irradiated to 2 Gy with four delivery methods and a clonogenic assay performed. Theoretical incomplete repair model calculations were performed using the incomplete repair model. RESULTS: Treatment times ranged from 1.67 min (conformal radiotherapy, CRT) to 15 min (gated IMRT). Survival fraction calculations ranged from 68.2% for CRT to 68.7% for gated IMRT. For the same treatment time (5 min), gated delivery alone and IMRT delivery alone both had a calculated survival fraction of 68.3%. The experimental values ranged from 65.7% +/- 1.0% to 67.3% +/- 1.3%, indicating no significant difference between the experimental observations and theoretical calculations. CONCLUSION: The theoretical results predicted that of the three temporal effects of radiation delivery caused by gating and IMRT, extended treatment time was the dominant effect. Care should be taken clinically to ensure that the use of gated IMRT does not significantly increase treatment times, by evaluating appropriate respiratory gating duty cycles and IMRT delivery complexity.     

The role of external beam radiotherapy in the treatment of small-cell lung cancer

External beam radiotherapy plays a significant role in the treatment of small cell lung cancer. In patients with limited stage disease (LD), thoracic irradiation improves locoregional tumor control, increases the percentage of patients achieving a complete response (CR), and produces significant increases in survival. As a result, combined modality therapy (chemotherapy/radiotherapy) is considered the treatment of choice in patients with LD. Radiotherapy plays a less significant role in extensive diseased patients, but nonetheless increases CR in the chest and has palliative benefit. Elective cranial irradiation decreases the development of central nervous system failure, thereby improving the quality of life of many patients. Its use, however, should be restricted to patients achieving CR to therapy and doses should be modest. Both whole-body and hemi-body irradiation have significant activity against the disease but should be considered strictly investigational.     

Evaluation of underdosage in the external photon beam radiotherapy of glottic carcinoma: Monte Carlo study.

PURPOSE: Underdosage in the human larynx may be the true factor behind the decrease in local control rates. PATIENTS AND METHODS: To evaluate underdosage with Monte Carlo a CT-based geometrical model of the patient's neck (mathematical neck) was created. Dose was calculated for a pair of 6 Me V parallel-opposed photon beams modulated with 15 degree steel wedges. RESULTS: At least 5% of volume of 3.5 cm(3) hypothetical tumor near the air wall of the larynx receives less than 86% of the maximum tumor dose. The same volume received less than 91% of the maximum tumor dose when the mathematical neck had no air cavities. CONCLUSIONS: We conclude the significant underdosage at the air-tissue interface in the larynx occurs in traditional radiotherapy treatments, especially in the glottic part of the larynx.     

Short-course palliative radiotherapy in non-small-cell lung cancer: results of a prospective study

From February 1993 to October 1997, 91 consecutive patients with inoperable (stage IIIB-IV) histologically confirmed non-small-cell lung cancer underwent palliative hypofractionated radiotherapy. Recently, the Medical Research Council studies on hypofractionated short-course radiotherapy (8.5 Gy x 2) have reported high control of symptoms caused by thoracic disease without toxicity. Based on these experiences and our previous positive trial on short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression, a prospective study of short-course palliative radiotherapy in non-small-cell lung cancer was carried out. The regimen was 16 Gy given in two 8-Gy fractions, 1 week apart. Eighty-one patients were evaluable for response to treatment. Forty-eight (59%) patients were 65 years or older. Forty (49%) patients were naive to radiotherapy, whereas 41 (51%) had previous cisplatin-based chemotherapy. All but four stage IV patients (95%) had poor Eastern Cooperative Oncology Group performance status (i.e., 2-3). Clinical palliation was achieved in 62 (77%) patients. Performance status improved in 59 (73%) patients. The median palliation time ranged from 28% to 57% of patient survival. The median survival from the beginning of treatment was 148 days (range, 5-681 days). No difference in overall survival according to stage and previous chemotherapy was observed. Only performance status conditioned survival (performance status 1-2 vs. performance status 3; p = 0.0289). Short-course radiotherapy gave good results in terms of clinical palliation for thoracic symptoms, even in patients with poor performance status and pretreated with chemotherapy. The median palliation time was approximately 50% of patient survival time. Treatment was generally well tolerated-only 4 (5%) patients experienced World Health Organization grade III dysphagia. No late toxicity was recorded. The two-fraction regimen had social and economic advantages compared with the conventional ones.     

ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC.

BACKGROUND: Non small cell lung cancers (NSCLC) are rapidly proliferating tumours, which are characterized by the presence of extensive hypoxic components, especially in patients with advanced loco-regional disease. Previous studies suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome of radiotherapy for these tumours. AIM: This pilot study was aimed at determining the feasibility and tumour response rates that can be achieved with an ARCON regime in patients with locally advanced, staged IIIA or B, NSCLC tumours. METHODS: The phase I/II study included three steps: accelerated fractionation (AF) combined with carbogen (ten analysable patients), AF together with the daily administration of nicotinamide (n = 11 ) and AF with both carbon and nicotinamide (n = 14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient per treatment day and carbogen was inhaled for 5 min before and during radiotherapy. RESULTS: The incidence of grade 3 + acute toxicity during the irradiation did not exceed 10%, neither in the lung parenchyma nor in the mediastinum. No significant difference was found in loco-regional, radio-induced toxicity among the three study steps. Although a similar fraction of patients showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions which significantly detracted from their quality of life. There was no significant difference in tumour clearance rate among the three steps. The percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2 and 3, respectively. CONCLUSION: The feasibility of this ARCON protocol, using 2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related side effects but it appears necessary in future to reduce the dose of Nicotinamide to reduce the incidence of nausea and vomiting. There was no significant difference in time to progression among the three study steps.     

MCM2 - a promising marker for premalignant lesions of the lung: a cohort study

Background  

Because cells progressing to cancer must proliferate, marker proteins specific to proliferating cells may permit detection of premalignant lesions. Here we compared the sensitivities of a classic proliferation marker, Ki-67, with a new proliferation marker, MCM2, in 41 bronchial biopsy specimens representing normal mucosa, metaplasia, dysplasia, and carcinoma in situ.     

MCM2 - a promising marker for premalignant lesions of the lung: a cohort study

Background  

We investigated the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12,0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in Swiss albino mice. Curcumin, a yellow coloring matter isolated from roots of Curcuma longa Linn, is a phenolic compound possessing antioxidant, free radical scavenger, and antiinflammatory properties. It has been shown by previously reported work that TPA-induced skin tumors were inhibited by topical application of curcumin, and curcumin has been shown to inhibit a variety of biological activities of TPA. Topical application of curcumin was reported to inhibit TPA-induced c-fos, c-jun and c-myc gene expression in mouse skin. This paper reports the effects of orally administered curcumin, which was consumed as a dietary component at concentrations of 0.2 % or 1 %, in ad libitum feeding.     

Held-breath self-gating technique for radiotherapy of non-small-cell lung cancer: a feasibility study

PURPOSE: To examine the feasibility of a held-breath self-gating (HBSG) technique in the radiotherapy of lung cancer. MATERIAL AND METHODS: Sixteen consecutive eligible and consenting patients undergoing radiotherapy for non-small-cell lung cancer were accrued for this study. The patients underwent a standardized training session and were then asked to breath hold at four points in the breathing cycle (maximal and end tidal, inspiration and expiration) while under fluoroscopic visualization. Plain films and video imaging with digital image analysis were used to record and measure the movement of the diaphragm, a tumor surrogate, in the superior-inferior axis. These measurements were obtained during and between multiple separate breath holds within one session and between breath holds in sessions held at least one day apart. RESULTS: Maximal inspiration and expiration tend to provide the best positional reliability, and the standard deviation of diaphragmatic position ranged from 0.13 to 2.57 mm, with an average of 0.97 mm. During a single breath hold, the diaphragmatic movement averaged 2.62 mm with a standard deviation of 1.28 mm. The day-to-day variation of diaphragmatic positions was less than 5 mm. The held-breath self-gating technique resulted in a reduction of diaphragmatic movement by an average of 11.9 mm when compared to that seen during tidal breathing. CONCLUSION: In the radiotherapeutic management of non-small-cell lung cancer, this HBSG technique offers a simple method that provides superior immobilization of the diaphragm compared to tidal breathing. Clinical implementation of this technique should allow for a reduction of treatment margins, thus sparing more normal tissues and facilitating dose escalation.     

Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study

PURPOSE: The purpose of this study was to investigate changes in respiratory symptoms and quality of life (QoL) in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC) receiving thoracic radiotherapy. Additionally, the correlation between the level of symptom relief and objective tumor response was investigated. METHODS AND MATERIALS: Sixty-five patients were entered in this prospective study. The EORTC QLQ-C30 and EORTC QLQ-LC13 were used to investigate changes in QoL. Assessments were performed before radiotherapy and 2 weeks, 6 weeks, and 3 months after radiotherapy. RESULTS: The QoL response rates were excellent for hemoptysis (79%); good for arm/shoulder pain (56%), chest wall pain (53%), and cough (49%); moderate for dyspnea (39%); and minimal for the general symptoms fatigue (22%) and appetite loss (11%). The QoL response rates for the five functioning scales of the QLQ-C30 varied from 35% for role functioning to 57% for emotional functioning. Global QoL improved in 37% of the cases. In general, there was a tendency for better palliation of symptoms and improvement of QoL among patients with an objective tumor response than among those without objective tumor response, which was statistically significant for dyspnea (p = 0.02) and social functioning (p = 0.04). CONCLUSIONS: This study confirms that conventional thoracic radiotherapy offers palliation of respiratory symptoms and improved QoL in a substantial proportion of patients with locally advanced and metastatic NSCLC. Tumor reduction is only one of the mechanisms by which palliation of symptoms and improvement of QoL is achieved.     

Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.

BACKGROUND: Preoperative radiotherapy has been shown to decrease the local recurrence rate of patients with locally advanced rectal cancer. Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer and have radiosensitizing properties. Therefore, these drugs would be expected to improve effectiveness of preoperative radiotherapy in terms of local control and prevention of distant metastases. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4 and/or N+) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformational technique) in combination with intravenous oxaliplatin 50 mg/m2 once weekly for 5 weeks and oral capecitabine 825 mg/m2 twice daily on each day of radiation. Surgery was performed 6-8 weeks after completion of radiotherapy. The main end points were safety and efficacy as assessed by the pathological complete response (pCR). RESULTS: The most frequent grade 3/4 adverse event was diarrhea, occurring in 30% of patients. pCR was found in five (14%) patients. According to Dworak's classification, good regression was found in six (18%) additional patients. CONCLUSIONS: Combination of preoperative radiotherapy with capecitabine and oxaliplatin is feasible for downstaging rectal cancer.