Three-dimensional Conformal Radiotherapy In Patients Research Articles

A comparison of the incidence of ≥ grade 2 radiation pneumonitis between intensity-modulated radiotherapy and three-dimensional conformal radiotherapy in patients with unresectable non-small cell lung cancer treated with durvalumab after concurrent chemoradiotherapy.

Intensity-modulated radiation therapy (IMRT) has been increasingly used as a new radiation modality for unresectable non-small cell lung cancer (NSCLC). The risk factors for radiation pneumonitis (RP) during consolidation durvalumab following concurrent chemoradiotherapy (CCRT) using IMRT have not been thoroughly investigated. This retrospective study analyzed medical record data from consecutive patients diagnosed with NSCLC who underwent CCRT and consolidation durvalumab at our institution between April 2018 and September 2022. Since we adopted IMRT for the treatment of NSCLC in April 2020, these patients were categorized into two groups: those treated with IMRT after April 2020 and those treated with three-dimensional conformal radiotherapy (3D-CRT) before April 2020. A total of 31 patients underwent IMRT (the IMRT group), while 25 patients underwent 3D-CRT (the 3D-CRT group). In both groups, the total dose was 60Gy in 30 fractions. The cumulative incidence of ≥ grade 2 RP at 12months was significantly lower in the IMRT group than in the 3D-CRT group (27.0% vs. 64.0%, hazard ratio [HR]: 0.338, 95% confidence interval [CI]: 0.144-0.793, p=0.013). In the multivariable analysis, V20 (≥ 25.6%, HR: 2.706, 95% CI: 1.168-6.269, p=0.020) and radiotherapy technique (IMRT, HR: 0.414, 95% CI: 0.172-0.994, p=0.048) were identified as significant risk factors for ≥ grade 2 RP. IMRT is associated with a lower rate of ≥ grade 2 RP in patients with NSCLC who received CCRT followed by durvalumab.

Comparison of Acute Gastrointestinal Toxicity of Intensity-Modulated Radiotherapy Versus Three-Dimensional Conformal Radiotherapy in Patients of Carcinoma Cervix.

Introduction Cervical cancer is the most common gynaecological malignancy worldwide, with a higher prevalence in middle- and low-income countries. Chemoradiotherapy, followed by intracavitary brachytherapy, is the treatment of choice in locally advanced cervical cancer. The most common acute side effect of external beam radiotherapy (EBRT) is bowel toxicity in the form of diarrhoea and abdominal cramps. The treatment techniques of EBRT were revolutionised with the advent of intensity modulation. This study aims to prospectively analyse whether the dosimetric advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3DCRT) is translated clinically into a decrease in acute toxicity. Method Twenty-four patients were randomised into two groups: the 3DCRT and the IMRT. Acute gastrointestinal (GI) toxicity was assessed during treatment using radiation therapy oncology group grading. The factors under consideration were age, stage of the disease, treatment technique, chemotherapy, and the intention of therapy (radical or adjuvant). The mean bowel bag dose of the two techniques was analysed. Result Among the factors under consideration, it was found that the treatment technique was the only factor that had a significant association with acute bowel toxicity in both univariate (p = 0.036) and multivariate analyses (p = 0.028). The mean V25 (the volume receiving 25 Gy), V45, and V50 of the bowel bag in the IMRT arm were significantly less than the 3DCRT arm. Grades 2 and 3 acute bowel toxicities were also higher in the 3DCRT arm. Conclusion The treatment technique is essential to determining acute GI toxicity during pelvic radiotherapy. With IMRT, the dose to the bowel bag and, in turn, the acute bowel toxicity can be reduced.

Relationship Between Changes in Myocardial F-18 Fluorodeoxyglucose Uptake and Radiation Dose After Adjuvant Three-Dimensional Conformal Radiotherapy in Patients with Breast Cancer.

This study aimed to assess the relationship between radiation dose and changes in the irradiated myocardial F-18 fluorodeoxyglucose (FDG) uptake after radiotherapy (RT) in breast cancer patients. The data of 55 patients with left and 48 patients with right breast cancer who underwent curative surgical resection and adjuvant three-dimensional conformal RT and staging (PET1), post-adjuvant chemotherapy (PET2), post-RT (PET3), and surveillance (PET4) FDG positron emission tomography/computed tomography (PET/CT) were retrospectively reviewed. The median interval between PET1 and curative surgical resection, between the end of adjuvant chemotherapy and PET2, between the end of RT and PET3, and between the end of RT and PET4 were five days, 13 days, 132 days, and 353 days, respectively. The myocardial-to-blood pool uptake ratio was measured in all patients. For patients with left breast cancer, the 30 Gy- (30 Gy) and 47.5 Gy-irradiated myocardium-to-low-irradiated myocardium (47.5 Gy) FDG uptake ratios were additionally measured. There were no differences in the myocardial-to-blood pool uptake ratios between left and right breast cancer on all PET scans. For left breast cancer, higher 30 Gy and 47.5 Gy uptake ratios were observed on PET3 than on PET1 and PET2. Both uptake ratios decreased on PET4 compared to PET3, but, were still higher compared to PET1. On PET3 and PET4, the 47.5 Gy were higher than the 30 Gy uptake ratios, while there were no differences between them on PET1 and PET2. Although the whole myocardium FDG uptake showed no significant change, the irradiated myocardium FDG uptake significantly increased after RT and was related to radiation dose to the myocardium in breast cancer patients. These results might be an imaging evidence that supports the increased risk of heart disease after RT in patients with left breast cancer.

A Randomized Comparison of Radiation Therapy Techniques in the Management of Node-Positive Breast Cancer: Primary Outcomes Analysis

Although inverse-planned intensity modulated radiotherapy (IMRT) and deep inspiration breath hold (DIBH) may allow for more conformal dose distributions, it is unknown whether using these technologies reduces cardiac or pulmonary toxicity of breast radiotherapy. A randomized controlled trial compared IMRT-DIBH versus standard, free-breathing, forward-planned, three-dimensional conformal radiotherapy in patients with left-sided, node-positive breast cancer in whom the internal mammary nodal region was targeted. Endpoints included dosimetric parameters and changes in pulmonary and cardiac perfusion and function, measured by single photon emission computed tomography (SPECT) scans and pulmonary function testing performed at baseline and 1year post treatment. Of 62 patients randomized, 54 who completed all follow-up procedures were analyzed. Mean doses to the ipsilateral lung, left ventricle, whole heart, and left anterior descending coronary artery were lower with IMRT-DIBH; the percent of left ventricle receiving ≥5Gy averaged 15.8% with standard radiotherapy and 5.6% with IMRT-DIBH (P<.001). SPECT revealed no differences in perfusion defects in the left anterior descending coronary artery territory, the study's primary endpoint, but did reveal statistically significant differences (P=.02) in left ventricular ejection fraction (LVEF), a secondary endpoint. No differences were found for lung perfusion or function. The small but statistically significant benefit in preservation of cardiac LVEF observed here should motivate future studies that include LVEF as a potentially meaningful endpoint. Future studies should disaggregate the impact of IMRT from that of DIBH. Clinical practice should recognize the importance of minimizing cardiac dose, even when already low in comparison to historical levels.

Intensity-modulated radiotherapy has superior outcomes to three-dimensional conformal radiotherapy in patients with stage IE-IIE extranodal nasal-type natural killer/T-cell lymphoma.

We compared the treatment outcomes, toxicities and prognoses of patients with stage IE-IIE extranodal natural killer/T-cell lymphoma (ENKTL) treated with intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3DCRT). Newly diagnosed early-stage ENKTL patients (N = 173) were enrolled and received extended involved-field radiotherapy following induction chemotherapy. Patients were treated with 3DCRT (n = 98) or IMRT (n = 75). One-to-one matching of the IMRT and 3DCRT groups was performed through propensity score matching, which yielded 23 pairs of patients. The two groups achieved similar complete remission rates before and after radiotherapy (P > 0.05). All patients were followed up for a median of 41 months. The rates of local recurrence-free survival (LRFS, P < 0.001), progression-free survival (PFS, P = 0.003) and overall survival (OS, P = 0.003) were longer in the IMRT than 3DCRT group. In the matched patients, IMRT was still associated with superior LRFS (P = 0.024), but not with improved PFS (P = 0.113) or OS (P = 0.115). Multivariate analysis also suggested IMRT was a favorable independent factor for LRFS (HR = 2.230, P = 0.043), but not for PFS (P = 0.195) or OS (P = 0.116). Equivalent acute toxicities were observed for 3DCRT and IMRT; however, among stage II patients who had received cervical irradiation, the rate of late xerostomia was lower in the IMRT than 3DCRT group (38.5% vs. 66.7%, P = 0.046). Overall, IMRT yielded a better treatment response and local control than 3DCRT, and tended to reduce late xerostomia in patients with cervical irradiation, but failed to enhance OS. Thus, IMRT is recommended for the treatment of stage IE-IIE ENKTL patients.

Postoperative Capecitabine with Concurrent Intensity-Modulated Radiotherapy or Three-Dimensional Conformal Radiotherapy for Patients with Stage II and III Rectal Cancer.

BackgroundThe aim of this study was to evaluate the survival outcomes and toxicity of postoperative chemoradiotherapy with capecitabine and concurrent intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) in patients with stage II and III rectal cancer.PatientsWe recruited 184 patients with pathologically proven, stage II or III rectal cancer. Following total mesorectal excision (TME), the patients were treated with capecitabine and concurrent IMRT/3D-CRT. The treatment regimen consisted of two cycles of oral capecitabine (1600 mg/m2/day), administered twice daily from day 1–14 of radiotherapy, followed by a 7-day rest. The median pelvic dose was 50 Gy in 25 fractions. Oxaliplatin-based adjuvant chemotherapy was administered after the chemoradiotherapy.ResultsThe 5-year overall survival, disease-free survival and locoregional control (LRC) rates were 85.1%, 80% and 95.4%, respectively. Grade 3 and 4 toxicities were observed in 28.3% of patients during treatment. Grade 3 or 4 late toxicity, including neurotoxicity or gastrointestinal toxicity, was only observed in nine patients (4.9%).ConclusionsThis study demonstrated that capecitabine chemotherapy with concurrent IMRT/3D-CRT following TME is safe, is well tolerated and achieves superior LRC and favorable survival rates, with acceptable toxicity.

Dosimetric Comparison of Intensity-Modulated Radiotherapy versus Three-Dimensional Conformal Radiotherapy for Patients with Brain Tumors

Purpose: To compare target dose distribution and dose to normal tissue for brain tumors using intensity-modulated and three-dimensional conformal radiotherapy. Methods and Materials: Twelve patients selected in the present study compared the dosimetry of intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) techniques in patients treated with different diagnosis brain tumor. All patients underwent computed tomography planning in conjunction with magnetic resonance imaging fusion. Prescription dose and normal-tissue constraints were identical for both plans. The tolerance level for maximum dose was 6.0 Gy for lenses and 54.0 Gy for brain stem, and optical nerves. Target coverage was evaluated with the D98%, D95% and D2%. Normal tissue dose was evaluated with the maximum dose to lenses, brain stem, and optical nerves. Results: Mean and standard deviation values of PTV 98%, PTV 95% and PTV 2% in IMRT these values were 94.6 ± 2.3, 96.56 ± 1.67 and 106.5 ± 1.87 respectively; for 3DCRT were 92.7 ± 3.09, 95.58 ± 1.24 and 104.45 ± 2.73 respectively. IMRT plan provided reduced dose to brainstem (72.17 ± 29.967) and lenses (2.43 ± 2.39) relative to the 3DCRT plans for brainstem (73.05 ± 34.59) and lenses (7.65 ± 23.24). But optic nerves with IMRT significantly received higher doses (38.86 ± 32.15) than 3D-CRT (27.57 ± 31.45). Conclusion: Dose coverage of the planning target volume (PTV) and organ at risk (OAR) was better with IMRT. If PTV is distant to optical nerves and brainstem 3DCRT technique can be applied, and if the PTV is nearby OAR intensity-modulated treatment technique should be used.

Utilization of PET-CT in target volume delineation for three-dimensional conformal radiotherapy in patients with non-small cell lung cancer and atelectasis

BackgroundTo investigate the utilization of PET-CT in target volume delineation for three-dimensional conformal radiotherapy in patients with non-small cell lung cancer (NSCLC) and atelectasis.MethodsThirty NSCLC patients who underwent radical radiotherapy from August 2010 to March 2012 were included in this study. All patients were pathologically confirmed to have atelectasis by imaging examination. PET-CT scanning was performed in these patients. According to the PET-CT scan results, the gross tumor volume (GTV) and organs at risk (OARs, including the lungs, heart, esophagus and spinal cord) were delineated separately both on CT and PET-CT images. The clinical target volume (CTV) was defined as the GTV plus a margin of 6-8 mm, and the planning target volume (PTV) as the GTV plus a margin of 10-15mm. An experienced physician was responsible for designing treatment plans PlanCT and PlanPET-CT on CT image sets. 95% of the PTV was encompassed by the 90% isodose curve, and the two treatment plans kept the same beam direction, beam number, gantry angle, and position of the multi-leaf collimator as much as possible. The GTV was compared using a target delineation system, and doses distributions to OARs were compared on the basis of dose-volume histogram (DVH) parameters.ResultsThe GTVCT and GTVPET-CT had varying degrees of change in all 30 patients, and the changes in the GTVCT and GTVPET-CT exceeded 25% in 12 (40%) patients. The GTVPET-CT decreased in varying degrees compared to the GTVCT in 22 patients. Their median GTVPET-CT and median GTVPET-CT were 111.4 cm3 (range, 37.8 cm3-188.7 cm3) and 155.1 cm3 (range, 76.2 cm3-301.0 cm3), respectively, and the former was 43.7 cm3 (28.2%) less than the latter. The GTVPET-CT increased in varying degrees compared to the GTVCT in 8 patients. Their median GTVPET-CT and median GTVPET-CT were 144.7 cm3 (range, 125.4 cm3-178.7 cm3) and 125.8 cm3 (range, 105.6 cm3-153.5 cm3), respectively, and the former was 18.9 cm3 (15.0%) greater than the latter. Compared to PlanCT parameters, PlanPET-CT parameters showed varying degrees of changes. The changes in lung V20, V30, esophageal V50 and V55 were statistically significant (Ps< 0.05 for all), while the differences in mean lung dose, lung V5, V10, V15, heart V30, mean esophageal dose, esophagus Dmax, and spinal cord Dmax were not significant (Ps> 0.05 for all).ConclusionsPET-CT allows a better distinction between the collapsed lung tissue and tumor tissue, improving the accuracy of radiotherapy target delineation, and reducing radiation damage to the surrounding OARs in NSCLC patients with atelectasis.

Utilization of PET-CT in target volume delineation for three-dimensional conformal radiotherapy in patients with non-small cell lung cancer and atelectasis

Background: To investigate the utilization of PET-CT in target volume delineation for three-dimensional conformal radiotherapy in patients with non-small cell lung cancer (NSCLC) and atelectasis.&#x0D; Methods: Thirty NSCLC patients who underwent radical radiotherapy from August 2010 to March 2012 were included in this study. All patients were pathologically confirmed to have atelectasis by imaging examination. PET-CT scanning was performed in these patients. According to the PET-CT scan results, the gross tumor volume (GTV) and organs at risk (OARs, including the lungs, heart, esophagus and spinal cord) were delineated separately both on CT and PET-CT images. The clinical target volume (CTV) was defined as the GTV plus a margin of 6-8 mm, and the planning target volume (PTV) as the GTV plus a margin of 10-15 mm. An experienced physician was responsible for designing treatment plans PlanCT and PlanPET-CT on CT image sets. 95% of the PTV was encompassed by the 90% isodose curve, and the two treatment plans kept the same beam direction, beam number, gantry angle, and position of the multi-leaf collimator as much as possible. The GTV was compared using a target delineation system, and doses distributions to OARs were compared on the basis of dose-volume histogram (DVH) parameters.&#x0D; Results: The GTVCT and GTVPET-CT had varying degrees of change in all 30 patients, and the changes in the GTVCT and GTVPET-CT exceeded 25% in 12 (40%) patients. The GTVPET-CT decreased in varying degrees compared to the GTVCT in 22 patients. Their median GTVPET-CT and median GTVPET-CT were 111.4 cm3 (range, 37.8 cm3-188.7 cm3) and 155.1 cm3 (range, 76.2 cm3-301.0 cm3), respectively, and the former was 43.7 cm3 (28.2%) less than the latter. The GTVPET-CT increased in varying degrees compared to the GTVCT in 8 patients. Their median GTVPET-CT and median GTVPET-CT were 144.7 cm3 (range, 125.4 cm3-178.7 cm3) and 125.8 cm3 (range, 105.6 cm3-153.5 cm3), respectively, and the former was 18.9 cm3 (15.0%) greater than the latter. Compared to PlanCT parameters, PlanPET-CT parameters showed varying degrees of changes. The changes in lung V20, V30, esophageal V50 and V55 were statistically significant (Ps&lt; 0.05 for all), while the differences in mean lung dose, lung V5, V10, V15, heart V30, mean esophageal dose, esophagus Dmax, and spinal cord Dmax were not significant (Ps&gt; 0.05 for all).&#x0D; Conclusions: PET-CT allows a better distinction between the collapsed lung tissue and tumor tissue, improving the accuracy of radiotherapy target delineation, and reducing radiation damage to the surrounding OARs in NSCLC patients with atelectasis.

Clinical effects of accelerated partial breast irradiation using three-dimensional conformal radiotherapy in patients with early breast cancer after breast-conserving therapy

Objective To assess the clinical effects of accelerated partial breast irradiation (APBI)using three-dimensional conformal radiotherapy (3DCRT) in patients with low-risk early breast cancer after breast-conserving therapy (BCT) with respect to dosimetric parameters,local control,toxicities,and cosmetic outcome.Methods Thirty-nine patients with early breast cancer (stage 0-1) were enrolled in a prospective phase Ⅱ trial of APBI using 3DCRT in 2008-2010.Of all the patients,28 had invasive ductal carcinoma,5 had ductal carcinoma in situ,and 6 had other types of invasive carcinoma.The prescribed dose was 38.5 Gy/10 fractions twice daily,with an inter-fraction interval greater than 6 h.The toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria,version 3.0.The cosmetic outcome was assessed according to the Harris breast cosmesis scale.Results The planning target volume coverage and normal-tissue dosimetry were appropriate in the APBI using 3DCRT.Dose homogeneity without deviation was achieved in 33 patients (85％).Of the total 39 patients,46％ ASTRO's cautionary criteria,and 18％ met unsuitable criteria; also,31％ GEC-ESTRO's intermediate-risk criteria,and 3％ met high-risk criteria.The follow-up rate was 100％.No patient experienced local recurrence,and no grade 3-4 toxicities were found.Cosmesis was good to excellent in 35 patients (90％)at 6 months after APBI.Conclusions The patients with early breast cancer after BCT are properly selected for APBI using 3DCRT,with satisfactory preliminary assessment results for local control,toxicities,and cosmetic outcome. Key words: Breast neoplasms/three-dimensional radiotherapy; Accelerated partial breast irradiation ; Breast neoplasms/surgery; Mastectomy, segmental; Treatment outcome

Dosimetric comparison of intensity modulated radiotherapy and three-dimensional conformal radiotherapy in patients with gynecologic malignancies: a systematic review and meta-analysis

BackgroundTo quantitatively evaluate the safety and related-toxicities of intensity modulated radiotherapy (IMRT) dose–volume histograms (DVHs), as compared to the conventional three-dimensional conformal radiotherapy (3D-CRT), in gynecologic malignancy patients by systematic review of the related publications and meta-analysis.MethodsRelevant articles were retrieved from the PubMed, Embase, and Cochrane Library databases up to August 2011. Two independent reviewers assessed the included studies and extracted data. Pooled average percent irradiated volumes of adjacent non-cancerous tissues were calculated and compared between IMRT and 3D-CRT for a range of common radiation doses (5-45Gy).ResultsIn total, 13 articles comprised of 222 IMRT-treated and 233 3D-CRT-treated patients were included. For rectum receiving doses ≥30 Gy, the IMRT pooled average irradiated volumes were less than those from 3D-CRT by 26.40% (30 Gy, p = 0.004), 27.00% (35 Gy, p = 0.040), 37.30% (40 Gy, p = 0.006), and 39.50% (45 Gy, p = 0.002). Reduction in irradiated small bowel was also observed for IMRT-delivered 40 Gy and 45 Gy (by 17.80% (p = 0.043) and 17.30% (p = 0.012), respectively), as compared with 3D-CRT. However, there were no significant differences in the IMRT and 3D-CRT pooled average percent volumes of irradiated small bowel or rectum from lower doses, or in the bladder or bone marrow from any of the doses. IMRT-treated patients did not experience more severe acute or chronic toxicities than 3D-CRT-treated patients.ConclusionsIMRT-delivered high radiation dose produced significantly less average percent volumes of irradiated rectum and small bowel than 3D-CRT, but did not differentially affect the average percent volumes in the bladder and bone marrow.

Cancer of the pelvis: definitive three-dimensional conformal radiotherapy for patients with isolated recurrence in the para-aortic lymph nodes

The purpose of this study was to evaluate the outcome of definitive three-dimensional conformal radiotherapy (RT) for isolated para-aortic lymph node (LN) recurrence in patients with controlled primary cancer of the pelvis. Twenty-four consecutive patients with isolated para-aortic LN recurrence were retrospectively analyzed. The patients were included in this study if they were eligible to receive definitive RT for abdominal para-aortic LN recurrence with controlled primary cancer of the pelvis without other distant/recurrent diseases. The median time between the front-line therapy and RT for isolated para-aortic LN metastases was 21 months. Nineteen (79%) patients had an objective tumor response. In-field failure occurred in four patients (17%), while failure outside of the irradiated field was recognized in 12 patients (50%). The overall survival, progression-free survival and local control rates at 5 years were 56%, 29% and 72%, respectively. Statistically significant prognostic factors of the overall survival rate in the univariate analyses were an objective tumor response (P = 0.0098) and the time between front-line therapy and RT (P = 0.033). The maximum tumor size was a significant prognostic factor of the overall survival rates in the multivariate analyses (P = 0.046). The toxicities were mild; leukopenia of Grade 3 was detected in one patient, and no Grade 3 or higher non-hematological toxicity was observed. In conclusion, definitive three-dimensional RT for isolated abdominal para-aortic LN recurrence in patients with controlled primary cancer of the pelvis may be feasible, and can provide a relatively longer-term survival. The results justify further investigation of higher dose RT using modern RT planning techniques.

Phase II Trial of Full-Dose Gemcitabine and Bevacizumab in Combination With Attenuated Three-Dimensional Conformal Radiotherapy in Patients With Localized Pancreatic Cancer

To evaluate response rate, survival, and toxicity in patients with nonmetastatic pancreatic cancer treated with gemcitabine, bevacizumab, and radiotherapy. Patients received three cycles of therapy over 10 weeks. In total, treatment consisted of intravenous (IV) gemcitabine, 1,000 mg/m(2), every 1 to 2 weeks (7 doses), IV bevacizumab, 10 mg/kg every 2 weeks (5 doses), and 36 Gy of radiotherapy (2.4-Gy fractions during cycle two). Response was assessed by cross-sectional imaging and carbohydrate antigen 19-9 (CA 19-9) levels. Patients with resectable tumors underwent surgery 6 to 8 weeks after the last dose of bevacizumab. Maintenance gemcitabine and bevacizumab doses were delivered to patients who had unresected tumors and no progression. Twenty-eight of the 32 enrolled patients completed all three cycles. The median follow-up was 11.07 months. Most grade 3 or 4 toxicities occurred in the initial treatment phase; the most frequent toxicities were leukopenia (21%), neutropenia (17%), and nausea (17%). At week 10, 1 patient (4%) had a complete response, 2 patients (7%) had partial responses, 21 patients (75%) had stable disease, and 4 patients (14%) had progressive disease. The median pretreatment and posttreatment CA 19-9 levels (25 patients) were 184.3 and 57.9 U/ml, respectively (p = 0.0006). One of 10 patients proceeding to surgery experienced a major complication. Two of 6 patients undergoing resection had complete pathologic responses. The median progression-free and overall survival durations were 9.9 months and 11.8 months, respectively. The combination of full-dose gemcitabine, bevacizumab, and radiotherapy was active and was not associated with a high rate of major surgical complications.

Intensity-Modulated Radiotherapy Might Increase Pneumonitis Risk Relative to Three-Dimensional Conformal Radiotherapy in Patients Receiving Combined Chemotherapy and Radiotherapy: A Modeling Study of Dose Dumping

To model the possible interaction between cytotoxic chemotherapy and the radiation dose distribution with respect to the risk of radiation pneumonitis. A total of 18 non-small-cell lung cancer patients previously treated with helical tomotherapy at the University of Wisconsin were selected for the present modeling study. Three treatment plans were considered: the delivered tomotherapy plans; a three-dimensional conformal radiotherapy (3D-CRT) plan; and a fixed-field intensity-modulated radiotherapy (IMRT) plan. The IMRT and 3D-CRT plans were generated specifically for the present study. The plans were optimized without adjusting for the chemotherapy effect. The effect of chemotherapy was modeled as an independent cell killing process by considering a uniform chemotherapy equivalent radiation dose added to all voxels of the organ at risk. The risk of radiation pneumonitis was estimated for all plans using the Lyman and the critical volume models. For radiotherapy alone, the critical volume model predicts that the two IMRT plans are associated with a lower risk of radiation pneumonitis than the 3D-CRT plan. However, when the chemotherapy equivalent radiation dose exceeds a certain threshold, the radiation pneumonitis risk after IMRT is greater than after 3D-CRT. This threshold dose is in the range estimated from clinical chemoradiotherapy data sets. Cytotoxic chemotherapy might affect the relative merit of competing radiotherapy plans. More work is needed to improve our understanding of the interaction between chemotherapy and the radiation dose distribution in clinical settings.

A Phase I/II Trial of Gefitinib Given Concurrently With Radiotherapy in Patients With Nonmetastatic Prostate Cancer

To estimate the safety and tolerability of daily administration of 250 mg of gefitinib given concurrently with three-dimensional conformal radiotherapy for patients with nonmetastatic prostate cancer. A total of 42 patients with T2-T3N0M0 tumors were treated in a nonrandomized single-center study. A prostate-specific antigen (PSA) level of <20 and a good performance status (WHO, 0-1) were required. Adjuvant or neoadjuvant hormone treatments were not allowed. A daily regimen of 250 mg of gefitinib was started 1 week before radiation therapy began and lasted for the duration of radiation therapy. A dose of 50.4 Gy (1.8 Gy/day) was administered to the tumor, prostate, and seminal vesicles, followed by a 22-Gy booster (2 Gy/day) for a total dose of 72.4 Gy. Correlative studies included analysis of epidermal growth factor receptor (EGFR), EGFRvIII, and phosphorylated EGFR in tumors and tumor necrosis factor, interleukin-1alpha (IL-1alpha), and IL-6 in serum. Maximum tolerated dose was not reached in phase I (12 patients), and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication. Dose-limiting toxicities were recorded for 16 (38.1%) patients, the most common of which was a grade 3 to 4 increase in transaminase (6 patients). After a median follow-up of 38 months, there were no deaths due to prostate cancer. The estimated PSA relapse-free survival rate at 4 years (Kaplan-Meier) was 97%, the salvage therapy-free survival rate was 91%, and the overall survival rate was 87%. These figures compared favorably with those of matched patients treated with radiation only at higher doses. The combination of gefitinib and radiation is reasonably well tolerated and has promising activity against nonmetastatic prostate cancer.

Conformal radiotherapy (3D CRT) for non-metastatic androgen-independent prostate cancer: costly and sophisticated but ineffective treatment?

Purpose Patients with diagnosis of hormone-refractory prostate cancers (HRPC) present a very heterogeneous population, and therefore it has been proposed to sub-categorize them into two subgroups depending on presence or absence of distant metastases. While the former subgroup has been typically treated with palliative intention, for the latter apparently there is no standard approach. The role of three-dimensional conformal radiotherapy (3D-CRT) for this subgroup has not been well documented in the literature. Thus, the purpose of this work is to analyze the results of treatment of non-metastatic androgen-refractory prostate cancer (ARPC) with 3D-CRT and to investigate the potential prognostic factors which influenced the results. Material and Methods Of 424 patients with diagnosis of localized and locally advanced prostate cancer who were treated between 1999 and 2004 in our centre, forty-three (n=43) patients were classified as non-metastatic ARPC. Distant metastases were excluded by negative bone scan, negative chest X-ray and negative pelvic CT for lymph node metastases. The median pre-hormone therapy PSA (pre-HT PSA) level for this group was 24 ng/ml (range 1 to 120) and 5.7 ng/ml (range 0.06 to 27) at the beginning of radiotherapy (pre-RT PSA). Clinical T stage distribution, defined according to the 2002 AJCC, was as follows: T1c = 12, T2 = 23, and T3 = 8 patients, respectively. Of 44 patients, 39 had a Gleason score of 2-7 and 4 had a Gleason score of 8–10. All patients with diagnosis of non-metastatic ARPC were treated with 3D-CRT with the daily fraction dose of 2 Gy to a median total dose of 68 Gy (range from 60 to 74 Gy). The median duration of androgen ablation therapy before RT was 26 months (range from 7 to 96). The median time of follow-up after 3D-CRT was 27 months (range from 13 to 62) and from the beginning of androgen ablation was 53 months (range from 20 to 158). The following prognostic factors were evaluated in univariate and multivariate analysis: age, pre-HT PSA, pre-RT PSA, Gleason score, total dose, PSA doubling time (PSADT< 6 months vs. PSADT > 6 months). Results The 5-year actuarial overall survival was 82% and 5-year clinical relapse free-survival rate was 49%. During the follow-up 14 patients developed disease progression (locoregional and/or distant and/or biochemical) and two patients died of prostate cancer. The univariate analysis indicated that pre-HT PSA > 20 ng/ml, pre-RT PSA > 4ng/ml, and the high-risk group defined according to NCCN criteria (PSA >20 ng/ml and Gleason score >7) were statistically significant factors for the risk of disease progression. Conclusions Three-dimensional conformal radiotherapy for patients with non-metastatic ARPC is a valuable method of treatment for the subgroup of patients with pre-HT PSA<20 ng/ml and Gleason score < 8. For patients classified as the high-risk group according to NCCN criteria 3D-CRT seems to be an ineffective treatment due to the observed high incidence of distant failure, and should be viewed as costly and sophisticated yet ineffective intervention. For this subgroup a systemic modality of treatment such as chemotherapy or biological manipulation should be considered.

Toxicity and outcome results of RTOG 9311: A phase I–II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non–small-cell lung carcinoma

To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non-small-cell lung cancer. A total of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V(20) > or =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method. The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V(20). The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50-78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure. The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V(20) values of <25% (Group 1) and to 77.4 Gy for patients with V(20) values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients.

High-Dose proton beam radiotherapy of hepatocellular carcinoma: Preliminary results of a phase II trial

This phase II trial was undertaken to determine the efficacy and toxicity of proton beam radiotherapy for patients with locally unresectable hepatocellular carcinoma. Cirrhotic patients were eligible if they had a Child-Pugh score of 10 or less. Eligible patients included those with T 1 -T 3 hepatocellular carcinoma; selected T 4 patients also were eligible. Patients with lymph node or distant metastases were ineligible. Daily proton beam radiotherapy was directed to the liver tumor with an additional 1-2 cm margin. The total dose was 63 cobalt Gray equivalents, administered in 15 divided fractions over 3 weeks. Thirty-four patients have completed treatment and have been followed up for a minimum of 6 months, with a median follow-up period of 20 months. The mean age was 65 years, and average tumor size was 5.7 cm. Posttreatment toxicity included a small but significant decline in albumin levels and increased total bilirubin; 3 experienced duodenal or colonic bleeding when bowel was immediately adjacent to the treated tumor. Two-year actuarial data showed a 75% local tumor control rate and an overall survival rate of 55%. Of patients with an elevated pretreatment alpha-fetoprotein, 85% were found to have declining alpha-fetoprotein levels from a pretreatment mean of 1405 to 35 at 6 months after treatment. Six patients underwent liver transplantation between 6 and 16 months after completion of radiotherapy with 2 showing no evidence of residual carcinoma within the explanted liver. Overall the majority of patients responded to treatment, and the therapy was well tolerated.

Radiotherapy of liver malignancies. From whole liver irradiation to stereotactic hypofractionated radiotherapy.

Until recently radiotherapy of hepatic malignancies has played a limited role due to the well-known limited radiotolerance of the liver. The aim of this paper is to review the available data on the risk of radiation-induced liver disease (RILD) and to define the modern role of radiotherapy in the management of patients with metastatic or primary liver malignancies. The advent of three-dimensional conformal treatment planning with dose-volume histogram analysis has made the study of partial liver irradiation possible. Limited portions of the liver may withstand high doses of radiation with minimal risk of RILD. Patients with solitary unresectable liver tumors may be treated with high-dose radiotherapy with curative intent. Recently, the feasibility of stereotactically guided treatment techniques with a single fraction or few treatment sessions has been explored in numerous institutions. The radiation tolerance of the whole liver found by several investigations is in the order of approximately 30 Gy, which seriously restricts its clinical application. The role of whole liver irradiation therefore appears of limited benefit in the palliation of patients with multiple liver metastases. The use of three-dimensional conformal techniques has made partial liver irradiation possible to doses in the 70-80 Gy range with conventional fractionation. At least two published series have reported improved local control and survival rates with dose escalation with three-dimensional conformal radiotherapy in patients with unresectable liver metastases. Similar outcomes have been recently reported with single dose (or hypofractionated) stereotactic radiotherapy both in metastatic and primary hepatic malignancies with minimal morbidity. Accurate target delineation and treatment reproducibility are the key to the success of this novel treatment approach, and specific treatment planning techniques and patient setup procedures must be developed to implement it. Stereotactic high-dose radiotherapy is technically feasible for the treatment of inoperable liver malignancies, with the potential of high local control and low morbidity. Definitive evidence on the clinical advantages of this technique over other more established treatments can only be gathered from well-designed clinical studies.

Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication

Purpose: To analyze the correlation of radiation-induced liver disease (RILD) with patient-related and treatment-related dose-volume factors and to describe the probability of RILD by a normal tissue complication probability (NTCP) model for patients with hepatocellular carcinoma (HCC) treated with three-dimensional conformal radiotherapy (3D-CRT). Methods and Materials: Between November 1993 and December 1999, 93 patients with intrahepatic malignancies were treated with 3D-CRT at our institution. Sixty-eight patients who were diagnosed with HCC and had complete 3D dose-volume data were included in this study. Of the 68 patients, 50 had chronic viral hepatitis before treatment, either type B or type C. According to the Child-Pugh classification for liver cirrhosis, 53 patients were in class A and 15 in class B. Fifty-two patients underwent transcatheter arterial chemoembolization with an interval of at least 1 month between transcatheter arterial chemoembolization and 3D-CRT to allow adequate recovery of hepatic function. The mean dose of radiation to the isocenter was 50.2 ± 5.9 Gy, in daily fractions of 1.8–2Gy. No patient received whole liver irradiation. RILD was defined as Grade 3 or 4 hepatic toxicity according to the Common Toxicity Criteria of the National Cancer Institute. All patients were evaluated for RILD within 4 months of RT completion. Three-dimensional treatment planning with dose-volume histogram analysis of the normal liver was used to compare the dosimetric difference between patients with and without RILD. Maximal likelihood analysis was conducted to obtain the best estimates of parameters of the Lyman NTCP model. Confidence intervals of the fitted parameters were estimated by the profile likelihood method. Results: Twelve of the 68 patients developed RILD after 3D-CRT. None of the patient-related variables were significantly associated with RILD. No difference was found in tumor volume (780 cm 3 vs. 737 cm 3, p = 0.86), normal liver volume (1210 cm 3 vs. 1153 cm 3, p = 0.64), percentage of normal liver volume with radiation dose >30 Gy (V 30 Gy; 42% vs. 33%, p = 0.05), and percentage of normal liver volume with >50% of the isocenter dose (V 50%; 45% vs. 36%, p = 0.06) between patients with and without RILD. The mean hepatic dose was significantly higher in patients with RILD (2504 cGy vs. 1965 cGy, p = 0.02). The probability of RILD in patients could be expressed as follows: probability = 1/[1 + exp −(0.12 × mean dose − 4.29)], with coefficients significantly different from 0. The best estimates of the parameters in the Lyman NTCP model were the volume effect parameter of 0.40, curve steepness parameter of 0.26, and 50% tolerance dose for uniform irradiation of whole liver [TD 50(1)] of 43 Gy. Patients with RILD had a significantly higher NTCP than did those with no RILD (26.2% vs. 15.8%; p = 0.006), using the best-estimated parameters. Conclusion: Dose-volume histogram analysis can be effectively used to quantify the tolerance of the liver to RT. Patients with RILD had received a significantly higher mean dose to the liver and a significantly higher NTCP. The fitted volume effect parameter of the Lyman NTCP model was close to that from the literature, but much lower in our patients with HCC and prevalent chronic viral hepatitis than that reported in other series with patients with normal liver function. Additional efforts should be made to test other models to describe the radiation tolerance of the liver for Asian patients with HCC and preexisting compromised hepatic reserve.